Ordering of anisotropic nanoparticles in diblock copolymer lamellae: Simulations with dissipative particle dynamics and a molecular theory.
Local distribution and orientation of anisotropic nanoparticles in microphase-separated symmetric diblock copolymers has been simulated using dissipative particle dynamics and analyzed with a molecular theory. It has been demonstrated that nanoparticles are characterized by a non-trivial orientational ordering in the lamellar phase due to their anisotropic interactions with isotropic monomer units. In the simulations, the maximum concentration and degree of ordering are attained for non-selective nanorods near the domain boundary. In this case, the nanorods have a certain tendency to align parallel to the interface in the boundary region and perpendicular to it inside the domains. Similar orientation ordering of nanoparticles located at the lamellar interface is predicted by the molecular theory which takes into account that the nanoparticles interact with monomer units via both isotropic and anisotropic potentials. Computer simulations enable one to study the effects of the nanorod concentration, length, stiffness, and selectivity of their interactions with the copolymer components on the phase stability and orientational order of nanoparticles. If the volume fraction of the nanorods is lower than 0.1, they have no effect on the copolymer transition from the disordered state into a lamellar microstructure. Increasing nanorod concentration or nanorod length results in clustering of the nanorods and eventually leads to a macrophase separation, whereas the copolymer preserves its lamellar morphology. Segregated nanorods of length close to the width of the diblock copolymer domains are stacked side by side into smectic layers that fill the domain space. Thus, spontaneous organization and orientation of nanorods leads to a spatial modulation of anisotropic composite properties which may be important for various applications.


Association between elasticity of tissue and pain pressure threshold in the tender points present in subjects with fibromyalgia: a cross-sectional study.
Fibromyalgia (FM) is a multicomponent illness and despite its worldwide prevalence, a complete understanding of its aetiology and pathogenesis remains unclear. The goal of the study is to analyze the level of association between elastic properties of tissue measured by strain elastography (SEL) and pain pressure threshold (PPT) in the characteristic painful points described in patients suffering from FM. This was a cross-sectional, observational study. A sample comprised of 42 subjects with FM was recruited from a private care centre. The occiput, low cervical, trapezius, supraspinatus, paraspinous, lateral pectoral, second rib, lateral epicondyle, medial epicondyle, gluteus, greater trochanter, knee, and anterior tibial PPTs were bilaterally assessed using a standard pressure algometer and elastic properties of tissue were evaluated by SEL. Linear regression analysis showed significant associations between SEL and dominant trapezius PPT (β = 0.487, 95% CI [0.045, 0.930], p = 0.032) after adjustments for the age, body mass index, and menopause status (higher SEL and higher pain sensitivity). No significant associations between SEL and the other PPTs variables were found in women diagnosed with FM. The PPT of the dominant trapezius is associated with SEL measurements in subjects suffering from FM. More studies are required to fully explain the underlying mechanisms.


Contrast Phase Classification with a Generative Adversarial Network.
Dynamic contrast enhanced computed tomography (CT) is an imaging technique that provides critical information on the relationship of vascular structure and dynamics in the context of underlying anatomy. A key challenge for image processing with contrast enhanced CT is that phase discrepancies are latent in different tissues due to contrast protocols, vascular dynamics, and metabolism variance. Previous studies with deep learning frameworks have been proposed for classifying contrast enhancement with networks inspired by computer vision. Here, we revisit the challenge in the context of whole abdomen contrast enhanced CTs. To capture and compensate for the complex contrast changes, we propose a novel discriminator in the form of a multi-domain disentangled representation learning network. The goal of this network is to learn an intermediate representation that separates contrast enhancement from anatomy and enables classification of images with varying contrast time. Briefly, our unpaired contrast disentangling GAN(CD-GAN) Discriminator follows the ResNet architecture to classify a CT scan from different enhancement phases. To evaluate the approach, we trained the enhancement phase classifier on 21060 slices from two clinical cohorts of 230 subjects. The scans were manually labeled with three independent enhancement phases (non-contrast, portal venous and delayed). Testing was performed on 9100 slices from 30 independent subjects who had been imaged with CT scans from all contrast phases. Performance was quantified in terms of the multi-class normalized confusion matrix. The proposed network significantly improved correspondence over baseline UNet, ResNet50 and StarGAN's performance of accuracy scores 0.54. 0.55, 0.62 and 0.91, respectively (p-value<0.0001 paired t-test for ResNet versus CD-GAN). The proposed discriminator from the disentangled network presents a promising technique that may allow deeper modeling of dynamic imaging against patient specific anatomies.


Melatonin prevents ethanol-induced gastric mucosal damage possibly due to its antioxidant effect.
Oxygen radical release has been proposed as a pathogenic factor of the ethanol-induced acute gastric injury. Melatonin, a pineal hormone, is known to scavenge oxygen free radicals. We investigated whether parenteral administration of melatonin prevented ethanol-induced macroscopic damage, polymorphonuclear (PMN) leukocyte infiltration, depletion of total glutathione (tGSH) concentration, and glutathione reductase (GSSG-Rd) activity in the rat gastric mucosa. We compared the effects of melatonin with those of omeprazole. Ethanol-induced mucosal damage was evaluated using three different parameters: gastric total glutathione (tGSH) concentration and glutathione reductase (GSSG-Rd) activity, the number of PMN leukocytes, and macroscopic investigation. Gatric tGSH concentration and GSSG-Rd activity decreased and the number of PMNs increased after ethanol administration. It was found that pretreatment with melatonin increased both tGSH concentration and GSSG-Rd activity. Melatonin also reduced ethanol-induced PMN infiltration in the stomach. Ethanol administration damaged the entire gastric mucosa. Melatonin significantly decreased the extent of ethanol-induced macroscopic injury. In conclusion, these findings support the conclusion that the protection conferred by melatonin in gastric ulcer is presumably due to its antioxidant activity.


Pancreatitis and severe metabolic abnormalities due to phenformin therapy.
Two elderly diabetic patients with abdominal pain were demonstrated to have complications of phenformin hydrochloride therapy. The first developed severe lactic acidosis treated with sodium bicarbonate given intravenously and followed by rebound alkalosis. The second showed severe acidosis (specimens for lactate determination were unfortunately unsatisfactory for analysis) and similar alkalotic rebound after therapy. She then developed severe pancreatitis, proved at operation, no cause for which other than phenformin was apparent. Poor renal and hepatic function predispose to these conditions by increasing serum phenformin levels and by decreasing urinary excretion of its metabolites. The acidosis should be treated judiciously with sodium bicarbonate administered intravenously. A rebound alkalosis, ensuring as the accumulated lactate is metabolized, is best treated by potassium chloride and ammonium chloride given intravenously. The mechanism by which phenformin causes pancreatitis is unknown, but termination of therapy causes cessation of the pancreatitis.


Antibodies to cardiac conducting tissue in progressive systemic sclerosis.
Cardiac conducting tissue antibodies (CCTA) were detected, using indirect immunofluorescence, in 8 (25%) out of 32 sera from patients with progressive systemic sclerosis (PSS) and in 39 (35%) out of 110 with rheumatoid arthritis (RA). Conduction abnormalities, namely right bundle branch block, were present in 19 (59%) of the PSS patients and in 37 (32%) of the RA cases. No significant correlation was found between the prevalence of CCTA and conduction abnormalities in PSS patients, while this was present in RA patients (p less than 0.001). CCTA were always negative in 18 patients with systemic lupus erythematosus and were found in one out of 8 cases with Sjögren's syndrome, also positive for rheumatoid factor without clinical RA. These data suggest that CCTA are evoked when involvement of cardiac conducting tissue (as in RA) or working myocardium (as in PSS) is present. Whether CCTA should be mainly regarded as an expression of the immunological derangement underlying these pathological conditions or whether they are secondary to myocardial tissue damage, must still be clarified.


3D imaging for driving cancer discovery.
Our understanding of the cellular composition and architecture of cancer has primarily advanced using 2D models and thin slice samples. This has granted spatial information on fundamental cancer biology and treatment response. However, tissues contain a variety of interconnected cells with different functional states and shapes, and this complex organization is impossible to capture in a single plane. Furthermore, tumours have been shown to be highly heterogenous, requiring large-scale spatial analysis to reliably profile their cellular and structural composition. Volumetric imaging permits the visualization of intact biological samples, thereby revealing the spatio-phenotypic and dynamic traits of cancer. This review focuses on new insights into cancer biology uniquely brought to light by 3D imaging and concomitant progress in cancer modelling and quantitative analysis. 3D imaging has the potential to generate broad knowledge advance from major mechanisms of tumour progression to new strategies for cancer treatment and patient diagnosis. We discuss the expected future contributions of the newest imaging trends towards these goals and the challenges faced for reaching their full application in cancer research.


Expression of NCAM and OCIAD1 in well-differentiated thyroid carcinoma: correlation with the risk of distant metastasis.
The biomarkers representing the metastatic potential of well-differentiated thyroid carcinoma remain to be established. A study was undertaken to find whether the expression status of neural cell adhesion molecule (NCAM) and/or ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) is associated with the metastatic potential of differentiated thyroid carcinoma. NCAM and OCIAD1 were analysed by immunohistochemistry on tissue microarrays. Among 214 well-differentiated thyroid carcinomas, 68 patients had distant metastases. Immunohistochemical analyses showed that the majority of benign thyroid lesions expressed NCAM while a significant proportion of thyroid carcinomas lost or had reduced NCAM expression. Both follicular and papillary carcinomas with distant metastasis had a significantly higher frequency of preserving NCAM expression. Hierarchical clustering analysis showed that OCIAD1 had significant differential expression between benign and malignant thyroid lesions. The overall metastatic-to-localised tumour ratio was higher in NCAM-expressing clusters, but the difference between ratios of OCIAD1-positive and OCIAD1-negative subclusters was not significant. These analyses suggest that the preservation of NCAM expression in well-differentiated thyroid carcinoma is an indicator for a higher risk of distant metastasis. OCIAD1 is a potential biomarker of thyroid carcinoma but had no significant additive effect on the risk of distant metastasis. Further elucidation of the molecular mechanisms underlying the NCAM-mediated cellular processes will be beneficial for the development of effective treatments against the metastasis of thyroid carcinoma.


Social context affects testosterone-induced singing and the volume of song control nuclei in male canaries (Serinus canaria).
The contribution of social factors to seasonal plasticity in singing behavior and forebrain nuclei controlling song, and their interplay with gonadal steroid hormones are still poorly understood. In many songbird species, testosterone (T) enhances singing behavior but elevated plasma T concentrations are not absolutely required for singing to occur. Singing is generally produced either to defend a territory or to attract a mate and it is therefore not surprising that singing rate can be influenced by the sex and behavior of the social partner. We investigated, based on two independent experiments, the effect of the presence of a male or female partner on the rate of song produced by male canaries. In the first experiment, song rate was measured in dyads composed of one male and one female (M-F) or two males (M-M). Birds were implanted with T-filled Silastic capsules or with empty capsules as control. The number of complete song bouts produced by all males was recorded during 240 min on week 1, 2, 4, and 8 after implantation. On the day following each recording session, brains from approximately one-fourth of the birds were collected and the volumes of the song control nuclei HVC and RA were measured. T increased the singing rate and volume of HVC and RA but these effects were affected by the social context. Singing rates were higher in the M-M than in the M-F dyads. Also, in the M-M dyads a dominance-subordination relationship soon became established and dominant males sang at higher rates than subordinates in T-treated but not in control pairs. The differences in song production were not reflected in the size of the song control nuclei: HVC was larger in M-F than in M-M males and within the M-M dyads, no difference in HVC or RA size could be detected between dominant and subordinate males. At the individual level, the song rate with was positively correlated with RA and to a lower degree HVC volume, but this relationship was observed only in M-M dyads, specifically in dominant males. A second experiment, carried out with castrated males that were all treated with T and exposed either to another T-treated castrate or to an estradiol-implanted female, confirmed that song rate was higher in the M-M than in the M-F condition and that HVC volume was larger in heterosexual than in same-sex dyads. The effects of T on singing rate and on the volume of the song control nuclei are thus modulated by the social environment, including the presence/absence of a potential mate and dominance status among males.


The impact of AIDS on adult mortality: evidence from national and regional statistics.
To measure trends in adult mortality in countries with significant levels of HIV prevalence using data sources other than those that collect information on HIV status. Data sources consisted of national population censuses and sample surveys, Demographic and Health Surveys (DHS), vital registration, and longitudinal surveillance systems. Estimates of adult mortality were derived from censuses using intercensal survival and questions on deaths of household members and orphanhood. From DHS adult mortality was measured from data on survival of siblings and orphanhood. Death registration should be tested for changes in the level of coverage before drawing conclusions on mortality trends. Demographic surveillance systems record trends and age patterns of mortality, but are not nationally representative. Census and survey data from Kenya, Malawi and Zimbabwe showed increasing adult mortality in the 1990s, reversing previous downward trends. DHS data for over 20 sub-Saharan countries showed that most had increasing mortality, which was steepest in eastern and southern Africa, with high HIV prevalences. Death registration in Zimbabwe and South Africa showed increasing adult mortality, as in Thailand and Trinidad, both countries with appreciable levels of HIV. Surveillance systems in Tanzania and South Africa showed radically different age patterns of mortality, with relatively high rates among younger adults compared with data from countries with lower HIV prevalences. Adult mortality is increasing in countries with high HIV/AIDS prevalences, although the contribution of the epidemic to this increase is difficult to measure. More data and improved methods of analysis are needed before firm conclusions can be drawn.


American monitoring: standard and state of the art.
Monitoring of the anesthetized patient, the anesthesia machine, and the patient-machine interface is an essential component of anesthetic practice in order to prevent anesthetic-related injuries resulting from equipment failure or human error. While the optimal monitor to detect anesthetic problems (hypoxia, esophageal intubation, hemodynamic compromise, for example) is unclear at present, American standards require continuous presence of qualified personnel who evaluate patient oxygenation, ventilation, circulation, and temperature. A common monitoring array includes electrocardiogram, autosphygmomanometer, pulse plethysmography/oximetry, stethoscope, anesthetic gas analyzer, thermistor, and nerve stimulator. The role of emerging technologies, including transesophageal echocardiography, automated electrocardiographic analysis of ST segments, transcranial Doppler, and transcranial near infrared spectroscopy are discussed.


Emergent multicellular life cycles in filamentous bacteria owing to density-dependent population dynamics.
Filamentous bacteria are the oldest and simplest known multicellular life forms. By using computer simulations and experiments that address cell division in a filamentous context, we investigate some of the ecological factors that can lead to the emergence of a multicellular life cycle in filamentous life forms. The model predicts that if cell division and death rates are dependent on the density of cells in a population, a predictable cycle between short and long filament lengths is produced. During exponential growth, there will be a predominance of multicellular filaments, while at carrying capacity, the population converges to a predominance of short filaments and single cells. Model predictions are experimentally tested and confirmed in cultures of heterotrophic and phototrophic bacterial species. Furthermore, by developing a formulation of generation time in bacterial populations, it is shown that changes in generation time can alter length distributions. The theory predicts that given the same population growth curve and fitness, species with longer generation times have longer filaments during comparable population growth phases. Characterization of the environmental dependence of morphological properties such as length, and the number of cells per filament, helps in understanding the pre-existing conditions for the evolution of developmental cycles in simple multicellular organisms. Moreover, the theoretical prediction that strains with the same fitness can exhibit different lengths at comparable growth phases has important implications. It demonstrates that differences in fitness attributed to morphology are not the sole explanation for the evolution of life cycles dominated by multicellularity.


Differential distribution of aggrecan isoforms in perineuronal nets of the human cerebral cortex.
Aggrecan is a component of the CNS extracellular matrix (ECM) and we show here that the three primary alternative spliced transcripts of the aggrecan gene found in cartilage are also present in the adult CNS. Using a unique panel of core protein-directed antibodies against human aggrecan we further show that different aggrecan isoforms are deposited in perineuronal nets (PNNs) and neuropil ECM of Brodmann's area 6 of the human adult cerebral cortex. According to their distribution pattern, the identified cortical aggrecan isoforms were subdivided into five clusters spanning from cluster 1, comprised isoforms that appeared widespread throughout the cortex, to cluster 5, which was an aggrecan-free subset. Comparison of brain and cartilage tissues showed a different relative abundance of aggrecan isoforms, with cartilage-specific isoforms characterizing cluster 5, and PNN-associated isoforms lacking keratan sulphate chains. In the brain, isoforms of cluster 1 were disclosed in PNNs surrounding small-medium interneurons of layers II-V, small-medium pyramidal neurons of layers III and V and large interneurons of layer VI. Aggrecan PNNs enveloped both neuron bodies and neuronal processes, encompassing pre-terminal nerve fibres, synaptic boutons and terminal processes of glial cells and aggrecan was also observed in continuous 'coats' associated with satellite, neuron-associated cells of a putative glial nature. Immunolabelling for calcium-binding proteins and glutamate demonstrated that aggrecan PNNs were linked to defined subsets of cortical interneurons and pyramidal cells. We suggest that in the human cerebral cortex, discrete, layer-specific PNNs are assembled through the participation of selected aggrecan isoforms that characterize defined subsets of cortical neurons.


Insights from Clonal Expansion and HIV Persistence in Perinatal Infections.
The latent HIV reservoir forms early in the course of infection and is maintained for life despite effective antiretroviral treatment (ART), including early treatment. Perinatal HIV infection presents a unique opportunity to limit seeding of the reservoir through early ART. However, a greater understanding of the persistence of the integrated proviruses is needed for targeting the residual proviruses that form barriers to cure. A study was performed by Bale and Katusiime et al. (M. J. Bale, M. G. Katusiime, D. Wells, X. Wu, et al., mBio 12:e00568-21, 2021, https://doi.org/10.1128/mBio.00568-21) using in-depth integration site analysis in 11 children before ART and after up to nine years of ART. They have identified early development of long-lived proviruses, although the replication competence is unknown. A small fraction of cells bearing integrated proviruses clonally expand early during infection and persist. Integration in the oncogenes STAT5B and BACH2 were also found; these findings confirm the early development of clonal proliferation in perinatal HIV infection despite early effective ART, with a propensity for oncogenes.


Role of dietary potassium in the treatment of hypertension.
This review summarizes the historical development and recent resurgence of interest in dietary potassium as a factor in hypertension. Some epidemiologic evidence has suggested that potassium intake by humans may be inversely related to the level of arterial blood pressure. Other studies have suggested that a marked reduction in the Na+/K+ ratio of the human diet reduces the blood pressure of normotensives. Further, the administration of high potassium diets has resulted in a lowering of blood pressure in some animal models of hypertension. Several possible mechanisms for this putative antihypertensive effect are evident. Some observations suggest that potassium could act as a diuretic agent and thereby reduce extracellular fluid volume, which in turn could result in decreased blood pressure. An alternative mechanism of action is that potassium may alter the activity of the renin-angiotensin system and reduce angiotensin influences on vascular, adrenal, or renal receptors. Other evidence supports the possibility that potassium modifies central or the peripheral neural mechanisms that regulate blood pressure. In addition, high potassium diets could reduce blood pressure by relaxing vascular smooth muscle and reducing peripheral vascular resistance directly. Although diets high in potassium content do appear to modify arterial blood pressure under some circumstances, particularly in salt-dependent hypertension, a high potassium intake has not always attenuated blood pressure in all models examined. Further, evaluation of these data do not allow definite conclusions regarding a common mechanism through which potassium exerts these effects.


Human neuronal maturation comes of age: cellular mechanisms and species differences.
The delayed and prolonged postmitotic maturation of human neurons, compared with neurons from other species, may contribute to human-specific cognitive abilities and neurological disorders. Here we review the mechanisms of neuronal maturation, applying lessons from model systems to understand the specific features of protracted human cortical maturation and species differences. We cover cell-intrinsic features of neuronal maturation, including transcriptional, epigenetic and metabolic mechanisms, as well as cell-extrinsic features, including the roles of activity and synapses, the actions of glial cells and the contribution of the extracellular matrix. We discuss evidence for species differences in biochemical reaction rates, the proposed existence of an epigenetic maturation clock and the contributions of both general and modular mechanisms to species-specific maturation timing. Finally, we suggest approaches to measure, improve and accelerate the maturation of human neurons in culture, examine crosstalk and interactions among these different aspects of maturation and propose conceptual models to guide future studies.


Kinetic roughening and porosity scaling in film growth with subsurface lateral aggregation.
We study surface and bulk properties of porous films produced by a model in which particles incide perpendicularly to a substrate, interact with deposited neighbors in its trajectory, and aggregate laterally with probability of order a at each position. The model generalizes ballisticlike models by allowing attachment to particles below the outer surface. For small values of a, a crossover from uncorrelated deposition (UD) to correlated growth is observed. Simulations are performed in 1+1 and 2+1 dimensions. Extrapolation of effective exponents and comparison of roughness distributions confirm Kardar-Parisi-Zhang roughening of the outer surface for a>0. A scaling approach for small a predicts crossover times as a(-2/3) and local height fluctuations as a(-1/3) at the crossover, independent of substrate dimension. These relations are different from all previously studied models with crossovers from UD to correlated growth due to subsurface aggregation, which reduces scaling exponents. The same approach predicts the porosity and average pore height scaling as a(1/3) and a(-1/3), respectively, in good agreement with simulation results in 1+1 and 2+1 dimensions. These results may be useful for modeling samples with desired porosity and long pores.


Evaluation of Pre-marketing Factors to Predict Post-marketing Boxed Warnings and Safety Withdrawals.
An important goal in drug regulation is understanding serious safety issues with new drugs as soon as possible. Achieving this goal requires us to understand whether information provided during the Food and Drug Administration (FDA) drug review can predict serious safety issues that are usually identified after the product is approved. However, research on this topic remains understudied. In this paper, we examine whether any pre-marketing drug characteristics are associated with serious post-marketing safety actions. We study this question using an internal FDA database containing every new small molecule drug submitted to the FDA's Center for Drug Evaluation and Research (CDER) on or after November 21, 1997, and approved and commercially launched before December 31, 2009. Serious post-marketing safety actions include whether these drugs ever experienced either a post-marketing boxed warning or a withdrawal from the market due to safety concerns. A random effects logistic regression model was used to test whether any pre-marketing characteristics were associated with either post-marketing safety action. A total of 219 new molecular entities were analyzed. Among these drugs, 11 experienced a safety withdrawal and 30 received boxed warnings by July 31, 2016. Contrary to prevailing hypotheses, we find that neither clinical trial sample sizes nor review time windows are associated with the addition of a post-marketing boxed warning or safety withdrawal. However, we do find that new drugs approved with either a boxed warning or priority review are more likely to experience post-marketing boxed warnings. Furthermore, drugs approved with boxed warnings tend to receive post-marketing boxed warnings resulting from new safety information that are unrelated to the original warning. Drugs approved with a boxed warning are 3.88 times more likely to receive a post-marketing boxed warning, while drugs approved with a priority review are 3.51 times more likely to receive a post-marketing boxed warning. Although drugs approved with a boxed warning or priority review are more likely to experience serious post-marketing safety events, other information provided during the FDA drug review that is easy to quantify is generally not associated with post-marketing safety events. It appears that these post-marketing events are not discernible during a pre-marketing review and therefore might not be avoidable using current review data.


Inferring developmental modularity from morphological integration: analysis of individual variation and asymmetry in bumblebee wings.
Organisms are built from distinct modules, which are internally coherent but flexible in their relationships among one another. We examined morphological variation within and between two candidate modules: the fore- and hindwings of bumblebees (Hymenoptera: Apidae: Bombus empatiens). We used the techniques of geometric morphometrics (Procrustes superimposition) to analyze the variation of landmark configurations in fore- and hindwings. Regression was used to correct for size-related shape variation (allometry). Principal component analysis revealed patterns of variation that were remarkably similar for individual variation and fluctuating asymmetry (FA). Because covariation of FA among parts must be due to direct transmission of the developmental perturbations causing FA, this agreement of patterns suggests that much of individual variation is also due to direct developmental interactions within each developing wing. Moreover, partial least squares analysis indicated that the patterns of shape covariation between fore- and hindwings were nearly the same as the patterns of within-wing variation. Shape covariation of FA was only found in bees that had been reared under elevated CO(2) concentration but not in bees from the control treatment, suggesting that the mechanisms of developmental interactions between fore- and hindwings are related to gas exchange. We conclude that the fore- and hindwings are developmental modules that maintain internal coherence through direct developmental interactions and are connected to each other only by relatively few links that use the system of interactions within modules.


Contrasting modes of evolution of the visual pigments in Heliconius butterflies.
The adult compound eyes of passion-vine butterflies in the genus Heliconius contain one more UV opsin than other butterflies. Together with an 11-cis-3-hydroxyretinal chromophore, their four opsin genes UVRh1, UVRh2, BRh, and LWRh produce four rhodopsins that are UV-, blue-, or long wavelength absorbing. One of the Heliconius UV opsin genes, UVRh2, was found to have evolved under positive selection following recent gene duplication, using the branch-site test of selection. Using a more conservative test, the small-sample method, we confirm our prior finding of positive selection of UVRh2 and provide new statistical evidence of episodic evolution, that is, positive selection followed by purifying selection. We also newly note that one of the positively selected amino acid sites contains substitutions with known spectral tuning effects in avian ultraviolet- and violet-sensitive visual pigments. As this is one of a handful of described examples of positive selection of any specific gene in any butterfly where functional variation between copies has been characterized, we were interested in examining the molecular and physiological context of this adaptive event by examining the UV opsin genes in contrast to the other visual pigment genes. We cloned BRh and LWRh from 13 heliconiine species and UVRh1 and UVRh2 from Heliconius elevatus. In parallel, we performed in vivo epi-microspectrophotometric experiments to estimate the wavelength of peak absorbance, λ(max), of several rhodopsins in seven heliconiine species. In contrast to UVRh2, we found both physiological and statistical evidence consistent with purifying selection on UVRh1, BRh, and LWRh along the branch leading to the common ancestor of Heliconius. These results underscore the utility of combining molecular and physiological experiments in a comparative context for strengthening evidence for adaptive evolution at the molecular level.


Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein.
The relationship between altered metabolism of the amyloid-β precursor protein (APP) and Alzheimer's disease is well established but the physiological roles of APP still remain unclear. Here, we studied Ca(2+) signaling in primary cultured and freshly dissociated cortical astrocytes from APP knockout (KO) mice and from Tg5469 mice overproducing by five- to sixfold wild-type APP. Resting cytosolic Ca(2+) (measured with fura-2) was not altered in cultured astrocytes from APP KO mice. The stored Ca(2+) evaluated by measuring peak amplitude of cyclopiazonic acid [CPA, endoplasmic reticulum (ER) Ca(2+) ATPase inhibitor]-induced Ca(2+) transients in Ca(2+)-free medium was significantly smaller in APP KO astrocytes than in wild-type cells. Store-operated Ca(2+) entry (SOCE) activated by ER Ca(2+) store depletion with CPA was also greatly reduced in APP KO astrocytes. This reflected a downregulated expression in APP KO astrocytes of TRPC1 (C-type transient receptor potential) and Orai1 proteins, essential components of store-operated channels (SOCs). Indeed, silencer RNA (siRNA) knockdown of Orai1 protein expression in wild-type astrocytes significantly attenuated SOCE. SOCE was also essentially reduced in freshly dissociated APP KO astrocytes. Importantly, knockdown of APP with siRNA in cultured wild-type astrocytes markedly attenuated ATP- and CPA-induced ER Ca(2+) release and extracellular Ca(2+) influx. The latter correlated with downregulation of TRPC1. Overproduction of APP in Tg5469 mice did not alter, however, the stored Ca(2+) level, SOCE, and expression of TRPC1/4/5 in cultured astrocytes from these mice. The data demonstrate that the functional role of APP in astrocytes involves the regulation of TRPC1/Orai1-encoded SOCs critical for Ca(2+) signaling.


The genomic response of skeletal muscle to methylprednisolone using microarrays: tailoring data mining to the structure of the pharmacogenomic time series.
High-throughput data collection using gene microarrays has great potential as a method for addressing the pharmacogenomics of complex biological systems. Similarly, mechanism-based pharmacokinetic/pharmacodynamic modeling provides a tool for formulating quantitative testable hypotheses concerning the responses of complex biological systems. As the response of such systems to drugs generally entails cascades of molecular events in time, a time series design provides the best approach to capturing the full scope of drug effects. A major problem in using microarrays for high-throughput data collection is sorting through the massive amount of data in order to identify probe sets and genes of interest. Due to its inherent redundancy, a rich time series containing many time points and multiple samples per time point allows for the use of less stringent criteria of expression, expression change and data quality for initial filtering of unwanted probe sets. The remaining probe sets can then become the focus of more intense scrutiny by other methods, including temporal clustering, functional clustering and pharmacokinetic/pharmacodynamic modeling, which provide additional ways of identifying the probes and genes of pharmacological interest.


Risk factors of perioperative mortality from complicated peptic ulcer disease in Africa: systematic review and meta-analysis.
In 2013, peptic ulcer disease (PUD) caused over 300 000 deaths globally. Low-income and middle-income countries are disproportionately affected. However, there is limited information regarding risk factors of perioperative mortality rates in these countries. To assess perioperative mortality rates from complicated PUD in Africa and associated risk factors. We performed a systematic review and a random-effect meta-analysis of literature describing surgical management of complicated PUD in Africa. We used subgroup analysis and meta-regression analyses to investigate sources of variations in the mortality rates and to assess the risk factors contributing to mortality. From 95 published reports, 10 037 patients underwent surgery for complicated PUD. The majority of the ulcers (78%) were duodenal, followed by gastric (14%). Forty-one per cent of operations were for perforation, 22% for obstruction and 9% for bleeding. The operations consisted of vagotomy (38%), primary repair (34%), resection and reconstruction (12%), and drainage procedures (6%). The overall PUD mortality rate was 6.6% (95% CI 5.4% to 8.1%). It increased to 9.7% (95% CI 7.1 to 13.0) when we limited the analysis to studies published after the year 2000. The correlation was higher between perforated PUD and mortality rates (r=0.41, p<0.0001) than for bleeding PUD and mortality rates (r=0.32, p=0.001). Non-significant differences in mortality rates existed between sub-Saharan Africa (SSA) and North Africa and within SSA. Perioperative mortality rates from complicated PUD in Africa are substantially high and could be increasing over time, and there are possible regional differences.


Incidental encoding of emotional pictures: affective bias studied through event related brain potentials.
Emotional stimuli are better remembered than neutral stimuli. Most of the studies taking into account this emotional bias refer to explicit memory, use behavioral measures of the recall and predict better recall of negative stimuli. The few studies taking into account implicit memory and the valence emotional dimension are inconclusive on the effect of the stimulus' emotional valence. In the present study, 120 pictures (30 positive, 30 negative, 30 relaxing and 30 neutral) were shown to, and assessed by, 28 participants (study phase). Subsequently, event related brain potentials (ERPs) were recorded during the presentation of 120 new (shown for the first time) and 120 old (already shown in the study phase) pictures (test phase). No explicit instructions or clues related to recovery were given to participants, and a distractor task was employed, in order to maintain implicit the memory assessment. As expected from other studies' data, our results showed that old stimuli elicited an enhanced late positive component 450 ms after stimulus onset (repetition effect). Moreover, this effect was modulated by the stimuli's emotional valence, since the most positively valenced stimuli were associated with a decreased repetition effect with respect to the most negatively valenced stimuli. This effect was located at ventromedial prefrontal cortex. These results suggest the existence of a valence-mediated bias in implicit memory.


Evaluation of sera from patients with Lyme disease in the fluorescent treponemal antibody-absorption test for syphilis.
To determine whether the cross-reactivity between Treponema pallidum and Borrelia burgdorferi affects the specificity of the fluorescent treponemal antibody-absorption (FTA-Abs) test for syphilis, sera from patients with Lyme disease or syphilis were examined in a quantitative FTA-Abs test. Sera were diluted serially in phosphate-buffered saline, then in sorbent, and were tested with T. pallidum and B. burgdorferi antigens. Nine of 40 sera from patients with known Lyme disease were reactive at the 1:5 dilution with antigen from T. pallidum; only one serum was reactive at the 1:10 dilution. When both antigens were tested, the titer against B. burgdorferi was always higher than that against T. pallidum. Similarly, sera from patients with syphilis showed cross-reactivity with B. burgdorferi. Although reactivity could be absorbed with Treponemal phagedenis (Reiter strain), simultaneous titration with both antigens was easily performed and designated the etiologic agent.


Somatic Tumor Mutations Detected by Targeted Next Generation Sequencing in Minute Amounts of Serum-Derived Cell-Free DNA.
The use of blood-circulating cell-free DNA (cfDNA) as 'liquid-biopsy' is explored worldwide, with hopes for its potential in providing prognostic or predictive information in cancer treatment. In exploring cfDNA, valuable repositories are biobanks containing material collected over time, however these retrospective cohorts have restrictive resources. In this study, we aimed to detect tumor-specific mutations in only minute amounts of serum-derived cfDNA by using a targeted next generation sequencing (NGS) approach. In a retrospective cohort of ten metastatic breast cancer patients, we profiled DNA from primary tumor tissue (frozen), tumor-adjacent normal tissue (formalin-fixed paraffin embedded), and three consecutive serum samples (frozen). Our presented workflow includes comparisons with matched normal DNA or in silico reference DNA to discriminate germline from somatic variants, validation of variants through the detection in at least two DNA samples of an individual, and the use of public databases on variants. By our workflow, we were able to detect a total of four variants traceable as circulating tumor DNA (ctDNA) in the sera of three of the ten patients.


Myeloid-derived suppressor cells in the development of lung cancer.
Myeloid-derived suppressor cells (MDSC) are widely implicated in immune suppression associated with tumor progression and chronic inflammation. However, very little is known about their possible role in tumor development. Here, we evaluated the role of MDSC in two experimental models of lung cancer: inflammation-associated lung cancer caused by chemical carcinogen urethane in combination with exposure to cigarette smoke; and a transgenic CC10Tg model not associated with inflammation. Exposure of mice to cigarette smoke alone resulted in significant accumulation in various organs of cells with typical MDSC phenotype (Gr-1(+)CD11b(+)). However, these cells lacked immunosuppressive activity and could not be defined as MDSC. When cigarette smoke was combined with a single dose of urethane, it led to the development of tumor lesions in lungs within 4 months. By that time, Gr-1(+)CD11b(+) cells accumulated in the spleen and lung and had potent immunosuppressive activity, and thus could be defined as MDSC. In the CC10Tg model, accumulation of immunosuppressive MDSC was observed only at 4 months of age, after the appearance of tumor lesions in the lungs. Accumulation of MDSC in both models was abrogated in S100A9 knockout mice. This resulted in a dramatic improvement in survival of mice in both models. Thus, cigarette smoke results in the expansion of immature myeloid cells lacking suppressive activity. Accumulation of bona fide MDSC in both models was observed only after the development of tumor lesions. However, MDSC played a major role in tumor progression and survival, which suggests that their targeting may provide clinical benefits in lung cancer.


[Poverty, malnutrition and obesity: interrelationships among the nutritional status of members of the same family].
Chronic malnutrition in infancy and obesity associated with short stature in adulthood may share common biological and socio-environmental determinants. An analysis of intra-family nutrition status distribution patterns may provide elements for understanding the risk factors common to these physiological conditions. The purpose of this study is to ascertain how the intra-family distribution of nutritional conditions in pauperized families occurs, examining related social, environmental and biological factors. An impoverished population (income less than US$ 70) was studied in two rural areas of São Paulo State, Brazil: Monteiro Lobato and Santo Antônio do Pinhal. The sample consisted of members of these families, with 215 children younger than 71.11 months; mothers (197), fathers (167) and siblings (6 to 18 years of age). A hierarchical logistic regression analysis model was prepared. The mothers' educational levels, the number of rooms in the home, age below 24 months and problems at birth, were all associated with height deficits in children, together with short maternal stature, especially when associated with obesity. Additionally, a marked association was noted between height deficits in these children and chronic malnutrition among their older siblings (6 to 18 years old). Children aged 24 months or less presented more severe risks of delayed growth.


Hazardous substances. Determination of pentachlorophenol in toy paints.
A simple procedure is described for the routine determination of pentachlorophenol (PCP) in various types of toy paints. PCP can be determined in water colors, body colors, showcard paints, gouache paints, and colored inks. PCP is extracted from the sample with acetone, followed by quantitative gas chromatographic analysis of the concentrated acetone extract on stainless steel columns containing 15% Carbo-wax 20M on 60-80 mesh Chromosorb P (AW). As little as 1 ppm PCP can be determined with recoveries ranging from 50 to 100%, depending on the type of paint. The presence of PCP in samples is confirmed by thin layer chromatography, using dansyl chloride as a fluorescent labeling compound. By this method as little as 4 ppm can be determined. The results of PCP determinations in 65 commerical samples are presented.


[Alpha-Lactalbumin as an ingredient of infant formula].
Alpha-Lactalbumin is the main whey protein in human milk rising 2,44 g/L in mature milk. It has a key function in the synthesis of lactose from glucose and galactose in the mammary gland although this compound has also other beneficial effects on the infant health due to the high proportion of essential aminoacids (tryptophan and cysteine). It seems also to increase iron absorption in the digestive track, and in in vitro experiments, linked to oleic acid (HAMLET complex), has shown anticarcinogenic effects against cellular tumor such as human papilloma. In addition, this complex has been reported to exhibit antimicrobial properties against Streptococcus pneumoniae, Haemophilus influenzae, enteropathogenic strains of Escherichia coli and Salmonella thypimurium. However, the in vivo synthesis of HAMLET complex during milk digestion has not been proved yet. Infant formula have been improved considerably during the last decades not only adapting nutrient concentrations to infants requirements but also by the addition of new bioactive ingredients such as alpha-lactalbumin, to have the same functional effect as in breast fed babies.


Using a multigene phylogenetic analysis to assess generic delineation and character evolution in Verrucariaceae (Verrucariales, Ascomycota).
Verrucariaceae are a family of mostly crustose lichenized ascomycetes colonizing various habitats ranging from marine and fresh water to arid environments. Phylogenetic relationships among members of the Verrucariaceae are mostly unknown and the current morphology-based classification has never been confronted to molecular data. A multilocus phylogeny (nuLSU, nuSSU and RPB1) was reconstructed for 83 taxa representing all main genera of this family to provide a molecular phylogenetic framework necessary to assess the current morphology-based classification. Four main well-supported monophyletic groups were recovered, one of which contains seven robust monophyletic subgroups. Most genera, as traditionally delimited, were not monophyletic. A few taxonomic changes are proposed here to reconcile the morphology-based classification with the molecular phylogeny (Endocarpon diffractellum comb. nov., Heteroplacidium fusculum comb. nov., and Bagliettoa marmorea comb. nov.). Ancestral state reconstructions show that the most recent common ancestor of the Verrucariaceae was most likely crustose with a weakly differentiated upper cortex, simple ascospores, and hymenium free of algae. As shown in this study, the use of symplesiomorphic traits to define Verrucaria, the largest and type genus for the Verrucariaceae, as well as the non monophyly of the genera Polyblastia, Staurothele and Thelidium, explain most of the discrepancies between the current classification based on morphological similarity and a classification using monophyly as a grouping criterion.


Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions.
Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.


Vitamin D deficiency in children and its management: review of current knowledge and recommendations.
Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated with these recommendations.


Active fungal GH115 α-glucuronidase produced in Arabidopsis thaliana affects only the UX1-reactive glucuronate decorations on native glucuronoxylans.
Expressing microbial polysaccharide-modifying enzymes in plants is an attractive approach to custom tailor plant lignocellulose and to study the importance of wall structures to plant development. Expression of α-glucuronidases in plants to modify the structures of glucuronoxylans has not been yet attempted. Glycoside hydrolase (GH) family 115 α-glucuronidases cleave the internal α-D-(4-O-methyl)glucopyranosyluronic acid ((Me)GlcA) from xylans or xylooligosaccharides. In this work, a GH115 α-glucuronidase from Schizophyllum commune, ScAGU115, was expressed in Arabidopsis thaliana and targeted to apoplast. The transgene effects on native xylans' structures, plant development, and lignocellulose saccharification were evaluated and compared to those of knocked out glucuronyltransferases AtGUX1 and AtGUX2. The ScAGU115 extracted from cell walls of Arabidopsis was active on the internally substituted aldopentaouronic acid (XUXX). The transgenic plants did not show any change in growth or in lignocellulose saccharification. The cell wall (Me)GlcA and other non-cellulosic sugars, as well as the lignin content, remained unchanged. In contrast, the gux1gux2 double mutant showed a 70% decrease in (Me)GlcA to xylose molar ratio, and, interestingly, a 60% increase in the xylose content. Whereas ScAGU115-expressing plants exhibited a decreased signal in native secondary walls from the monoclonal antibody UX1 that recognizes (Me)GlcA on non-acetylated xylan, the signal was not affected after wall deacetylation. In contrast, gux1gux2 mutant was lacking UX1 signals in both native and deacetylated cell walls. This indicates that acetyl substitution on the xylopyranosyl residue carrying (Me)GlcA or on the neighboring xylopyranosyl residues may restrict post-synthetic modification of xylans by ScAGU115 in planta. Active GH115 α-glucuronidase has been produced for the first time in plants. The cell wall-targeted ScAGU115 was shown to affect those glucuronate substitutions of xylan, which are accessible to UX1 antibody and constitute a small fraction in Arabidopsis, whereas majority of (Me)GlcA substitutions were resistant, most likely due to the shielding by acetyl groups. Plants expressing ScAGU115 did not show any defects under laboratory conditions indicating that the UX1 epitope of xylan is not essential under these conditions. Moreover the removal of the UX1 xylan epitope does not affect lignocellulose saccharification.


Guiding Bone Cell Network Formation in 3D via Photosensitized Two-Photon Ablation.
A long-standing challenge in skeletal tissue engineering is to reconstruct a three-dimensionally (3D) interconnected bone cell network in vitro that mimics the native bone microarchitecture. While conventional hydrogels are extensively used in studying bone cell behavior in vitro, current techniques lack the precision to manipulate the complex pericellular environment found in bone. The goal of this study is to guide single bone cells to form a 3D network in vitro via photosensitized two-photon ablation of microchannels in gelatin methacryloyl (GelMA) hydrogels. A water-soluble two-photon photosensitizer (P2CK) was added to soft GelMA hydrogels to enhance the ablation efficiency. Remarkably, adding 0.5 mM P2CK reduced the energy dosage threshold five-fold compared to untreated controls, enabling more cell-compatible ablation. By employing low-energy ablation (100 J/cm2) with a grid pattern of 1 µm wide and 30 µm deep microchannels, we induced dendritic outgrowth in human mesenchymal stem cells (hMSC). After 7 days, the cells successfully utilized the microchannels and formed a 3D network. Our findings reveal that cellular viability after low-energy ablation was comparable to unablated controls, whereas high-energy ablation (500 J/cm2) resulted in 42% cell death. Low-energy grid ablation significantly promoted network formation and >40 µm long protrusion outgrowth. While the broad-spectrum matrix metalloproteinase inhibitor (GM6001) reduced cell spreading by inhibiting matrix degradation, cells invaded the microchannel grid with long protrusions. Collectively, these results emphasize the potential of photosensitized two-photon hydrogel ablation as a high-precision tool for laser-guided biofabrication of 3D cellular networks in vitro. STATEMENT OF SIGNIFICANCE: The inaccessible nature of osteocyte networks in bones renders fundamental research on bone biology a major challenge. This limit is partly due to the lack of high-resolution tools that can manipulate the pericellular environment in 3D cultures in vitro. To create bone-like cellular networks, we employ a two-photon laser in combination with a two-photon sensitizer to erode microchannels with low laser dosages into GelMA hydrogels. By providing a grid of microchannels, the cells self-organized into a 3D interconnected network within days. Laser-guided formation of 3D networks from single cells at micron-scale resolution is demonstrated for the first time. In future, we envisage in vitro generation of bone cell networks with user-dictated morphologies for fundamental and translational bone research.


Community Pharmacy Personnel Understanding of Antibiotic Dispensing in Eastern Nepal.
Community pharmacies are easily accessible outlets providing medicines to the general public in Nepal, but it is known that irrational dispensing of antibiotics from such outlets contributes to antimicrobial resistance. To assess the understanding of community pharmacy personnel around antibiotic-dispensing in Eastern Nepal and the relationship between this understanding and their personal characteristics. A cross-sectional survey was conducted on 312 pharmacy personnel working in community pharmacies of three districts within Eastern Nepal using a self-administered questionnaire. Descriptive statistics were used to analyze participants' characteristics and their understanding of antibiotic dispensing. The relationships between their understanding of antibiotic dispensing and their characteristics were determined using Chi-square tests. Most of the pharmacy personnel considered that dispensing antibiotics without a valid prescription is a problem (76.9%), and that it would not be legal to do so (86.9%). In the survey, 34.9% of participants agreed that they had dispensed antibiotics without prescription, and 26.9% disagreed with the assertion that inappropriate dispensing of antibiotics could promote antimicrobial resistance. Most (94.5%) reported that they would advise patients to follow their antibiotic dosage regimen, but 34.3% reported that they believed antibiotics to reduce pain and inflammation. Bivariate analysis showed that the level of understanding about antibiotic indication was significantly associated with age (p<0.001), work experience (p<0.001) and qualifications (p=0.017) of the pharmacy personnel. Work experience and qualifications also had significant but independent relationships with the level of understanding that irrational dispensing of antibiotics promotes antimicrobial resistance (p=0.018 and p=0.004) and is on the need for patient follow-up after dispensing antibiotics (p<0.001 and p=0.042). The understanding of community pharmacy personnel about antibiotic dispensing in Eastern Nepal requires significant improvement. Degree of understanding of some aspects of antibiotic dispensing was influenced by age, work experience and qualifications.


Inclusive Entrepreneurship and Motivation Among People With Intellectual Disability: "Why They Act".
Social entrepreneurship is a growing trend for people with intellectual disability (ID). This trend reflects a shift in contemporary policy towards entrepreneurship and self-employment as a viable employment option for people with disability in general; a strategy which is intended to promote autonomy and reduce dependence on entitlement-based services as well as to reduce employment disparities and stimulate business and job creation. However, it is not well understood what exactly this means for people with ID involved in social entrepreneurial ventures. This research approached the issue by conducting dyadic interviews to explore the motivations of people with ID who are participating and supported in social entrepreneurship-"why they act." In exploring these motivations, this article investigates push-pull factors, the role of the social mission, and how support influences motivation.


Arthrobacter siderocapsulatus Dubinina and Zhdanov 1975AL is a later subjective synonym of Pseudomonas putida (Trevisan 1889) Migula 1895AL.
The taxonomic position of Arthrobacter siderocapsulatus Dubinina and Zhdanov 1975AL was investigated using 16S rDNA, fatty acid and phenotypic analyses. The type strain (NCIMB 11286T) showed 99.85% 16S rDNA similarity to the type strain of Pseudomonas putida. Phenotypic properties of the two strains were compared using API 20NE and BIOLOG kits. Identical reactions were recorded for all tests, except for assimilation of malonic acid. The two strains also showed almost identical cellular fatty acid profiles. On the basis of evidence presented in this and earlier studies, it is proposed that Arthrobacter siderocapsulatus is a later subjective synonym of Pseudomonas putida (Trevisan 1889) Migula 1895AL.


Effectiveness of Yoga as the Public Health Intervention Module in the Management of Diabetes and Diabetes Associated Dementia in South East Asia: A Narrative Review.
Diabetes mellitus (DM) is widely spread in South Asian (ASEAN) and Indian sub-continent. The increasing healthcare costs of DM can be prevented in the developing world by improved public healthcare interventions. Modifiable risk factors of DM like sedentary lifestyle, obesity, and stressful conditions are associated with its progression; however, the epidemiological data collected by Public Institutions are limited. A review of published literature describing geographic distribution of DM and associated dementia in South Asian region, particularly India, was conducted with the purpose of assessing the feasibility and challenges associated with the Yoga-based risk reduction. PubMed and Google Scholar databases were searched for DM and dementia-related articles by using a combination of keywords: Diabetes, Diabetes related Dementia Southeast Asia, Pre-diabetes, Yoga, lifestyle modification, Dementia and Exercise. The epidemiological data generated from these diseases have not prompted to any major public health policies. Yoga can be a cost-effective intervention for the prevention of Type 2 DM (T2DM) and its associated cognitive decline when detected early. If nationwide intervention of Yoga is brought about by the state, its integration in health care will become more meaningful and acceptable. Key Message: Studies suggest that Yoga and change in lifestyle can modify the health risks associated with T2DM and associated dementia if it is mainstreamed with the public health initiative of Ayushman Bharat scheme.


Zebrafish models relevant to studying central opioid and endocannabinoid systems.
The endocannabinoid and opioid systems are two interplaying neurotransmitter systems that modulate drug abuse, anxiety, pain, cognition, neurogenesis and immune activity. Although they are involved in such critical functions, our understanding of endocannabinoid and opioid physiology remains limited, necessitating further studies, novel models and new model organisms in this field. Zebrafish (Danio rerio) is rapidly emerging as one of the most effective translational models in neuroscience and biological psychiatry. Due to their high physiological and genetic homology to humans, zebrafish may be effectively used to study the endocannabinoid and opioid systems. Here, we discuss current models used to target the endocannabinoid and opioid systems in zebrafish, and their potential use in future translational research and high-throughput drug screening. Emphasizing the high degree of conservation of the endocannabinoid and opioid systems in zebrafish and mammals, we suggest zebrafish as an excellent model organism to study these systems and to search for the new drugs and therapies targeting their evolutionarily conserved mechanisms.


Binocular interactions in normal and anomalous binocular vision: effects of flicker.
Temporal modulation thresholds were determined for monocular viewing and for binocular viewing of stimuli presented in phase or in counterphase to each eye of observers with normal binocular vision and those lacking stereopsis. The results showed that in individuals with normal binocular vision sensitivity was much greater for in-phase than for counterphase stimulation at low temporal frequencies, but that this superiority declined at higher temporal frequencies. Averaged across frequencies, binocular sensitivity for in-phase stimulation was 40-50% higher than monocular sensitivity. In contrast, in the observers lacking stereopsis the ratios of binocular in-phase/monocular sensitivity averaged 1.02, and there were no significant differences in sensitivity to in-phase and counterphase stimulation. This failure of binocular integration at threshold does not result from differences in transmission time between the 2 eyes. However, while individuals lacking stereopsis showed an absence of binocular interaction for uniform-field flicker at threshold, they showed suprathreshold dichoptic temporal frequency masking which was similar to that found in normal persons.


The excess incidence of squamous cell esophageal cancer among us black men. Role of social class and other risk factors.
PURPOSE: To investigate the relationship between social class factors and squamous cell esophageal cancer and the extent to which alcohol, tobacco, diet, and social class contribute to the five-fold higher incidence among black than white men in the United States.METHODS: Interviews were conducted with 347 incident cases of squamous cell esophageal cancer (119 white males and 228 black males) and 1354 population-based controls (743 white males and 611 black males) from Atlanta, Detroit, and New Jersey. Risks were estimated using unconditional logistic regression controlling for potential confounders.RESULTS: Elevated risks of squamous cell esophageal cancer were associated with indicators of low social class, especially low annual income. The adjusted odds ratios (ORs) for subjects with incomes < $10,000 versus incomes of $25,000 or more were 4.3 (95% CI = 2.1-8.7) for whites and 8.0 (95% CI = 4.3-15.0) for blacks. The combination of all four major risk factors: annual income less than $25,000, moderate/heavy use of alcohol, use of tobacco for six months or longer, and consumption of less than 2.5 servings of raw fruits and vegetables per day accounted for almost all of the squamous cell esophageal cancers in whites (98%) and blacks (99%), and for 99% of the excess incidence among black men.CONCLUSIONS: Lifestyle modifications, especially a lower intake of alcoholic beverages, would markedly decrease the incidence of this cancer in both races and narrow the racial disparity in risk. Further studies into the determinants of social class may help identify a new set of exposures for this tumor that are amendable to intervention.


A new insight into non-specific abdominal pain.
This review aims to change clinical practice and alert clinicians to consider that unrecognised coeliac disease may present acutely with abdominal pain. Targeting patients who have non-specific abdominal pain or coeliac-associated symptoms/diseases may improve diagnosis.


Artificial Intelligence for the Characterization of Pulmonary Nodules, Lung Tumors and Mediastinal Nodes on PET/CT.
Lung cancer is the leading cause of cancer related death around the world although early diagnosis remains vital to enabling access to curative treatment options. This article briefly describes the current role of imaging, in particular 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET/CT, in lung cancer and specifically the role of artificial intelligence with CT followed by a detailed review of the published studies applying artificial intelligence (ie, machine learning and deep learning), on FDG PET or combined PET/CT images with the purpose of early detection and diagnosis of pulmonary nodules, and characterization of lung tumors and mediastinal lymph nodes. A comprehensive search was performed on Pubmed, Embase, and clinical trial databases. The studies were analyzed with a modified version of the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) and Prediction model Risk Of Bias Assessment Tool (PROBAST) statement. The search resulted in 361 studies; of these 29 were included; all retrospective; none were clinical trials. Twenty-two records evaluated standard machine learning (ML) methods on imaging features (ie, support vector machine), and 7 studies evaluated new ML methods (ie, deep learning) applied directly on PET or PET/CT images. The studies mainly reported positive results regarding the use of ML methods for diagnosing pulmonary nodules, characterizing lung tumors and mediastinal lymph nodes. However, 22 of the 29 studies were lacking a relevant comparator and/or lacking independent testing of the model. Application of ML methods with feature and image input from PET/CT for diagnosing and characterizing lung cancer is a relatively young area of research with great promise. Nevertheless, current published studies are often under-powered and lacking a clinically relevant comparator and/or independent testing.


[Brain dysfunction in subjects at risk of Alzheimer's disease].
Visual evoked potentials versus flash (VEP) and brain DC-potentials were studied in the first-order relatives of patients (mean age 42.6 +/- 1.6 years) with Alzheimer's disease (AD) and probands (mean age 60.9 +/- 0.9 years) and age-matched healthy controls for the relatives and probands. In the relatives of AD patients, the latencies of N2, P3, N3 components were found to be delayed as compared with the controls. There was a delay in the latencies of the same components in the patients and their relatives, but it was smaller in the relatives of AD patients. The brain DC-potentials were higher in the relatives of AD patients than in the controls. Neurophysiological changes in the relatives of AD patients may be considered to be signs of latent neurodegeneration in the limbicoreticulocortical pathways, which may be associated with the excitotoxic processes and abnormal hyperactivity in the limbicoreticulocortical structures.


Human fertility variation, size-related obstetrical performance and the evolution of sexual stature dimorphism.
In several animal species, change in sexual size dimorphism is a correlated response to selection on fecundity. In humans, different hypotheses have been proposed to explain the variation of sexual dimorphism in stature, but no consensus has yet emerged. In this paper, we evaluate from a theoretical and an empirical point of view the hypothesis that the extent of sexual dimorphism in human populations results from the interaction between fertility and size-related obstetric complications. We first developed an optimal evolutionary model based on extensive simulations and then we performed a comparative analysis for a total set of 38 countries worldwide. Our optimization modelling shows that size-related mortality factors do indeed have the potential to affect the extent of sexual stature dimorphism. Comparative analysis using generalized linear modelling supports the idea that maternal death caused by deliveries and complications of pregnancy (a variable known to be size related) could be a key determinant explaining variation in sexual stature dimorphism across populations. We discuss our results in relation to other hypotheses on the evolution of sexual stature dimorphism in humans.


Characterization of the hepatitis B virus major surface antigen promoter hepatocyte nuclear factor 3 binding site.
Transcription of the HBV 2.1 kb RNAs is regulated by the major surface antigen promoter. Previously, transient transfection analysis identified regulatory sequence elements in this promoter located between -189 and +1 which govern the level of transcription from this promoter and appear to bind only ubiquitous transcription factors including NF1, Sp1 and NF-Y. However, in vivo transcription analysis in transgenic mice has demonstrated that the expression of the HBV 2.1 kb RNAs is largely restricted to hepatocytes. In this study, the presence of a functional HNF3 transcription factor binding site located between -231 and -240 in the major surface antigen promoter suggests that the in vivo liver-restricted expression of the 2.1 kb RNAs may be governed by this liver-enriched transcription factor. The identification of a functional HNF3 binding site upstream of the DNA polymerase open reading frame also supports the contention that transient transfection analysis may fail to detect all of the cis-acting regulatory sequence elements involved in modulating the level of transcription from the viral promoters.


Gene Expression and Cellular Markers of Occupational Radiation Exposure in Chernobyl Shelter Construction Workers.
Low-dose radiation effects were studied in Ukrainian personnel of the Chernobyl exclusion zone. The aim of this study was to determine the influence of borderline exposure to annual professional limits and age on expression of molecular markers. Study groups included 300 radiation workers performing construction work on the New Safe Confinement (Arch) upon the Chernobyl "Shelter" [external dose, 26.1 ± 18.1 mSv; age, 43.1 ± 10.3 y overall and 48.7 ± 5.9 y for 69 control persons]. Methods included gene expression using RT-PCR, flow cytometry of lymphocyte antigens, gamma-H2AX, Cyclin D1 expression, and relative telomere length using flow-FISH. A statistically significant upregulation of VEGFA BAX, DDB2, NFKB1 was shown at doses below 35 mSv. In workers aged under 40 y with doses higher than 35 mSv, an upregulation of 16 genes was revealed-VEGFA, TERF2, TERF1, BIRC5, BAX, TP53, DDB2, CDKN1B, CDKN2A, NFKB2, MAPK14, TGFBR1, MKNK2, CDKN1A, NFKB1, TP53I3; and four genes were downregulated-MADD, FASL, CSF2, and TERT. In workers older than 40 y, 8 genes were upregulated and 12 were downregulated. All groups showed an increased and dose-dependent gamma-H2AX expression. Downregulation of CCND1 genes in older groups was accompanied by lower numbers of Cyclin D1 protein expression and lower CD3 and CD4 cell counts. Upregulation of CSF2 in those over 40 y old positively correlated with B-cell and NK-cell counts. A non-linear type of gene expression response was demonstrated: in doses over 35 mSv for those over 40 y, the increased expression of gamma-H2AX is associated with upregulation of cell survival positive regulators-BIRC5, BRCA1, DDB2, CCND1, TERT genes, and longer telomeres; the younger age group was characterized by TERF1 and TERF2 upregulation and telomere shortening.


Endovenous radiofrequency ablation for the treatment of varicose veins.
Chronic venous insufficiency (CVI) is the most common vascular disease and represents a significant health care problem in the United States. Reflux of the great saphenous vein is the most common cause of this condition, whose symptoms include varicose veins, leg swelling, skin discoloration, and ulceration. The traditional treatment of this condition is saphenofemoral ligation with stripping of the saphenous vein followed by varicose vein removal, if necessary. Recent advances in minimally invasive endovenous therapy have led to the development of catheter-based radiofrequency ablation (RFA) of the saphenous vein, which has gained an increasing acceptance in clinical practice. Endovenous RFA was introduced into clinical practice in Europe in 1998 and in the United States in 1999. Since then, over 250,000 procedures have been performed worldwide. Procedure safety and efficacy are well understood, with over 60 publications on the subject in the peer review literature, including four randomized trials comparing this technology with traditional vein stripping surgery. With the advent of tumescent anesthesia, the majority of RFA procedures are now performed in an office setting. This article examines the current technology using RFA in saphenous vein ablation with the Closure catheter system. Procedural techniques and clinical outcome using RFA in saphenous vein ablation are discussed. Clinical data comparing RFA versus saphenous vein stripping are also examined. Lastly, the clinical utility of a new RFA catheter, ClosureFAST, is discussed. ClosureFAST is a new generation of RFA catheter and has exhibited significant improvement in the ease of use and the procedure speed over the previous generation catheters while maintaining the favorable patient recovery profile seen with the RFA technology.


Cell-Free Synthesis of a Transmembrane Mechanosensitive Channel Protein into a Hybrid-Supported Lipid Bilayer.
Supported lipid bilayers (SLBs) hold tremendous promise as cellular-mimetic structures that can be readily interfaced with analytical and screening tools. The incorporation of transmembrane proteins, a key component in biological membranes, is a significant challenge that has limited the capacity of SLBs to be used for a variety of biotechnological applications. Here, we report an approach using a cell-free expression system for the cotranslational insertion of membrane proteins into hybrid-supported lipid bilayers (HSLBs) containing phospholipids and diblock copolymers. We use cell-free expression techniques and a model transmembrane protein, the large conductance mechanosensitive channel (MscL), to demonstrate two routes to integrate a channel protein into a HSLB. We show that HSLBs can be assembled with integrated membrane proteins by either cotranslational integration of protein into hybrid vesicles, followed by fusion of these proteoliposomes to form a HSLB, or preformation of a HSLB followed by the cell-free synthesis of the protein directly into the HSLB. Both approaches lead to the assembly of HSLBs with oriented proteins. Notably, using single-particle tracking, we find that the presence of diblock copolymers facilitates membrane protein mobility in the HSLBs, a critical feature that has been difficult to achieve in pure lipid SLBs. The approach presented here to integrate membrane proteins directly into preformed HSLBs using cell-free cotranslational insertion is an important step toward enabling many biotechnology applications, including biosensing, drug screening, and material platforms requiring cell membrane-like interfaces that bring together the abiotic and biotic worlds and rely on transmembrane proteins as transduction elements.


Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 1: Epidemiology and Clinical Management.
There is growing interest in the interaction between type 2 diabetes mellitus (DM) and TB, but many research questions remain unanswered. Epidemiologists, basic scientists, and clinical experts recently convened and identified priorities. This is the first of two reviews on this topic, summarizing priority areas of research regarding epidemiology, clinical management, and public health. First, from an epidemiologic point of view, more study is needed to determine the importance of transient hyperglycemia in patients with TB and on the importance of DM for the global epidemic of multidrug resistant (MDR)-TB. Second, regarding the screening and clinical management of combined TB and DM (TB-DM), clinical trials and large cohort studies should examine the benefits of improved DM care as well as prolonged or intensified TB treatment on the outcome of TB-DM and investigate the cost-effectiveness of screening methods for DM among patients newly diagnosed with TB. Third, from a public health and health systems point of view, the population health impact and cost-effectiveness of different interventions to prevent or treat DM and TB in high-burden populations should be examined, and health-system interventions should be developed for routine TB-DM screening, management of DM after completion of TB treatment, and better access to DM services worldwide. Studies are needed across different ethnicities and settings given the heterogeneity of metabolic perturbations, inflammatory responses, medications, and access to health care. Finally, studies should address interactions between TB, DM, and HIV because of the convergence of epidemics in sub-Saharan Africa and some other parts of the world.


Delayed sleep wake phase disorder in adolescents: an updated review.
This review examines the most common circadian rhythm disorder in adolescents, delayed sleep phase disorder. It explores the etiology, prevalence, clinical features, diagnostic tools and criteria, and treatment options to identify sleep disorders early in the course. This is important to help improve youths in terms of education and quality of life. Recent studies indicate that delayed sleep wake phase disorder has a range of prevalence between 1% and 16%. It is often associated with neurodevelopmental disorders (i.e. attention deficit hyperactivity disorder and autism spectrum disorder) as well as psychopathology (i.e. substance use, anxiety, and depression). It can present with a myriad of symptoms, such as insomnia, restless sleep, and poor daytime cognitive function, often seen in pediatric practice. Important diagnostic measures incorporate history-taking, sleep logs, actigraphy (i.e. Apple watches) and measurement of dim light melatonin onset. Treatments include improved sleep hygiene, chronotherapy, exogenous melatonin administration, and bright light therapy. There are many environmental and genetic factors that can predispose an individual to circadian rhythm disorders. Delayed sleep phase disorder has detrimental effects on overall health, cognition, and behavior. It is important to screen for this disorder in routine pediatric clinic visits. The goal of early intervention is to prevent health and behavioral complications and treat adolescents using a multimodal approach, especially those with affective/neurodevelopmental conditions, who are prone to having delayed sleep wake phase disorder.


Effect of fermented wheat germ extract with lactobacillus plantarum dy-1 on HT-29 cell proliferation and apoptosis.
This study aimed to evaluate the anticarcinogenic activities of aqueous extract of fermented wheat germ with Lactobacillus plantarum dy-1 (LFWGE). The anticarcinogenic activities, including antiproliferative effects and the induction of apoptosis, were studied in human HT-29 colon cancer cells. The 2,6-dimethoxybenzoquinone and total phenol contents in LFWGE were determined by HPLC and the Folin-Ciocalteu method. In addition, some functional proteins were separated and purified by gel filtration chromatography. There were 21 proteins identified by LC-MS/MS. The sugars isolated from LFWGE did not possess any anticarcinogenic activity. The results of an MTT assay showed high antiproliferative effects of LFWGE. In addition, LFWGE attenuated the progression from the G0-G1 to the G2-M phase of the cell cycle, and LFWGE-induced cell apoptosis was associated with the activation of caspase-3. LFWGE and its major bioactive ingredients inhibited the proliferation of HT-29 cells via apoptosis and thus may be a potential anticarcinogenic agent.


Current trends in the enhancement of biomaterial osteointegration: biophysical stimulation.
To enhance bone implant osteointegration, many strategies for improving biomaterial properties have been developed which include optimization of implant material, implant design, surface morphology and osteogenetic coatings. Other methods that have been attempted to enhance endogenous bone healing around biomaterials are different forms of biophysical stimulations such as pulsed electromagnetic fields (PEMFs) and low intensity pulsed ultrasounds (LIPUS), which were initially developed to accelerate fracture healing. To aid in the use of adjuvant biophysical therapies in the management of bone-implant osteointegration, the present authors reviewed experimental and clinical studies published in the literature over the last 20 years on the combined use of biomaterials and PEMFs or LIPUS, and summarized the methodology, and the possible mechanism of action and effectiveness of the different biophysical stimulations for the enhancement of bone healing processes around bone implanted biomaterials.


Measles. The GP view.
Measles is still a common disease in Australia and causes significant morbidity both in itself and in its complications. Dr Clarke Munro discusses the clinical features and management. Although measles can now be prevented by vaccination, immunisation rates remain disappointingly low.


Arrested glutamatergic synapse development in human partial epilepsy.
While studying the brain function of the human partial epilepsy gene, leucine-rich glioma-inactivated 1 (LGI1), a new mechanism of human epileptogenesis was revealed-persistent immaturity of glutamatergic circuitries. LGI1, a novel secreted protein, was found to be increased during the postnatal period; when glutamatergic synapses both downregulate their presynaptic vesicular release probability and reduce their postsynaptic NMDA-receptor subunit NR2B. During this same period, the dendritic arbor and spines are pruned and remodeled. Using bacterial artificial chromosome transgenic mouse techniques, excess wild-type LGI1 was shown to magnify these critical brain developmental events in the hippocampal dentate gyrus; while an epilepsy-associated, truncated, dominant-negative form of LGI1 blocked them. By contrast, the hippocampal dentate granule neuron GABAergic synapses and intrinsic excitability were unaltered. A role for LGI1 in downregulating glutamate synapse function was confirmed by germline gene deletion; this intervention also revealed a selective increase of glutamatergic synaptic transmission with unaltered GABAergic synapses and intrinsic excitability of hippocampal CA1 pyramidal neurons. Interestingly, the role of LGI1 in neurological disease was further expanded when a subset of patients with limbic encephalitis (an autoimmune disorder with memory loss in 100% and seizures in 80% of individuals) were discovered to carry autoantibodies to LGI1.


Alterations in GABAA receptor alpha 1 and alpha 4 subunit mRNA levels in thalamic relay nuclei following absence-like seizures in rats.
Modification of GABAA receptor mRNA levels by seizure activity can regulate general neuronal excitability. The possibility of absence seizure-induced alteration in GABAA receptor alpha 1, alpha 4, beta 2, and gamma 2 subunit gene expression in thalamic relay nuclei was studied in a rat model of absence seizures induced by gamma-hydroxybutyric acid (GHB). We observed a marked increase in alpha 1 mRNA and a corresponding decrease in alpha 4 mRNA in thalamic relay nuclei 2-4 h after the onset of GHB-induced absence seizures (when the seizures were terminating). These changes were selective to these alpha isoforms as neither beta 2 nor gamma 2 mRNA changed following seizures and occurred only in thalamic relay nuclei but not in hippocampus, a structure from which absence seizures do not evolve. The alterations in alpha 1 and alpha 4 mRNA persisted until about 12 h, and by 24 h after the seizure-onset the mRNA levels normalized. Blocking GHB-seizures produced no change in the levels of alpha 1 and alpha 4 mRNA in thalamic relay nuclei, suggesting that seizures themselves were responsible for mRNA alterations. In order to determine if absence seizure-induced changes in alpha 1 and alpha 4 mRNA had any physiological significance, GHB was readministered in rats 6 and 24 h after the onset of seizures. The total duration of GHB-seizures was found to be significantly decreased when GHB was readministered at 6 h but not 24 h after the seizure-onset. These results suggest that absence seizures regulate GABAA receptor alpha 1 and alpha 4 gene expression in thalamic relay nuclei as a compensatory mechanism by which absence seizures are terminated.


Polarized white light from LEDs using remote-phosphor layer sandwiched between reflective polarizer and light-recycling dichroic filter.
This study introduces an efficient polarized, white phosphor-converted, light-emitting diode (pc-LED) using a remote phosphor film sandwiched between a reflective polarizer film (RPF) and a short-wavelength pass dichroic filter (SPDF). The on-axis brightness of polarized white light emission of a RPF/SPDF-sandwiched phosphor film over a blue LED, showed greater recovery than that of a conventional unpolarized remote phosphor film over blue LED, due to the recycling effect of yellow light from an SPDF. The relative luminous efficacy of an RPF/SPDF-sandwiched phosphor film was made 1.40 times better by adding an SPDF on the backside of an RPF-capped phosphor film. A polarization ratio of 0.84 was demonstrated for a white LED with an RPF/SPDF-sandwiched phosphor film, in good agreement with the measured results from the RPF-only sample.


[Dynamics of interhemispheric asymmetry in fenamine stereotypy in the cat].
Stereotyped behaviour induced by d,1-amphetamine in cats is a stable rhythmical process. Expressed stereotypy is characterized by stabilization of the summate curve of motor activity fluctuations by amplitude and periods with different asynchronous changes in the number of the left and right head turnings. Low-frequency stimulation of the caudate nucleus and administration of neuroleptics (haloperidol and clozapine) facilitate destabilization of the fluctuations curve and synchronize changes in the frequency of the left and the right head turnings. Structural or functional elimination of the ventrolateral part of the caudate nucleus head leads to opposite effects. It is suggested that amphetamine-induced stereotypy may be due to dynamic dissociation in time of activity of nigro-striatal systems of both cerebral hemispheres.


T cell-induced mast cell activation: a role for microparticles released from activated T cells.
Close physical proximity between mast cells and T cells has been demonstrated in several T cell-mediated inflammatory processes. However, the way by which mast cells are activated in these T cell-mediated immune responses has not been fully elucidated. We previously identified and characterized a novel mast cell activation pathway initiated by physical contact with activated T cells and showed that this pathway is associated with degranulation and cytokine release. In this study, we provide evidence that mast cells may also be activated by microparticles released from activated T cells that are considered miniature versions of a cell. Microparticles were isolated from supernatants of activated T cells by Centricon filtration or by high-speed centrifugation and identified by electron microscopy, flow cytometry (Annexin stain), and expression of the integrin LFA-1. Stimulated T cells were found to generate microparticles that induce degranulation and cytokine (IL-8 and oncostatin M) release from human mast cells. Mast cell activation by T cell microparticles involved the MAPK signaling pathway. The results were similar when mast cells were stimulated by activated fixed T cells or by whole membranes of the latter. This suggests that microparticles carry mast cell-activating factors similar to cells from which they originate. By releasing microparticles, T cells might convey surface molecules similar to those involved in the activation of mast cells by cellular contact. By extension, microparticles might affect the activity of mast cells, which are usually not in direct contact with T cells at the inflammatory site.


Bioassay-guided isolation, identification and molecular ligand-target insight of lipoxygenase inhibitors from leaves of Anisomeles malabarica R.Br.
Anisomeles malabarica R. Br. (Lamiaceae) is extensively used in traditional medicine in major parts of India for several medicinal purposes, including their use in rheumatism. The air-dried leaves of A. malabarica were extracted with ethanol, defatted with n-hexane and then successively partitioned into chloroform and n-butanol fractions. Bioassay-guided fractionation and purification of chloroform fraction from A. malabarica lead to the isolation of lipoxygenase (LOX) inhibitors. The structures of isolated compounds were elucidated by ultraviolet, infrared, (1)H nuclear magnetic resonance (NMR), (13)C NMR and mass spectrometry spectroscopic techniques and assessed further by in vitro soybean lipoxygenase (sLOX) assay. In addition, the enzyme type inhibition was evaluated through molecular docking technique as a part of computational study. The bioactive compounds 3, 4 dihydroxy benzoic acid (1) and 4', 5, 7-trihydroxyflavone (2) were isolated from chloroform fraction of A. malabarica, whose bioactivity was observed to be dose-dependent compared to n-butanol fraction. Among the compounds, 3, 4 dihydroxy benzoic acid showed significant sLOX inhibitory activity with 74.04% ±2.6% followed by 4', 5, 7-trihydroxyflavone (34.68% ±1.9%). The computational analysis of compounds showed their molecular interaction with important amino acid residues and nonheme iron atom in the catalytic site of LOX by enlightening their potential binding mode at molecular level. The LOX inhibitory constituents were identified from A. malabarica by means of bioassay-guided fractionation process. The results derived from in vitro and computational experiments confirm the potential of the isolated compounds and provide additional evidence for its traditional use in inflammatory disorders.


Youth and the transition to adult status: Uganda.
This paper examines the transition to adult status in four ethnic groups in Uganda, including one with circumcision and one with age-sets. The formal status hierarchies and the recognized points of transition are described. Then the variations from these norms are examined to show that when one functionally becomes an adult may differ from the stated points of transition.


A salience hypothesis of stress in PTSD.
Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from post-traumatic stress disorder (PTSD). Interestingly, similar observations have been robustly replicated across many animal models of stress as well. By using evidence from such rodent stress paradigms, in the present review, we explore PTSD through the lens of salience processing. In this context, we propose that interaction between the neurotrophin brain-derived neurotrophic factor (BDNF) and glucocorticoids determines the long lasting cellular and behavioural consequences of stress salience. We also describe the dual effect of glucocorticoid therapy in the amelioration of PTSD symptoms. Finally, by integrating in vivo observations at multiple scales of plasticity, we propose a unifying hypothesis that pivots on a crucial role of glucocorticoid signalling in dynamically orchestrating stress salience.


Antineonatal Fc Receptor Antibody Treatment Ameliorates MOG-IgG-Associated Experimental Autoimmune Encephalomyelitis.
Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) is a rare, autoimmune demyelinating CNS disorder, distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Characterized by pathogenic immunoglobulin G (IgG) antibodies against MOG, a potential treatment strategy for MOGAD is to reduce circulating IgG levels, e.g., by interference with the IgG recycling pathway mediated by the neonatal Fc receptor (FcRn). Although the optic nerve is often detrimentally involved in MOGAD, the effect of FcRn blockade on the visual pathway has not been assessed. Our objective was to investigate effects of a monoclonal anti-FcRn antibody in murine MOG-IgG-associated experimental autoimmune encephalomyelitis (EAE). We induced active MOG35-55 EAE in C57Bl/6 mice followed by the application of a monoclonal MOG-IgG (8-18C5) 10 days postimmunization (dpi). Animals were treated with either a specific monoclonal antibody against FcRn (α-FcRn, 4470) or an isotype-matched control IgG on 7, 10, and 13 dpi. Neurologic disability was scored daily on a 10-point scale. Visual acuity was assessed by optomotor reflex. Histopathologic hallmarks of disease were assessed in the spinal cord, optic nerve, and retina. Immune cell infiltration was visualized by immunohistochemistry, demyelination by Luxol fast blue staining and complement deposition and number of retinal ganglion cells by immunofluorescence. In MOG-IgG-augmented MOG35-55 EAE, anti-FcRn treatment significantly attenuated neurologic disability over the course of disease (mean area under the curve and 95% confidence intervals (CIs): α-FcRn [n = 27], 46.02 [37.89-54.15]; isotype IgG [n = 24], 66.75 [59.54-73.96], 3 independent experiments), correlating with reduced amounts of demyelination and macrophage infiltration into the spinal cord. T- and B-cell infiltration and complement deposition remained unchanged. Compared with isotype, anti-FcRn treatment prevented reduction of visual acuity over the course of disease (median cycles/degree and interquartile range: α-FcRn [n = 16], 0.50 [0.48-0.55] to 0.50 [0.48-0.58]; isotype IgG [n = 17], 0.50 [0.49-0.54] to 0.45 [0.39-0.51]). We show preserved optomotor response and ameliorated course of disease after anti-FcRn treatment in an experimental model using a monoclonal MOG-IgG to mimic MOGAD. Selectively targeting FcRn might represent a promising therapeutic approach in MOGAD.


Influence of Lipid Fragmentation in the Data Analysis of Imaging Mass Spectrometry Experiments.
Imaging mass spectrometry (IMS) is becoming an essential technique in lipidomics. Still, many questions remain open, precluding it from achieving its full potential. Among them, identification of species directly from the tissue is of paramount importance. However, it is not an easy task, due to the abundance and variety of lipid species, their numerous fragmentation pathways, and the formation of a significant number of adducts, both with the matrix and with the cations present in the tissue. Here, we explore the fragmentation pathways of 17 lipid classes, demonstrating that in-source fragmentation hampers identification of some lipid species. Then, we analyze what type of adducts each class is more prone to form. Finally, we use that information together with data from on-tissue MS/MS and MS3 to refine the peak assignment in a real experiment over sections of human nevi, to demonstrate that statistical analysis of the data is significantly more robust if unwanted peaks due to fragmentation, matrix, and other species that only introduce noise in the analysis are excluded.


[Ophthalmic tone of myopic eyes: statistical evaluation and role in formation of acquired myopia].
The author summarizes the results of many-year profound statistical analysis of ophthalmic tone in myopic patients. Intraocular pressure (IOP) of myopic eyes in patients aged 10 to 62 years and refraction from 0.5 to -24.0 diopters was measured in 1220 eyes by the same type of Goldman's tonometer. Detailed distribution of IOP for age and refraction factor is presented. IOP has been studied in emmetropia, stable and progressive myopia, and in paired anisometropic eyes. The author emphasizes that myopia progresses at various levels of ophthalmic tone, whose increase is mainly functional and reversible, and is caused by organic changes in the anterior chamber angle in only 7% of cases. The author claims that IOP is an important characteristic of a myopic eye and is to be taken into consideration when prescribing pathogenetic therapy for progressive myopia.