Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells.
Among the angiotensin II (Ang II)-mediated signal events likely to be important in vascular smooth muscle cells (VSMCs) is activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). The upstream mediators by which Ang II activates ERK1/2 remain poorly defined. Recently, we showed that Ang II activated c-Src, a nonreceptor kinase, which is a candidate to mediate Ang II signal events. To determine whether c-Src is required for ERK1/2 activation by Ang II, we studied the effects of Src family-selective tyrosine kinase inhibitors on ERK1/2 activation and also studied Ang II-mediated signal events in Src-deficient and Src-overexpressing VSMCs. The tyrosine kinase inhibitors, genistein and CP-188,556, blocked Ang II-mediated ERK1/2 activation in rat VSMCs (rVSMCs). We derived Src-deficient VSMCs from the aortas of c-Src knockout mice (Src-/- mVSMCs). Basal ERK1/2 activity was lower, and activation of ERK1/2 by Ang II was significantly decreased in Src-/- mVSMCs compared with wild-type mVSMCs, whereas ERK1/2 protein expression and ERK1/2 activation by phorbol 12-myristate 13-acetate were similar. To examine the role of c-Src further, we overexpressed wild-type or dominant-negative c-Src in rVSMCs using retroviral vectors. ERK1/2 activation by Ang II was significantly increased in rVSMCs that overexpressed c-Src, whereas ERK1/2 activation by Ang II was significantly inhibited in rVSMCs that overexpressed dominant-negative c-Src compared with control rVSMCs. These findings demonstrate that c-Src activation is required for Ang II stimulation of ERK1/2 in VSMCs and suggest an important role for c-Src in Ang II-mediated signal transduction.


Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network.
The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were inversely correlated with expression of Hsp47 and ECM network genes in human breast cancer tissues. We found that miR-29 repressed expression of Hsp47 along with multiple ECM network genes. Ectopic expression of miR-29b suppressed malignant phenotypes of breast cancer cells in 3D culture. Clinically, increased expression of Hsp47 and reduced levels of miR-29b and -29c were associated with poor survival outcomes in breast cancer patients. Our results show that Hsp47 is regulated by miR-29 during breast cancer development and progression, and that increased Hsp47 expression promotes cancer progression in part by enhancing deposition of ECM proteins.


Falls and function. How to prevent falls and injuries in patients with impaired mobility.
Older persons, particularly those with compromised health, are at increased risk of falls, and these events can significantly affect a person's quality of life. Risk factors include age, neurologic and musculoskeletal conditions, decreased physical strength, foot disorders, and use of medications or alcohol. When evaluating a patient who has fallen, physicians should be on the alert for intrinsic pathologies or situational conditions that place an older patient at increased risk for these incidents. Physical examination should include consideration of postural vital signs, polypharmacy, and sensory decline. Performance assessments are excellent tools for observing the status of gait and balance. Proper documentation and evaluation of a fall is a key step in preventive management.


Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator.
Oral cancer is the leading cancer type among Southeast Asian men and is causally associated with the use of tobacco. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contribute to the high degree of variance in individual susceptibility to cancer risk. This study investigates the role of polymorphisms at CYP1A1, GSTM1 and GSTT1 to oral squamous cell carcinoma (OSCC) in a case-control study involving 155 patients with precancerous lesions, 458 cancer patients and 729 age and habit-matched controls. Genotypes at these loci were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism performed on genomic DNA extracted from peripheral blood lymphocytes. Risk to oral cancer was estimated among different tobacco exposure groups and doses using logistic regression analysis. GSTM1 null genotype conferred 1.29-fold increased risk [95% confidence interval (CI), 1.04-1.65] to OSCC. GSTT1 null genotype, however, conferred 0.57 times reduced risk to OSCC (95% CI, 0.39-0.83), specifically among tobacco chewers (odds ratio 0.27; 95% CI, 0.14-0.53). This risk was further reduced to 0.13 times (95% CI, 0.04-0.46) with increase in lifetime exposure to tobacco. We also investigated risk conferred by these genotypes at two different intra-oral sites, buccal mucosa and tongue. We found increased susceptibility to buccal mucosa cancer among individuals carrying these genetic markers. These results support the finding that GSTM1 null genotype is a risk factor to OSCC among Indian tobacco habits; GSTT1 null genotype, however, emerged as a protective factor.


Choroid plexus calcification: clinical, neuroimaging and histopathological correlations in schizophrenia.
Schizophrenia is recognized as a psychiatric disorder that causes the most pronounced disturbances of cognition and social integration. In the etiopathogenesis of the disease, genetic, neurobiological and vascular factors are involved. Functional integrity of the brain can be correlated with the integrity of the blood-brain barrier (BBB), and the dysfunction of this barrier is an indicator that suggests neurodevelopmental abnormalities, injuries of various etiologies and dysfunctions within the small vessels of the brain that disrupt the calcium homeostasis. Neuroimaging shows that in patients with poor evolution, cognitive dysfunction and therapeutic resistance, the presence of choroid plexus calcification associated with hippocampal, frontal, temporoparietal and cerebellar atrophies. Antipsychotics with high capacity to block D2 dopamine receptors (haloperidol model) can aggravate apoptotic mechanisms of the brain areas involved in cognition and disrupts the functional integrity of the BBB due to decreased of choroid plexus blood flow because of the narrowing of cerebral small vessels. Choroid plexus calcification may be a predictive indicator of poor evolution or of a neurodegenerative type.


Measuring Open Porosity of Porous Materials Using THz-TDS and an Index-Matching Medium.
The porosity of porous materials is a critical quality attribute of many products ranging from catalysis and separation technologies to porous paper and pharmaceutical tablets. The open porosity in particular, which reflects the pore space accessible from the surface, is crucial for applications where a fluid needs to access the pores in order to fulfil the functionality of the product. This study presents a methodology that uses terahertz time-domain spectroscopy (THz-TDS) coupled with an index-matching medium to measure the open porosity and analyze scattering losses of powder compacts. The open porosity can be evaluated without the knowledge of the refractive index of the fully dense material. This method is demonstrated for pellets compressed of pharmaceutical-grade lactose powder. Powder was compressed at four different pressures and measured by THz-TDS before and after they were soaked in an index-matching medium, i.e., paraffin. Determining the change in refractive index of the dry and soaked samples enabled the calculation of the open porosity. The results reveal that the open porosity is consistently lower than the total porosity and it decreases with increasing compression pressure. The scattering losses reduce significantly for the soaked samples and the scattering centers (particle and/or pore sizes) are of the order of or somewhat smaller than the terahertz wavelength. This new method facilitates the development of a better understanding of the links between material properties (particles size), pellet properties (open porosity) and performance-related properties, e.g., disintegration and dissolution performance of pharmaceutical tablets.


The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation.
People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113). Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.


Evolution of zinc, iron, and copper concentrations along the gastrointestinal tract of piglets weaned with or without in-feed high doses of zinc oxide compared to unweaned littermates.
High doses of ZnO are used to treat diarrhea in weaning pigs but are also an environmental concern. The mechanism of action of Zn against diarrhea is still not well understood. The amount of solubilized Zn, the relation of Zn with Fe and Cu, and the concentration of these elements in the gastrointestinal tract (GIT) are key data to understanding its mechanism of action and optimize its use. Therefore, we studied the Zn, Fe, and Cu concentrations in the GIT content of unweaned, weaned, and ZnO-treated pigs. Eight litters were used and 3 piglets were selected within each litter. Two piglets from each litter were weaned at 21 d of age and fed a commercial control diet (WCt) or WCt + 2000 mg/kg of Zn as ZnO (WZn). The third pig was kept unweaned (Uw) with the sow. All 24 pigs were killed at 28 d of age, GIT contents were sampled, soluble and insoluble fractions of the content were separated, and Zn, Fe, and Cu concentrations were analyzed. Concentration of Zn increased 3 to 5 fold along the GIT (2 to 10 fold in the soluble fraction) for weaned pigs on WZn compared to WCt and Uw pigs (P < 0.01 in all cases). The proportion of total Zn that was present in the soluble fraction was 4 to 10 folds higher in jejunum, ileum, and cecum of Uw pigs than in those weaned (P < 0.01 in all cases) but was not affected by ZnO treatment. Concentration of Fe in the soluble fraction was higher for Uw pigs compared to weaned pigs along the GIT (P < 0.05 in all cases) even when concentration in total content was lower for Uw pigs in stomach (P = 0.001) and jejunum (P = 0.029). Concentrations of Cu were lower in Uw pigs than in weaned pigs along the GIT (P < 0.05 in all cases). Surprisingly, animals on WZn showed a 5 to 10 fold increase of Cu solubilized in distal parts of the GIT (cecum and colon; P < 0.001) compared to other groups. Differences in Zn, Fe, and Cu concentrations found among treatments will be useful in future studies for understanding mechanism of action of ZnO and optimizing its use in order to avoid environmental concerns.


Two cases of recurrent ovarian clear cell carcinoma treated with sorafenib.
Sorafenib is an oral multikinase inhibitor targeting Raf and other kinases. The anti-tumor effect of sorafenib is thought to be mediated through its inhibition of the RAS-Raf-Erk pathway, as well as its inhibition of VEGFR and PDGFR. Sorafenib has been effective at treating patients with renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer. OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC. Using a microarray database, the gene expression profile of OCCC was similar to that of RCC. The effects of sorafenib against human OCCC are unknown. Therefore, we used sorafenib to treat two patients with recurrent chemoresistant OCCC, and observed good effect in both of them without severe side effects. We believe that sorafenib is an effective agent against OCCC. Given the chemoresistant nature of this tumor, this drug appears to be very valuable.


Tracking visual search demands and memory load through pupil dilation.
Continuously tracking cognitive demands via pupil dilation is a desirable goal for the monitoring and investigation of cognitive performance in applied settings where the exact time point of mental engagement in a task is often unknown. Yet, hitherto no experimentally validated algorithm exists for continuously estimating cognitive demands based on pupil size. Here, we evaluated the performance of a continuously operating algorithm that is agnostic of the onset of the stimuli and derives them by way of retrospectively modeling attentional pulses (i.e., onsets of processing). We compared the performance of this algorithm to a standard analysis of stimulus-locked pupil data. The pupil data were obtained while participants performed visual search (VS) and visual working memory (VWM) tasks with varying cognitive demands. In Experiment 1, VS was performed during the retention interval of the VWM task to assess interactive effects between search and memory load on pupil dilation. In Experiment 2, the tasks were performed separately. The results of the stimulus-locked pupil data demonstrated reliable increases in pupil dilation due to high VWM load. VS difficulty only affected pupil dilation when simultaneous memory demands were low. In the single task condition, increased VS difficulty resulted in increased pupil dilation. Importantly, online modeling of pupil responses was successful on three points. First, there was good correspondence between the modeled and stimulus locked pupil dilations. Second, stimulus onsets could be approximated from the derived attentional pulses to a reasonable extent. Third, cognitive demands could be classified above chance level from the modeled pupil traces in both tasks.


Modelling excitation energy transfer and trapping in the filamentous cyanobacterium Anabaena variabilis PCC 7120.
The phycobilisome (PBS) serves as the major light-harvesting system, funnelling excitation energy to both photosystems (PS) in cyanobacteria and red algae. The picosecond kinetics involving the excitation energy transfer has been studied within the isolated systems and intact filaments of the cyanobacterium Anabaena variabilis PCC 7120. A target model is proposed which resolves the dynamics of the different chromophore groups. The energy transfer rate of 8.5 ± 1.0/ns from the rod to the core is the rate-limiting step, both in vivo and in vitro. The PBS-PSI-PSII supercomplex reveals efficient excitation energy migration from the low-energy allophycocyanin, which is the terminal emitter, in the PBS core to the chlorophyll a in the photosystems. The terminal emitter of the phycobilisome transfers energy to both PSI and PSII with a rate of 50 ± 10/ns, equally distributing the solar energy to both photosystems. Finally, the excitation energy is trapped by charge separation in the photosystems with trapping rates estimated to be 56 ± 6/ns in PSI and 14 ± 2/ns in PSII.


Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease.
Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.


The porosity of the cell wall of Candida albicans.
Polyethylene glycols of different molecular sizes have been used to study the penetrability of the cell wall of Candida albicans harvested at the end of the growth phase and after prolonged incubation in the stationary phase. No differences were found which could account for the greater resistance of cells from stationary phase cultures of C. albicans to the antimycotic agents amphotericin B methyl ester and miconazole.


A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.
Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma. We performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. Twenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival. ClinicalTrials.gov identifier: NCT00031590.


The Effectiveness of Digital Health Interventions in the Management of Musculoskeletal Conditions: Systematic Literature Review.
Musculoskeletal conditions are the second greatest contributor to disability worldwide and have significant individual, societal, and economic implications. Due to the growing burden of musculoskeletal disability, an integrated and strategic response is urgently required. Digital health interventions provide high-reach, low-cost, readily accessible, and scalable interventions for large patient populations that address time and resource constraints. This review aimed to investigate if digital health interventions are effective in reducing pain and functional disability in patients with musculoskeletal conditions. A systematic review was undertaken to address the research objective. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review protocol was registered with the International Prospective Register of Systematic Reviews before commencement of the study. The following databases were searched: Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature, and Scopus from January 1, 2000, to November 15, 2019, using search terms and database specific-medical subject headings terms in various combinations appropriate to the research objective. A total of 19 English language studies were eligible for inclusion. Of the 19 studies that assessed musculoskeletal pain, 9 reported statistically significant reductions following digital intervention. In all, 16 studies investigated functional disability; 10 studies showed a statistically significant improvement. Significant improvements were also found in a range of additional outcomes. Due to the heterogeneity of the results, a meta-analysis was not feasible. This review has demonstrated that digital health interventions have some clinical benefits in the management of musculoskeletal conditions for pain and functional disability. Digital health interventions have the potential to contribute positively toward reducing the multifaceted burden of musculoskeletal conditions to the individual, economy, and society. PROSPERO CRD42018093343; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=93343.


A new fuzzy logic filter for image enhancement.
This paper presents a new fuzzy-logic-control based filter with the ability to remove impulsive noise and smooth Gaussian noise, while, simultaneously, preserving edges and image details efficiently. To achieve these three image enhancement goals, we first develop filters that have excellent edge-preserving capability but do not perform well in smoothing Gaussian noise. Next, we modify the filters so that they perform all three image enhancement tasks. These filters are based on the idea that individual pixels should not be uniformly fired by each of the fuzzy rules. To demonstrate the capability of our filtering approach, it was tested on several different image enhancement problems. These experimental results demonstrate the speed, filtering quality, and image sharpening ability of the new filter.


The surgical treatment of predominantly venous defects.
The predominantly venous defects consist of the truncular forms, as there is aplasia or obstruction in the truncular dilatation; and they consist of the extratruncular forms as there are the infiltrating ones and the limited ones, according to the Hamburg classification. The web or membranous obstruction of the inferior vena cava (IVC), dilatation or aneurysm of the jugular vein, infiltrating "cavernous angioma" and localized venous defects are the main lesions of those classifications reported in this communication. Jugular dilatation and localized extratruncular lesions have had good therapeutic results. Webs of the IVC can be treated by membranectomy, either by finger, transcardially, or balloon, percutaneously, and cavo- or mesoatrial shunt; however, membranectomy, along with cavoplasty as a radical treatment for such an entity, is advocated by the authors. The infiltrating extratruncular form is the unsolved important issue concerning its thorough resection. Skin graft taken from a resected tissue mass through a reversal split thickness skin graft by a drum type dermatome, removal of the lesion along with muscle layer(s), and staged operations are recommended.


Automated sequential injection-microcolumn approach with on-line flame atomic absorption spectrometric detection for implementing metal fractionation schemes of homogeneous and nonhomogeneous solid samples of environmental interest.
An automated sequential injection (SI) system incorporating a dual-conical microcolumn is proposed as a versatile approach for the accommodation of both single and sequential extraction schemes for metal fractionation of solid samples of environmental concern. Coupled to flame atomic absorption spectrometric detection and used for the determination of Cu as a model analyte, the potentials of this novel hyphenated approach are demonstrated by the ability of handling up to a 300 mg sample of a nonhomogeneous sewage amended soil (viz., CRM 483). The three steps of the endorsed Standards, Measurements, and Testing sequential extraction method have been also performed in a dynamic fashion and critically compared with the conventional batchwise protocols. The ecotoxicological relevance of the data provided by both methods with different operationally defined conditions is thoroughly discussed. As compared to traditional batch systems, the developed SI assembly offers minimal risks of sample contamination, the absence of metal re-distribution/readsorption, and dramatic saving of operational times (from 16 h to 40-80 min per partitioning step). It readily facilitates the accurate manipulation of the extracting reagents into the flow network and the minute, well-defined injection of the desired leachate volume into the detector. Moreover, highly time-resolved information on the ongoing extraction is given, which is particularly relevant for monitoring fast leaching kinetics, such as those involving strong chelating agents. On-line and off-line (for Cu, Pb, and Zn) single extraction schemes are also proven to constitute attractive alternatives for fast screening of metal pollution in solid samples and for predicting the current, rather than the potential, element bioavailability by the assessment of the readily mobilizable metal forms.


A new algorithm for reliable and general NMR resonance assignment.
The new FLYA automated resonance assignment algorithm determines NMR chemical shift assignments on the basis of peak lists from any combination of multidimensional through-bond or through-space NMR experiments for proteins. Backbone and side-chain assignments can be determined. All experimental data are used simultaneously, thereby exploiting optimally the redundancy present in the input peak lists and circumventing potential pitfalls of assignment strategies in which results obtained in a given step remain fixed input data for subsequent steps. Instead of prescribing a specific assignment strategy, the FLYA resonance assignment algorithm requires only experimental peak lists and the primary structure of the protein, from which the peaks expected in a given spectrum can be generated by applying a set of rules, defined in a straightforward way by specifying through-bond or through-space magnetization transfer pathways. The algorithm determines the resonance assignment by finding an optimal mapping between the set of expected peaks that are assigned by definition but have unknown positions and the set of measured peaks in the input peak lists that are initially unassigned but have a known position in the spectrum. Using peak lists obtained by purely automated peak picking from the experimental spectra of three proteins, FLYA assigned correctly 96-99% of the backbone and 90-91% of all resonances that could be assigned manually. Systematic studies quantified the impact of various factors on the assignment accuracy, namely the extent of missing real peaks and the amount of additional artifact peaks in the input peak lists, as well as the accuracy of the peak positions. Comparing the resonance assignments from FLYA with those obtained from two other existing algorithms showed that using identical experimental input data these other algorithms yielded significantly (40-142%) more erroneous assignments than FLYA. The FLYA resonance assignment algorithm thus has the reliability and flexibility to replace most manual and semi-automatic assignment procedures for NMR studies of proteins.


Biogeographic patterns of aerobic anoxygenic phototrophic bacteria reveal an ecological consistency of phylogenetic clades in different oceanic biomes.
In marine environments, aerobic anoxygenic phototrophic (AAP) bacterial assemblages vary in space and along environmental gradients but the factors shaping their diversity and distribution at different taxonomic levels remain poorly identified. Using sets of sequences encoding the M sub-unit of the photosynthetic apparatus from different oceanic regions, we prioritized the processes underlying AAP bacterial biogeographical patterns. The present analysis offers novel insights into the ecological distribution of marine AAP bacteria and highlights that physiological constraints play a key role in structuring AAP bacterial assemblages at a global scale. Salinity especially seems to favor lineage-specific adaptations. Moreover, by inferring the evolutionary history of habitat transitions, a substantial congruence between habitat and evolutionary relatedness was highlighted. The identification of ecological cohesive clades for AAP bacteria suggests that prediction of AAP bacterial assemblages is possible from marine habitat properties.


repE--the Dictyostelium homolog of the human xeroderma pigmentosum group E gene is developmentally regulated and contains a leucine zipper motif.
We have cloned and characterized the Dictyostelium discoideum repE gene, a homolog of the human xeroderma pigmentosum (XP) group E gene which encodes a UV-damaged DNA binding protein. The repE gene maps to chromosome 4 and it is the first gene identified in Dictyostelium that is homologous to those involved in nucleotide excision repair and their related XP diseases in humans. The predicted protein encodes a leucine zipper motif. The repE gene is not expressed by mitotically dividing cells, and repE mRNA is first detected during the aggregation phase of development when the cells have ceased dividing and replicating genomic DNA. The mRNA level plateaus by the time the developing cells have entered multicellular aggregates and remains at the same steady-state level for the remainder of development. In addition, we have demonstrated that the level of mRNA is very low in developing cells. These observations suggest that repE may play a regulatory role in development. The data indicate that potential developmental roles for XP-related genes can be profitably studied in this system.


Perceived barriers to mental health service utilization in the United States, Ontario, and the Netherlands.
Although rates of mental health service utilization differ dramatically across countries, little information is available about differences in self-reported barriers to mental health service utilization. Perceived barriers were examined in three locations with differing health care systems. Data came from three methodologically similar population-based surveys of adults conducted in the 1990s in Ontario, Canada (N=6,261), the United States (N=5,384), and the Netherlands (N=6,031) that assessed DSM-III-R nonpsychotic mental disorders with the Composite International Diagnostic Interview. Respondents who reported a need for professional help were asked to indicate reasons for not seeking care. Multiple logistic regression analyses were used to determine the sociodemographic, mental disorder, and location-specific correlates of each perceived barrier. The pattern of reported barriers to mental health service utilization was similar across locations: attitudinal barriers (thoughts that the problem would get better on its own) were more prevalent than structural barriers (inability to get an appointment). Fear of stigmatization was not commonly endorsed. With adjustment for sociodemographic factors and type of mental disorder, low-income respondents were significantly more likely to report a financial barrier in the United States than in either Ontario or the Netherlands. Across locations, attitudinal barriers were more likely to be endorsed than structural barriers to service utilization. The most striking reported cross-national difference was structural, with many more U.S. respondents (especially those with low incomes) reporting financial barriers than respondents in either Ontario or the Netherlands.


Toward Accurate Visual Reasoning With Dual-Path Neural Module Networks.
Visual reasoning is a critical stage in visual question answering (Antol et al., 2015), but most of the state-of-the-art methods categorized the VQA tasks as a classification problem without taking the reasoning process into account. Various approaches are proposed to solve this multi-modal task that requires both abilities of comprehension and reasoning. The recently proposed neural module network (Andreas et al., 2016b), which assembles the model with a few primitive modules, is capable of performing a spatial or arithmetical reasoning over the input image to answer the questions. Nevertheless, its performance is not satisfying especially in the real-world datasets (e.g., VQA 1.0& 2.0) due to its limited primitive modules and suboptimal layout. To address these issues, we propose a novel method of Dual-Path Neural Module Network which can implement complex visual reasoning by forming a more flexible layout regularized by the pairwise loss. Specifically, we first use the region proposal network to generate both visual and spatial information, which helps it perform spatial reasoning. Then, we advocate to process a pair of different images along with the same question simultaneously, named as a "complementary pair," which encourages the model to learn a more reasonable layout by suppressing the overfitting to the language priors. The model can jointly learn the parameters in the primitive module and the layout generation policy, which is further boosted by introducing a novel pairwise reward. Extensive experiments show that our approach significantly improves the performance of neural module networks especially on the real-world datasets.


Efficient Production of Acid-Form Sophorolipids from Waste Glycerol and Fatty Acid Methyl Esters by Candida floricola.
We discovered that Candida floricola ZM1502 is capable of selectively producing the promising hydrophilic biosurfactants, acid-form sophorolipids (SLs), from glycerol. However, productivity was very low (approximately 3.5 g L-1) under the initial culture conditions. Here, we describe the design of culture medium for abundant production of acid-form SLs by C. floricola ZM1502 using waste glycerol and hydrophobic substrates in order to develop a method for SL production and disposal of waste glycerol produced by oleo-chemical industries. Urea provided the best nitrogen source for acid-form SL production from glycerol among four nitrogen sources tested [urea, NaNO3, NH4NO3, and (NH4)2SO4]. Among carbon sources we compared, hydrophobic substrates (soybean oil and oleic acid) led to productivities of approximately 20 g L-1, indicating that hydrophobic substrates provided fatty acid moieties for SL production. Addition of olive oil and oleic acid to waste glycerol enhanced acid-form SL production to 42.1 ± 0.9 and 37.5 ± 3.4 g L-1, respectively. To develop a potential industrial process, we explored other suitable hydrophobic substrates for SL production, which were obtained on site from oleo-chemical industries. Alkyl C18 esters (Pastell M-182), along with waste glycerol, increased acid-form SL production to 48.0 ± 3.4 g L-1 over a 7-d period. Furthermore, we demonstrated abundant production of acidic SLs at the mini-jar fermenter scale, obtaining 169 g L-1 over 180 h using a fed-batch cultivation technique. Efficient acid-form SL production by C. floricola could have a great impact on the development of bio-industrial processes using waste glycerol as a substrate.


Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.
Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder. On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE). The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model. The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro. Smoking-induced global distal-to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs.


Brief Report: Does Most Mortality in Patients on ART Occur in Care or After Lost to Follow-Up? Evidence From the Themba Lethu Clinic, South Africa.
In resource-limited settings, early mortality on antiretroviral therapy (ART) is approximately 10%; yet, it is unclear how much of that mortality occurs in care or after lost to follow-up. We assessed mortality rates and predictors of death among 12,222 nonpregnant ART-naive adults initiating first-line ART between April 2004 and May 2012 in South Africa, stratified by person-years in care and lost. We found 14.6% of patients died and being lost accounted for a minority of deaths across multiple definitions of loss (population attributable-risk percent ranged from 10.4% to 42.5%). Although mortality rates in patients lost were much higher than in care, most ART-related mortality occurred on treatment.


A Forehead Wearable Sensor for the Objective Measurement of Chronic Pain.
Chronic pain impacts one in five Americans and is difficult to manage, costing ~USD 600 billion annually. The subjective experience of pain is a complex processing of central nervous system input. Recent advances in magnetic resonance imaging revealed the prefrontal cortex as vital to the perception of pain and that changes in the cerebral hemodynamics can be used to detect painful sensations. Current pain monitoring is dependent on the subjective rating provided by patients and is limited to a single time point. We have developed a biomarker for the objective, real-time and continuous chronic pain assessment using proprietary algorithms termed ROPA and cerebral optical spectrometry. Using a forehead sensor, the cerebral optical spectrometry data were collected in two clinical sites from 41 patients (19 and 22, respectively, from sites 1 and 2), who elected to receive an epidural steroid injection for the treatment of chronic pain. Patients rated their pain on a numeric rating scale, ranging from 0-10, which were used to validate the ROPA objective pain scoring. Multiple time points, including pre- and post-procedure were recorded. The steroid injection was performed per standard medical practice. There was a significant correlation between the patient's reported numeric rating scale and ROPA, for both clinical sites (Overall ~0.81). Holding the subjective pain ratings on a numeric rating scale as ground truth, we determined that the area under the receiver operator curves for both sites revealed at least good (AUC: 64%) to excellent (AUC > 98%) distinctions between clinically meaningful pain severity differentiations (no/mild/moderate/severe). The objective measure of chronic pain (ROPA) determined using cerebral optical spectrometry significantly correlated with the subjective pain scores reported by the subjects. This technology may provide a useful method of detection for the objective and continuous monitoring and treatment of patients with chronic pain, particularly in clinical circumstances where direct assessment is not available, or to complement the patient-reported pain scores.


Current situation of fire blight in China.
Fire blight, caused by the plant pathogenic bacterium Erwinia amylovora, is a devastating disease that occurs on rosaceous plants, including pears and apples, etc. E. amylovora is indigenous to North America and was spread to the Eurasian continent in the second half of the 20th century through contaminated plant materials. In 2016, fire blight was first observed in Yili, Xinjiang Province in Northwestern China. Since then, it has spread to most pear-producing regions in Xinjiang Province and parts of Gansu Province. The disease has caused severe damage to China's pear and apple industries, including the 2017 disease epidemic in Korla, Xinjiang, which caused an overall yield reduction of 30%~50% in Korla and the destruction of over one million pear trees. Over the past few years, a combined effort of research, extension, and education by the Chinese government, scientists and fruit growers has greatly alleviated outbreaks and epidemics in affected regions, while successfully limiting the further spread of fire blight to new geographical regions. Here, we review the occurrence, spread, and damage of this disease to the Chinese fruit industry, the management options used in China and their outcomes. We also discuss future perspectives for restraining the spread and alleviating the damage of fire blight in China.


Implications for mantle dynamics from the high melting temperature of perovskite.
Recent studies have implied that (Mg, Fe)SiO(3)-perovskite, a likely dominant mineral phase in the lower mantle, may have a high melting temperature. The implications of these findings for the dynamics of the lower mantle were investigated with the use of numerical convection models. The results showed that low homologous temperatures (0.3 to 0.5) would prevail in the modeled lower mantle, regardless of the effective Rayleigh number and internal heating rates. High-temperature ductile creep is possible under relatively cold conditions. In models with low rates of internal heating, local maxima of viscosity developed in the mid-lower mantle that were similar to those obtained from inversion of geoid, topography, and plate velocities.


Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury.
Although recent preclinical and clinical studies have demonstrated that recombinant human relaxin (rhRLX) may have important therapeutic potential in acute heart failure and chronic kidney diseases, the effects of acute rhRLX administration against renal ischaemia/reperfusion (I/R) injury have never been investigated. Using a rat model of 1-hr bilateral renal artery occlusion followed by 6-hr reperfusion, we investigated the effects of rhRLX (5 μg/Kg i.v.) given both at the beginning and after 3 hrs of reperfusion. Acute rhRLX administration attenuated the functional renal injury (increase in serum urea and creatinine), glomerular dysfunction (decrease in creatinine clearance) and tubular dysfunction (increase in urinary excretion of N-acetyl-β-glucosaminidase) evoked by renal I/R. These beneficial effects were accompanied by a significant reduction in local lipid peroxidation, free radical-induced DNA damage and increase in the expression/activity of the endogenous antioxidant enzymes Mn- and CuZn-superoxide dismutases (SOD). Furthermore, rhRLX administration attenuated the increase in leucocyte activation, as suggested by inhibition of myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, interleukin (IL)-1β, IL-18 and tumour necrosis factor-α production as well as increase in IL-10 production. Interestingly, the reduced oxidative stress status and neutrophil activation here reported were associated with rhRLX-induced activation of endothelial nitric oxide synthase and up-regulation of inducible nitric oxide synthase, possibly secondary to activation of Akt and the extracellular signal-regulated protein kinase (ERK) 1/2, respectively. Thus, we report herein that rhRLX protects the kidney against I/R injury by a mechanism that involves changes in nitric oxide signalling pathway.


Tumors of the small intestine.
An analysis of 80 cases of malignant and benign tumors of the small intestine is presented, and major clinical features of various histologic lesions are discussed. Tumors of the small intestine are rare, and the small bowel may have intrinsic protective systems against the development of neoplasms. Gastrointestinal bleeding and symptoms of intermittent obstruction are prominent findings in patients with symptomatic benign tumors, although many benign tumors are incidental findings at operation for an unrelated disease. Benign lesions should be removed by local excision. Virtually all malignant tumors are symptomatic with abdominal pain, nausea and vomiting, anorexia and weight loss, and gastrointestinal bleeding being common findings. Earlier diagnosis is essential if the prognosis for patients with small intestinal malignancies is to be improved. A high degree of suspicion must be aroused with any vague, nonspecific gastrointestinal complaints in patients over 40 years of age. Exploratory celiotomy should be performed in symptomatic patients even though no abnormality may be detected on roentgenographic examination.


Novel SARS-CoV-2 encoded small RNAs in the passage to humans.
The Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) has recently emerged as the responsible for the pandemic outbreak of the coronavirus disease 2019. This virus is closely related to coronaviruses infecting bats and Malayan pangolins, species suspected to be an intermediate host in the passage to humans. Several genomic mutations affecting viral proteins have been identified, contributing to the understanding of the recent animal-to-human transmission. However, the capacity of SARS-CoV-2 to encode functional putative microRNAs (miRNAs) remains largely unexplored. We have used deep learning to discover 12 candidate stem-loop structures hidden in the viral protein-coding genome. Among the precursors, the expression of eight mature miRNAs-like sequences was confirmed in small RNA-seq data from SARS-CoV-2 infected human cells. Predicted miRNAs are likely to target a subset of human genes of which 109 are transcriptionally deregulated upon infection. Remarkably, 28 of those genes potentially targeted by SARS-CoV-2 miRNAs are down-regulated in infected human cells. Interestingly, most of them have been related to respiratory diseases and viral infection, including several afflictions previously associated with SARS-CoV-1 and SARS-CoV-2. The comparison of SARS-CoV-2 pre-miRNA sequences with those from bat and pangolin coronaviruses suggests that single nucleotide mutations could have helped its progenitors jumping inter-species boundaries, allowing the gain of novel mature miRNAs targeting human mRNAs. Our results suggest that the recent acquisition of novel miRNAs-like sequences in the SARS-CoV-2 genome may have contributed to modulate the transcriptional reprograming of the new host upon infection. https://github.com/sinc-lab/sarscov2-mirna-discovery. Supplementary data are available at Bioinformatics online.


[Breast cancer risk through assessment tool of breast cancer risk].
A predictive model of breast cancer risk is the Breast Cancer Risk Assessment Tool (BCRAT), designed by scientists at the National Cancer Institute. The objective was to determine the risk of breast cancer (BC) through the BCRAT. A descriptive, prospective, observational study was done. We included 300 women over 35 years of age to whom we applied the BCRAT. We excluded women previously diagnosed with BC. The predominant age range was 35-45 years with 43.3 %; married 79.3 % and 56.3 % housewives; the respondents were Hispanic population. The statistical analysis showed significant age over 50 years and family background as major risk factors, respectively (OR = 5.06, p = 0.02, OR = 27.75, p = 0.000). Previous breast biopsy increases the risk (OR = 5.3, p = 0.009). According to the literature, the results obtained showed that sex, age over 50 years; family history and a previous conducted breast biopsy are the most important risk factors. According to the BCRAT risk was determined by averaging 0.6 probabilities to develop BC at five years in women over 35 years.


Effects of calcium phosphate nanocrystals on osseointegration of titanium implant in irradiated bone.
Radiotherapy may compromise the integration of implant and cause implant loss. Implant surface modifications have the possibility of promoting cell attachment, cell growth, and bone formation which ultimately enhance the osseointegration process. The present study aimed to investigate the effects of calcium phosphate nanocrystals on implant osseointegration in irradiated bone. Sixteen rabbits were randomly assigned into control and nano-CaP groups, receiving implants with dual acid-etched surface or dual acid-etched surface discretely deposited of nanoscale calcium-phosphate crystals, respectively. The left leg of all the rabbits received 15 Gy radiation, followed by implants placement one week after. Four animals in each group were sacrificed after 4 and 12 weeks, respectively. Implant stability quotient (ISQ), ratio of bone volume to total volume (BV/TV), bone growth rate, and bone-to-implant contact (BIC) were evaluated. The nano-CaP group showed significantly higher ISQ (week 12, P = 0.031) and bone growth rate (week 6, P = 0.021; week 9, P = 0.001) than that in control group. No significant differences in BV/TV and BIC were found between two groups. Titanium implant surface modified with CaP nanocrystals provides a potential alternative to improve bone healing around implant in irradiated bone.


Genetic linkage study of high-grade myopia in a Hutterite population from South Dakota.
Myopia is a common, complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and macular degeneration. Autosomal dominant (AD) non-syndromic high-grade myopia has been mapped to chromosomes 18p11.31, 12q21-23, 17q21-23, 7q36, 2q37.1, 7p15.3, 15q12-13, 3q26, 4q12, 8p23, 4q22-q27, 1p36, and Xq23-q25. Here, we demonstrate evidence of linkage for AD non-syndromic high-grade myopia in a large Hutterite family to a locus on chromosome 10q21.1. After clinical evaluation, genomic DNA was genotyped from 29 members of a Hutterite family from South Dakota (7 affected). The average refractive error of affected individuals was -7.04 diopters. Microsatellite markers were used to exclude linkage to the known AD nonsyndromic high-grade myopia loci as well as to syndromic high-grade myopia loci. A genome screen was then performed using 382 markers with an average inter-marker distance of 10 cM followed by fine-point mapping in all regions of the genome that gave positive LOD scores. SimWalk2 software was used for multipoint linkage based on AD and autosomal recessive (AR) models with a penetrance of 90% and a disease allele frequency of 0.001. A maximum multipoint LOD score of 3.22 was achieved under an AD model at microsatellite marker D10S1643. Fine point mapping and haplotype analysis defined a critical region of 2.67 cM on chromosome 10q21.1. Haplotype analysis demonstrated two distinct haplotypes segregating with high-grade myopia, indicative of two distinct mutations occurring in the same gene. We have identified a presumptive myopia locus for high-grade myopia based on linkage and haplotype analysis.


Endoscopic diagnosis and treatment of calcifying fibrous tumors.
The calcifying fibrous tumor (CFT) is classified as a benign fibrous lesion, and it is a rare pathologic entity. We evaluated the feasibility, efficacy and safety of endoscopy treatment for CFT. We retrospectively analyzed a total of 4 gastric CFTs that were treated with ESD or EFR at the endoscopic center of Zhongshan Hospital, Fudan University, in Shanghai, between Jan 2007 and Sept 2011. We used endoscopic ultrasound (EUS) to assess whether endoscopy treatment was suitable. Tumor characteristics, complications, the en bloc resection rate, and the local recurrence rate were evaluated. Of the 4 patients, the median age was 55.5 years old. The mean maximum size of the lesions was 1.95±0.67 (range: 1.0-2.5). The EUS features of the lesions included a mass in the muscularis propria of the gastric wall and a heterogeneous hypoechoic (1/4) or homogeneous (3/4) hypoechoic pattern. All of the endoscopic treatments were completed successfully. The en bloc resection rate was 100%. Confirmed diagnoses were made by pathologic results. No local recurrence or complications were observed during the follow-up period (ranging from 15 to 28 months). Endoscopic treatment, especially ESD/EFR, appears to be a feasible and safe procedure for CFT with relatively few complications and low mortality.


Preoperative intra-aortic balloon pump in patients undergoing coronary bypass surgery: a systematic review and meta-analysis.
To assess the effectiveness of preoperative intra-aortic balloon pump (IABP) placement in high-risk patients undergoing coronary bypass surgery (CABG). The primary outcome was hospital mortality and secondary outcomes were IABP-related complications (bleeding, leg ischemia, aortic dissection). MEDLINE, EMBASE, Cochrane registry of Controlled Trials, and reference lists of relevant articles were searched. We included randomized controlled trials (RCTs), and cohort studies that fulfilled our a priori inclusion criteria. Eligibility decisions, relevance, study validity, and data extraction were performed in duplicate using pre-specified criteria. Meta-analysis was conducted using a random effects model. Ten publications fulfilled our eligibility criteria, of which four were RCTs and six were cohort studies with controls. There were statistical as well as clinical heterogeneity among included studies. A total of 1034 patients received preoperative IABP and 1329 did not receive preoperative IABP. The pooled odds ratio (OR) for hospital mortality in patients treated with preoperative IABP was 0.41 (95% CI, 0.21-0.82, p = 0.01). The number needed to treat was 17. The pooled OR for hospital mortality from randomized trials was 0.18 (95% CI, 0.06-0.57, p = 0.003) and from cohort studies was 0.54 (95% CI, 0.24-1.2, p = 0.13). Overall, 3.7% (13 of 349) of patients who received preoperative IABP developed either limb ischemia or haematoma at the IABP insertion site, and most of these complications improved after discontinuation of IABP. Evidence from this meta-analysis support the use of preoperative IABP in high-risk patients to reduce hospital mortality.


MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2.
Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.


Enzyme design from the bottom up: an active nickel electrocatalyst with a structured peptide outer coordination sphere.
Catalytic, peptide-containing metal complexes with a well-defined peptide structure have the potential to enhance molecular catalysts through an enzyme-like outer coordination sphere. Here, we report the synthesis and characterization of an active, peptide-based metal complex built upon the well-characterized hydrogen production catalyst [Ni(P(Ph)2N(Ph))2](2+) (P(Ph)2N(Ph)=1,3,6-triphenyl-1-aza-3,6-diphosphacycloheptane). The incorporated peptide maintains its β-hairpin structure when appended to the metal core, and the electrocatalytic activity of the peptide-based metal complex (≈100,000 s(-1)) is enhanced compared to the parent complex ([Ni(P(Ph)2N(APPA))2](2+); ≈50,500 s(-1)). The combination of an active molecular catalyst with a structured peptide provides a scaffold that permits the incorporation of features of an enzyme-like outer-coordination sphere necessary to create molecular electrocatalysts with enhanced functionality.


In vivo tracking of orally-administered particles within the gastrointestinal tract of murine models using multispectral optoacoustic tomography.
While particle carriers have potential to revolutionize disease treatment, using these carriers requires knowledge of spatial and temporal biodistribution. The goal of this study was to track orally administered particle uptake and trafficking through the murine gastrointestinal (GI) tract using multispectral optoacoustic tomography (MSOT). Polylactic acid (PLA) particles encapsulating AlexaFluor 680 (AF680) dye conjugated to bovine serum albumin (BSA) were orally gavaged into mice. Particle uptake and trafficking were observed using MSOT imaging with subsequent confirmation of particle uptake via fluorescent microscopy. Mice treated with PLA-AF680-BSA particles exhibited MSOT signal within the small bowel wall at 1 and 6 h, colon wall at 6, 12, and 24 h, and mesenteric lymph node 24 and 48 h. Particle localization identified using MSOT correlated with fluorescence microscopy. Despite the potential of GI tract motion artifacts, MSOT allowed for teal-time tracking of particles within the GI tract in a non-invasive and real-time manner. Future use of MSOT in conjunction with particles containing both protein-conjugated fluorophores as well as therapeutic agents could allow for non-invasive, real time tracking of particle uptake and drug delivery.


Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis.
Lactoferrin (LF) is a multifunctional glycoprotein that can regulate lipid metabolism, lower cholesterol, reduce body weight, and prevent atherosclerosis. Bile acid (BA) metabolism plays an important role in removing excess cholesterol from the body. However, studies on the effects of LF on BA metabolism are limited and inconsistent. Male C57BL/6J mice aged 6-8 weeks were fed with a normal diet (control group), high-fat/high-cholesterol diet containing cholate (HFCCD group), or HFCCD and 1.0% LF in drinking water (LF group) for 8 weeks. Serum and hepatic lipid profiles, and glucose tolerance were measured. Fecal BA composition was determined through ultra-high performance liquid chromatography-tandem mass spectrometry. The gene expression of BA synthase in the liver and farnesoid X receptor (FXR)-mediated BA negative feedback regulation pathway in the liver and ileum were analyzed via RNA analysis. HFCCD resulted in abnormal cholesterol levels in the serum and liver. LF intervention significantly increased the serum high-density lipoprotein cholesterol level by 24.9% and decreased the hepatic total cholesterol content by 26%. LF treatment significantly increased the BA content per gram by 109.8%, the total amount of BA excretion by 153.5% and conjugated BAs by 87.6% in the feces. Furthermore, LF upregulated the expression of the hepatic sterol 12α-hydroxylase (CYP8B1) gene, which expresses important enzymes in the classical pathway of BA synthesis, and the bile acid-CoA amino acid N-acetyltransferase (BAAT) gene, which is responsible for the formation of conjugated BAs. The FXR-mediated pathways in the enterohepatic axis, including FXR, fibroblast growth factor 15, and fibroblast growth factor receptor 4, were inhibited by LF. LF ameliorated hepatic cholesterol deposition in mice fed with a high-fat and high cholesterol diet containing cholate. LF elevated the conjugated BA level, inhibited the ileum FXR and FXR-mediated enterohepatic axis, and increased BA synthesis and excretion.


Elastic matching of line drawings.
Recently a dynamic elastic model [1] was proposed for automatic image matching. Examples were shown applying the model to dot patterns and gray scale pictures. This paper extends the model to line drawings. Examples are shown on handprint and animation, suggesting the use of dynamic matching for shape recognition and for motion correspondence.


Functional genomic mRNA profiling of a large cancer data base demonstrates mesothelin overexpression in a broad range of tumor types.
The membrane bound glycoprotein mesothelin (MSLN) is a highly specific tumor marker, which is currently exploited as target for drugs. There are only limited data available on MSLN expression by human tumors. Therefore we determined overexpression of MSLN across different tumor types with Functional Genomic mRNA (FGM) profiling of a large cancer database. Results were compared with data in articles reporting immunohistochemical (IHC) MSLN tumor expression. FGM profiling is a technique that allows prediction of biologically relevant overexpression of proteins from a robust data set of mRNA microarrays. This technique was used in a database comprising 19,746 tumors to identify for 41 tumor types the percentage of samples with an overexpression of MSLN compared to a normal background. A literature search was performed to compare the FGM profiling data with studies reporting IHC MSLN tumor expression. FGM profiling showed MSLN overexpression in gastrointestinal (12-36%) and gynecological tumors (20-66%), non-small cell lung cancer (21%) and synovial sarcomas (30%). The overexpression found in thyroid cancers (5%) and renal cell cancers (10%) was not yet reported with IHC analyses. We observed that MSLN amplification rate within esophageal cancer depends on the histotype (31% for adenocarcinomas versus 3% for squamous-cell carcinomas). Subset analysis in breast cancer showed MSLN amplification rates of 28% in triple-negative breast cancer (TNBC) and 33% in basal-like breast cancer. Further subtype analysis of TNBCs showed the highest amplification rate (42%) in the basal-like 1 subtype and the lowest amplification rate (9%) in the luminal androgen receptor subtype.


Ascorbic acid does not enhance hypoxia-induced vasodilation in healthy older men.
In response to hypoxia, a net vasodilation occurs in the limb vasculature in young healthy humans and this is referred to as "hypoxia-induced vasodilation". We performed two separate experiments to determine (1) if hypoxia-induced forearm vasodilation is impaired in older men (n = 8) compared to young men (n = 7) and (2) if acute systemic infusion of ascorbic acid would enhance hypoxia-induced vasodilation in older men (n = 8). Heart rate, mean arterial pressure, oxygen saturation, minute ventilation, forearm vascular conductance (FVC, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were recorded continuously while subjects breathed 10% oxygen for 5 min. Changes from baseline were compared between groups and between treatments. The older adults had a significantly attenuated increase in FBF (13 ± 4 vs. 30 ± 7%) and FVC (16 ± 4 vs. 30 ± 7%) in response to 5 min of hypoxia. However, skin blood flow responses were comparable between groups (young: 35 ± 9, older: 30 ± 6%). In Experiment 2, FVC responses to 5 min of breathing 10% oxygen were not significantly different following saline (3 ± 10%) and ascorbic acid (8 ± 10%) in the older men. Ascorbic acid also had no physiological effects in the young men. These findings advance our basic understanding of how aging influences vascular responses to hypoxia and suggest that, in healthy humans, hypoxia-induced vasodilation is not restrained by reactive oxygen species.


Colloidal crystal films: advances in universality and perfection.
For three-dimensional photonic crystals, made either by top-down microfabrication or by bottom-up self-assembly approaches, to comply with the stringent requirements of optical telecommunication applications, their degree of structural perfection and optical quality must meet an exceptionally high standard. Only with such superior quality photonic crystals can their unique optical properties be harnessed in optical devices and circuits constructed from micrometer-sized optical components. In this paper, we present a new strategy for making silica colloidal crystal films with a sufficiently high level of structural perfection and optical quality to make it competitive as a practical route to photonic crystal optical components. The attainment of this goal takes due cognizance of three key synergistic factors in the film formation process. The first recognizes the necessity to prepare high-quality silica spheres, which are highly monodisperse, with a polydispersity index significantly better than 2%, and the second recognizes that the population of spheres must be devoid of even the smallest fraction of substantially smaller or larger spheres or sphere doublets. The latter turns out to have a minimal effect on the polydispersity index, and yet a major detrimental effect on the overall structural order of the film. The third concerns the film-forming method itself, which necessitated the development of a novel process founded upon isothermal heating evaporation-induced self-assembly (IHEISA) of spheres on a planar substrate. This new method has several advantages over previously reported ones. It is able to deposit very high-quality silica colloidal crystal film rapidly over large areas, with a controlled thickness and without any restrictions on sphere sizes.


Chemistry and toxicology of quinoxaline, organotin, organofluorine, and formamidine acaricides.
Quinoxaline, organotin, organofluorine, and formamidine compounds are among the newer pesticide chemicals used for acarine control. Included in these four classes are some of the most selective synthetic organic toxicants currently in the acaricide/insecticide arsenal. Oxythioquinox, Plictran (tricyclohexylhydroxytin), Nissol [2-fluoro-N-methyl-N-(1-naphthyl)acetamide], and chlordimeform are examples of quinoxaline, organotin, organofluorine, and formamidine acaricides, respectively. The chemistry and toxicology of these and related compounds are discussed.


Safety and efficacy of chimeric yellow Fever-dengue virus tetravalent vaccine formulations in nonhuman primates.
To construct chimeric YF/DEN viruses (ChimeriVax-DEN), the premembrane (prM) and envelope (E) genes of yellow fever (YF) 17D virus were replaced with those of each wild-type (WT) dengue (DEN) virus representing serotypes 1 to 4. ChimeriVax-DEN1-4 vaccine viruses were prepared by electroporation of Vero cells with RNA transcripts prepared from viral cDNA (F. Guirakhoo, J. Arroyo, K. V. Pugachev, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Soike, M. Ratteree, and T. P. Monath, J. Virol. 75:7290-7304, 2001; F. Guirakhoo, K. Pugachev, J. Arroyo, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Draper, and T. P. Monath, Virology 298:146-159, 2002). Progeny viruses were subjected to three rounds of plaque purifications to produce the Pre-Master Seed viruses at passage 7 (P7). Three further passages were carried out using U.S. current Good Manufacturing Practices (cGMP) to produce the Vaccine Lot (P10) viruses. Preclinical studies demonstrated that the vaccine candidates are replication competent and genetically stable and do not become more neurovirulent upon 20 passages in Vero cells. The safety of a tetravalent vaccine was determined and compared to that of YF-VAX in a formal monkey neurovirulence test. Brain lesions produced by the tetravalent ChimeriVax-DEN vaccine were significantly less severe than those observed with YF-VAX. The immunogenicity and protective efficacy of four different tetravalent formulations were evaluated in cynomolgus monkeys following a single-dose subcutaneous vaccination followed by a virulent virus challenge 6 months later. All monkeys developed low levels of viremia postimmunization, and all the monkeys that had received equal concentrations of either a high-dose (5,5,5,5) or a low-dose (3,3,3,3) formulation seroconverted against all four DEN virus serotypes. Twenty-two (92%) of 24 monkeys were protected as determined by lack of viremia post-challenge. This report is the first to demonstrate the safety of a recombinant DEN virus tetravalent vaccine in a formal neurovirulence test, as well as its protective efficacy in a monkey challenge model.


Telomeres and telomerase in stem cells during aging and disease.
Cell cycle checkpoints induced by telomere dysfunction represent one of the major in vivo tumor suppressor mechanisms preventing cancer but at the same time provoking age dependent decline in self-renewal and regeneration of tissues and organs. On the other hand, telomere shortening contributes to the initiation of cancer by inducing chromosomal instability. Telomere function and telomerase activity are mainly associated with actively proliferating cells. Since stem cells are continuously proliferating throughout lifetime, it is of great interest to explore the role of telomeres and telomerase in stem cells. Although most stem cell compartments express telomerase, the level of telomerase activity is not sufficient to maintain telomere length of stem cells during aging. Stem cells appear to have tighter DNAdamage checkpoint control in comparison to somatic cells, which may reflect the need to protect this long lasting cell compartment against malignant transformation. These enhanced checkpoint responses may have a detrimental impact on stem cell function, by causing increased sensitivity towards senescence or apoptosis induced by telomere shortening. This review summarizes our knowledge on telomere dynamics and its functional impact on stem cells during aging and transformation.


Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202.
Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202. RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system. On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index < or = 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort. Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.


Bacterial β-glucosidase function and metabolic activity depend on soil management in semiarid rainfed agriculture.
Genomic and transcriptomic approaches were used to gain insights into the relationship between soil management and bacterial-mediated functions in an olive orchard agroecosystem. Four management practices were assessed in a 30-year trial in a semiarid Mediterranean region. Transcriptional activity of bacterial 16S rRNA genes increased in noncovered soils, indicating higher microbial maintenance requirements to thrive in less favorable environmental conditions. The 16S rRNA transcript:gene copy ratio confirmed this assumption and pointed toward a much higher constitutive expression from rRNA operons in noncovered soils and to even higher expression levels when spontaneous vegetation was removed chemically. As described for 16S rRNA, potential transcription did not reveal the real transcription of bacterial β-glucosidase genes, and higher gene expression in noncovered soils plus herbicides was evidenced. Since no relationship between total or soluble organic carbon and bacterial β-glucosidase transcription was found, the above hypothesis could indicate either that soluble organic carbon is not the main pool of enzyme-inducing substrates or that constitutive production of bacterial β-glucosidase enzymes increases as soil conditions worsen.


Diastolic "locking" of the mitral valve: the importance of atrial systole and intraventricular volume.
Diastolic mitral valve "locking," defined as sustained diastolic closure of the mitral valve after atrial systole, was investigated by simultaneous hemodynamic and echocardiographic recordings during a protocol of programmed pacing in six dogs with surgically induced atrioventricular block. Atrial extrasystoles were introduced at progressively increasing coupling intervals during programmed prolonged pauses in ventricular pacing. As the coupling interval of the atrial extrasystole was increased, both the mitral reopening time (MRT) and the calculated left ventricular volume (LVV) at the end of the MRT increased proportionally. These interrelations could be best expressed by a general logarithmic function of the form y = a + b ln (x), where x = the coupling interval of the atrial extrasystole and y = the MRT or the LVV. Correlations between the measured data and the predicted data were excellent (r greater than or equal to 0.95). In each dog, a specific LVV had to be attained to allow a diastolic "locking" of the mitral valve. Atrial standstill and atrial fibrillation were also induced in each dog to study the relative role of atrial systole in locking of the mitral valve. During either atrial standstill or atrial fibrillation, the mitral valve closed transiently, but did not lock, despite the accumulation of a LVV larger than the LVV necessary to lock the valve during sinus rhythm. Thus, diastolic locking of the mitral valve has several determinants, including the presence of active atrial systole and the accumulation of a sufficient intraventricular volume.


Cure of mice infected with Trypanosoma rhodesiense by cis-diamminedichloroplatinum (II) and disulfiram rescue.
Mice infected with Trypanosoma rhodesiense were treatment concurrently with cis-diamminedichloroplatinum (II) (DDP), disulfiram, and hydration. Most of the mice (92.5 percent) were cured; inoculation of blood or suspensions of brain or heart from these animals did not produce disease in recipient mice. The dose of DDP needed to eliminate the trypanosomes, 3 milligrams per kilogram of body weight per day for 7 days, was lethally toxic unless the animals received disulfiram orally and subcutaneous injections of physiologic saline, which reduced the acute renal necrosis caused by DDP alone. Some mild to moderate reversible renal damage was noted upon pathologic examination of the treated mice.


Molecular Dynamics Simulations of Bimolecular Electron Transfer: the Distance-Dependent Electronic Coupling.
Understanding the distance dependence of the parameters underpinning Marcus theory is imperative when interpreting the results of experiments on electron transfer (ET). Unfortunately, most of these parameters are difficult or impossible to access directly with experiments, necessitating the use of computer simulations to model them. In this work, we use molecular dynamics simulations in conjunction with constrained density functional theory calculations to study the distance dependence of the electronic coupling matrix element, |HRP|, for bimolecular ET. Contrary to what is typically assumed for such intermolecular reactions, we find that the magnitude of |HRP| does not decay exponentially with the center-of-mass separation of the reactants, rCOM. The addition of other simple measures of donor/acceptor (D/A) orientation did not improve the correlation of |HRP| with rCOM. Using the minimum distance separation, rmin, of the reactants as the structural descriptor allowed the system to be partitioned into high-coupling/close-contact and low-coupling/non-contact regimes, but large fluctuations of |HRP| were still found for the close-contact reactant pairs. Despite the persistent large fluctuations of |HRP|, its mean value was found to decay piecewise exponentially with increasing rmin, which was attributed to significant changes in the average D/A pair structure. The results herein advise one to use caution when interpreting the experimental results derived from spherical reactant models of bimolecular ET.


Effect of ethanol on the hypothalamic-pituitary-adrenal axis in the rat: role of corticotropin-releasing factor (CRF).
The acute i.p. administration of alcohol (EtOH) to freely moving, nonanesthetized rats caused dose-related elevations in plasma adrenocorticotropin (ACTH) and corticosterone levels. In vivo, injection of anticorticotropin-releasing factor (CRF) serum (i.v.) totally abolished this stimulatory effect, suggesting that the induction of CRF secretion by EtOH represents an essential modulator of its ability to release ACTH. Exposure to high levels of alcohol vapors for 7 days was accompanied by a decrease in hypothalamic CRF content. The acute exposure of cultured pituitary cells to 0.2% EtOH did not modify basal or CRF-induced ACTH release, whereas pretreatment of the cells with EtOH for 24 hr resulted in a marked decrease in both spontaneous and stimulated ACTH secretion. It is therefore possible that the long-term exposure to alcohol may result in an increase of CRF release by the median eminence, as well as in some loss of pituitary responsiveness. From these data, we hypothesize that the acute EtOH-induced activation of the hypothalamic-pituitary-adrenal axis probably takes place at the level of CRF-secreting neurons and that this effect may play a role in the disturbance of ACTH and corticosteroid secretion observed during chronic exposure to alcohol.


Sensitivity and specificity of diagnostic modalities in pouchitis: a systematic review and meta-analysis.
Restorative proctocolectomy (RPC) is the most common surgical procedure to restore gastrointestinal continuity after surgical resection of the colon and rectum. Pouchitis is a common complication with several different modalities that can be used to aid diagnosis. This systematic review and meta-analysis aimed at exploring the sensitivity and specificity these diagnostic modalities. The medical literature was searched using MEDLINE, EMBASE and EMBASE classic and PubMed from 1978 to June 2022. We calculated descriptive statistics using sensitivity, specificity, and false-positive rate of the primary studies and also their positive and negative likelihood ratios, and their diagnostic odds ratios. The screen found 5477 records with 13 studies being included. Faecal lactoferrin was found to have the highest pooled sensitivity and specificity of 98% and 88% respectively with imaging modalities coming in second and faecal calprotectin third with pooled sensitivities and specificities of 87% and 79% and 74% and 81% respectively. Faecal biomarkers particularly lactoferrin and imaging modalities may have an important role to play in diagnosing pouchitis. Importantly due to delays in availability of pouchoscopy, our data supports early ordering of these tests to help delineate from other causes. Further studies are required with larger cohort sizes to further validate these tests.


Anderson transition in disordered bilayer graphene.
Employing the kernel polynomial method (KPM), we study the electronic properties of the graphene bilayers with Bernal stacking in the presence of diagonal disorder, within the tight-binding approximation and nearest neighbor interactions. The KPM method enables us to calculate local density of states (LDOS) without the need to exactly diagonalize the Hamiltonian. We use the geometrical averaging of the LDOS at different lattice sites as a criterion to distinguish the localized states from extended ones. We find that this model undergoes an Anderson metal-insulator transition at a critical value of disorder strength.


Leptin and autoimmune disease.
Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.


Care of Sexual and Gender Minorities in the Emergency Department: A Scoping Review.
This scoping review was conducted to collate and summarize the published research literature addressing sexual and gender minority care in the emergency department (ED). Using PRISMA-ScR criteria, an electronic search was conducted of CINAHL, Embase, Ovid Medline, and Web of Science for all studies that were published after 1995 involving sexual and gender minorities, throughout all life stages, presenting to an ED. We excluded non-US and Canadian studies and editorials. Titles and abstracts were screened, and full-text review was performed independently with 4 reviewers. Abstraction focused on study design, demographics, and outcomes, and the resulting data were analyzed using an ad hoc iterative thematic analysis. We found 972 unique articles and excluded 743 after title and abstract screening. The remaining 229 articles underwent full-text review, and 160 articles were included. Themes identified were HIV in sexual and gender minorities (n=61), population health (n=46), provider training (n=29), ED avoidance or barriers (n=23), ED use (n=21), and sexual orientation/gender identity information collection (n=9). The current literature encompassing ED sexual and gender minority care cluster into 6 themes. There are considerable gaps to be addressed in optimizing culturally competent and equitable care in the ED for this population. Future research to address these gaps should include substantial patient stakeholder engagement in all aspects of the research process to ensure patient-focused outcomes congruent with sexual and gender minority values and preferences.


Pathset graphs: a novel approach for comprehensive utilization of paired reads in genome assembly.
One of the key advances in genome assembly that has led to a significant improvement in contig lengths has been improved algorithms for utilization of paired reads (mate-pairs). While in most assemblers, mate-pair information is used in a post-processing step, the recently proposed Paired de Bruijn Graph (PDBG) approach incorporates the mate-pair information directly in the assembly graph structure. However, the PDBG approach faces difficulties when the variation in the insert sizes is high. To address this problem, we first transform mate-pairs into edge-pair histograms that allow one to better estimate the distance between edges in the assembly graph that represent regions linked by multiple mate-pairs. Further, we combine the ideas of mate-pair transformation and PDBGs to construct new data structures for genome assembly: pathsets and pathset graphs.


A movement-based approach to language development in children who are deaf-blind.
A movement-based approach to the development of language in children with deaf-blindness includes utilization of the four coactive movement phases: resonance, coactive movement, nonrepresentation reference, and deferred imitation. Such an approach stresses the use of structure in the environment as well as the use of a hierarchy of media cues. These cues range from concrete to symbolic in their characteristics and assist children in learning more complex concepts. A movement based approach uses the salient features of individuals or objects to develop an understanding of the person or object. Such features initially are used to stimulate use of language concerning objects or individuals in the immediate environment, and later to refer to persons or concepts in a more abstract fashion.


Evaluation of hepatoprotective activity of the commerson's anchovy (Stolephorus commersonnii).
In the present study, we have chosen a fish Stolephorus commersonnii which is abundant in whitebait catches along Kerala coast. This fish is reported to contain higher content of essential amino acids, monounsaturated fatty acids, polyunsaturated fatty acids and minerals. The medicinal values of this species have not been reported and remain unexplored. Hence, there is a necessity to explore their uses and to conduct the pharmacological studies to ascertain their therapeutic properties. Based on literature search, no study has been carried out to scientifically validate the fish S. commersonnii possesses hepatoprotective property. Hence, this study was carried out to investigate the hepatoprotective effect of the S. commersonnii. The fish was purchased from the fish market, Ernakulam, Kerala, India. The fish were kept on ice until processed in the lab. Fish is washed and cleaned properly. The tissue is homogenized and extracted with chloroform: methanol solvent system. The extract is transferred to a dark glass container and stored in a freezer. The preliminary analysis of fish extract was carried out by simple qualitative methods. The hepatoprotective activity of Stolephorus commersonnii (SC) extract at 300 mg/kg is carried out in isoniazid induced hepatotoxic model. The albino rats of either sex were used for these studies. The results of hepatoprotective study revealed that the SC extract showed a liver protective action against isoniazid induced toxicity. The present study suggests that the extract of S. commersonnii fish has therapeutic potential in the management of drug induced liver toxicity.


Phosphoproteome profiling of the macrophage response to different toll-like receptor ligands identifies differences in global phosphorylation dynamics.
Toll-like receptors (TLRs) are among the first sensors that detect infection and drive immune response. Macrophages encountering a pathogen are usually stimulated not by one TLR, but by a combination of TLRs engaged by distinct microbe ligands. To understand the integrated signaling under complex conditions, we investigated the differences in the phosphoprotein signaling cascades triggered by TLR2, TLR4, and TLR7 ligands using a single responding cell population. We performed a global, quantitative, early poststimulation kinetic analysis of the mouse macrophage phosphoproteome using stable isotope labeling with amino acids coupled to phosphopeptide enrichment and high-resolution mass spectrometry. For each TLR ligand, we found marked elevation of phosphorylation of cytoskeleton components, GTPases of the Rho family, and phospholipase C signaling pathway proteins. Phosphorylation of proteins involved in phagocytosis was only seen in response to TLR2 and TLR4 but not to TLR7 activation. Changes in the phosphorylation of proteins involved in endocytosis were delayed in response to TLR2 as compared to TLR4 ligands. These findings reveal that the phosphoproteomic response to stimulation of distinct TLRs varies both in the major modification targets and the phosphorylation dynamics. These results advance the understanding of how macrophages sense and respond to a diverse set of TLR stimuli.


The FUT1 and ESR genes--their variability and associations with reproduction in Prestice Black-Pied sows.
The determination of genetic variability by means of molecular genetic markers FUT1 and ESR2, and the evaluation of their associations with reproduction traits in population of Prestice Black-Pied sows have been implemented. A lower frequency of the allele FUT1A than the frequency of the allele FUT1G in the FUT1 gene was ascertained. In the ESR2 polymorphism, a higher frequency of the allele ESR2A compared with the allele ESR2B was determined. In the second to sixth litters as well as in the first to sixth litters, a significantly lower number of piglets born alive and number of weaned piglets from sows of the FUT1/IFUT1A genotype was found. Moreover, the homozygotes FUT1G /FUT1G significantly exceeded sows of the FUT1A/FUT1A genotype in the total number of born piglets in the first to sixth litters. No significant effect of the ESR2 polymorphism on reproduction was observed.


Mimicking oxygen delivery and waste removal functions of blood.
In addition to immunological and wound healing cell and platelet delivery, ion stasis and nutrient supply, blood delivers oxygen to cells and tissues and removes metabolic wastes. For decades researchers have been trying to develop approaches that mimic these two immediately vital functions of blood. Oxygen is crucial for the long-term survival of tissues and cells in vertebrates. Hypoxia (oxygen deficiency) and even at times anoxia (absence of oxygen) can occur during organ preservation, organ and cell transplantation, wound healing, in tumors and engineering of tissues. Different approaches have been developed to deliver oxygen to tissues and cells, including hyperbaric oxygen therapy (HBOT), normobaric hyperoxia therapy (NBOT), using biochemical reactions and electrolysis, employing liquids with high oxygen solubility, administering hemoglobin, myoglobin and red blood cells (RBCs), introducing oxygen-generating agents, using oxygen-carrying microparticles, persufflation, and peritoneal oxygenation. Metabolic waste accumulation is another issue in biological systems when blood flow is insufficient. Metabolic wastes change the microenvironment of cells and tissues, influence the metabolic activities of cells, and ultimately cause cell death. This review examines advances in blood mimicking systems in the field of biomedical engineering in terms of oxygen delivery and metabolic waste removal.


Marine Natural Products: A Source of Novel Anticancer Drugs.
Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.


Central nervous system tumours in children in Ibadan, Nigeria: a histopathologic study.
Contrary to some earlier teachings that central nervous system (CNS) tumours are uncommon in black children, these neoplasms are the fourth most common paediatric tumours in Ibadan. Our centre is the major referral centre for CNS tumours in Nigeria. The last major study of paediatric CNS neoplasms from Ibadan was in 1985. An update of the data on paediatric CNS neoplasms at our centre is presented. A retrospective review of all histologically diagnosed CNS tumours in children (0-14 years) from January 2001 to December 2010 from the database of the Department of Pathology, University College Hospital, Ibadan, Nigeria was done. The cases were classified using the 2007 WHO Classification of Tumours of the Central Nervous System and were also based on their supratentorial and infratentorial locations. Seventy-seven tumours, 44 in males, were included in the study. Astrocytic tumour comprised 20 cases, embryonal tumours 15, ependymal tumours 15, germ cell tumours 6, sellar tumours (all craniopharyngiomas) 9 and other histological types- 12 cases. Thirty-seven were WHO Grade 1, eleven Grade 2, ten Grade 3 and nineteen Grade 4 neoplasms. Thirty-six cases were supratentorial and thirty-eight were infratentorial in location. The most common tumours in this series were pilocytic astrocytomas, medulloblastomas, craniopharyngiomas and ependymomas in that order. Childhood CNS tumours are being increasingly diagnosed in our centre. This is largely explained by the recent expansion of the available neurosurgical services.


Measurements of intracellular pH and its relevance to cell differentiation in Dictyostelium discoideum.
A method was developed in this study to measure the intracellular pH (pHi) of Dictyostelium discoideum cells with a pH-sensitive fluorescence dye, carboxyfluorescein dibutyrate, and the pHi values of cells on the stalk and spore pathways were compared. The pHi of prestalk cells was lower than that of prespore cells by approximately 0.3 pH unit. In monolayer cultures of sporogenous mutants, which can differentiate into stalk cells and spores without cell contact, the pHi of the amoebae depended on the medium: media in which the majority of cells eventually become stalk cells reduced the pHi while conditions favouring spore formation increased the pHi. Addition of weak acids lowered the pHi. These results are in good accordance with the model presented by Gross and coworkers, which proposes that the choice between alternative pathways of cell differentiation is regulated via pHi and that low pHi favours stalk differentiation whereas high pHi favours spore formation.