Antipsychotic polypharmacy in schizophrenia patients in China and its association with treatment satisfaction and quality of life: findings of the third national survey on use of psychotropic medications in China.
This study examined the use, demographic and clinical correlates of antipsychotic polypharmacy (APP) and its associations with treatment satisfaction and quality of life (QOL) in schizophrenia patients in China. A total of 4239 patients in 45 nationwide Chinese psychiatric hospitals/centers were interviewed in 2012 in the third cross-sectional study, with the first two having been conducted in 2002 and 2006. Patients' socio-demographic and clinical characteristics, including psychopathology, side effects, satisfaction with treatment and QOL, were recorded using a standardized protocol and data collection procedure. The proportion of APP prescriptions in 2012 was 34.2%, which was significantly higher than the frequency of APP in 2002 (26.1%) and 2006 (26.4%) (p<0.001). Of patients on APP, 91.1% received two antipsychotics, 8.6% received three and 0.3% received four or more antipsychotics. Multiple logistic regression analyses revealed that compared to those on antipsychotic monotherapy, patients on APP and their families had lower satisfaction with treatment, had higher QOL in the mental domain, younger age of onset, more side effects, higher doses of antipsychotics and were more likely to receive first-generation antipsychotics and less likely to receive benzodiazepines (total R (2)=0.31, p<0.001). APP was found in about one in three schizophrenia patients. The prevalence of APP seems to have been increasing since 2002. Considering the increased frequency of drug-induced side effects and the patients' and their relatives' dissatisfaction with antipsychotic treatment, further examination of the rationale and appropriateness of APP and its alternatives is warranted.


Detection and identification of fungi in bronchoalveolar lavage fluid from immunocompromised patients using panfungal PCR.
Rapid diagnostics of fungal pneumonia and initiation of appropriate therapy are still challenging. In this study, we used two panfungal assays to test bronchoalveolar lavage fluid (BALF) samples to prove their ability to confirm invasive fungal disease diagnosis and identify causative agents. Two methods targeting different fungal rDNA regions were used, and the obtained PCR products were sequenced directly or after cloning. In total, 106 BALF samples from 104 patients were tested. After sequencing, we obtained 578 sequences. Four hundred thirty-seven sequences were excluded from further analysis due to duplication (n = 335) or similarity with sequences detected in the extraction control sample (n = 102); 141 unique sequences were analyzed. Altogether, 23/141 (16%) of the fungi detected belonged to pathogenic species, and 63/141 (45%) were identified as various yeasts; a variety of environmental or very rare fungal human pathogens represented 29/141 (21%) of the total and 26/141 (18%) were described as uncultured fungus. Panfungal PCR detected fungal species that would be missed by specific methods in only one case (probable cryptococcosis). Panfungal PCR followed by sequencing has limited use for testing BALF samples due to frequent commensal or environmental fungal species pickup.


Cholesterol and mental disorder.
Cholesterol plays an important part in cellular structure and function and changes in serum levels may affect neurotransmission in the central nervous system. A MEDLINE literature search was made covering the period 1990-95 with systematic searching of citations from the articles identified. Representative articles were selected, focusing on those aspects which had not been thoroughly reviewed elsewhere, namely suicidal ideation, depression, personality and schizophrenia. Lowering cholesterol levels have been associated with an increase in violent deaths in cardiovascular primary prevention studies. However, altered cholesterol levels have also been reported in relation to other psychiatric disorders. There is substantial evidence that serum cholesterol levels may be associated with variations in mental state or personality. Further work is needed to clarify this and to elucidate the mechanisms involved.


Expression of the JNK2-alpha1 gene in the developing chick brain.
We have isolated chicken JNK2-alpha1 encoding a c-Jun N-terminal kinase, and examined the expression during embryogenesis. The kinase domain sequence is well conserved between chicken and mammals, but carboxy-terminal sequence of JNK is divergent from subtype 1 and 2, possibly derived from alternative splicing. The JNK2-alpha1 gene is preferentially expressed in the neuroepithelium of developing brain at stages 16-26, and transcripts are not detectable in the other region including spinal cord. These results suggest that JNK2-alpha1 is involved in development of the central nervous system as a mediator of stress-activated protein kinase pathway conferring competence to the external stimuli such as growth factors.


Improved normalization of species count data in ecology by scaling with ranked subsampling (SRS): application to microbial communities.
Analysis of species count data in ecology often requires normalization to an identical sample size. Rarefying (random subsampling without replacement), which is the current standard method for normalization, has been widely criticized for its poor reproducibility and potential distortion of the community structure. In the context of microbiome count data, researchers explicitly advised against the use of rarefying. Here we introduce a normalization method for species count data called scaling with ranked subsampling (SRS) and demonstrate its suitability for the analysis of microbial communities. SRS consists of two steps. In the scaling step, the counts for all species or operational taxonomic units (OTUs) are divided by a scaling factor chosen in such a way that the sum of scaled counts equals the selected total number of counts Cmin. The relative frequencies of all OTUs remain unchanged. In the subsequent ranked subsampling step, non-integer count values are converted into integers by an algorithm that minimizes subsampling error with regard to the population structure (relative frequencies of species or OTUs) while keeping the total number of counts equal Cmin. SRS and rarefying were compared by normalizing a test library representing a soil bacterial community. Common parameters of biodiversity and population structure (Shannon index H', species richness, species composition, and relative abundances of OTUs) were determined for libraries normalized to different size by rarefying as well as SRS with 10,000 replications each. An implementation of SRS in R is available for download (https://doi.org/10.20387/BONARES-2657-1NP3). SRS showed greater reproducibility and preserved OTU frequencies and alpha diversity better than rarefying. The variance in Shannon diversity increased with the reduction of the library size after rarefying but remained zero for SRS. Relative abundances of OTUs strongly varied among libraries generated by rarefying, whereas libraries normalized by SRS showed only negligible variation. Bray-Curtis index of dissimilarity among replicates of the same library normalized by rarefying revealed a large variation in species composition, which reached complete dissimilarity (not a single OTU shared) among some libraries rarefied to a small size. The dissimilarity among replicated libraries normalized by SRS remained negligibly low at each library size. The variance in dissimilarity increased with the decreasing library size after rarefying, whereas it remained either zero or negligibly low after SRS. Normalization of OTU or species counts by scaling with ranked subsampling preserves the original community structure by minimizing subsampling errors. We therefore propose SRS for the normalization of biological count data.


Modafinil ameliorates cognitive deficits induced by maternal separation and sleep deprivation.
Animals exposed to an early adverse event may be more susceptible to a second source of stress later in life, and these stressors may have additive deleterious effects. Sleep deprivation is known to be a stressor, affecting multiple body functions such as the cognition. Modafinil enhances working memory and attention in healthy non-sleep deprived subjects and in animal models of sleep deprivation. The first aim of the present study was to investigate the effects of maternal separation (MS) combined with paradoxical sleep deprivation (PSD) in adulthood on recognition memory in rats. Second, we aimed to evaluate whether the administration of modafinil would be able to ameliorate memory deficits induced by MS and PSD. Wistar rat pups were initially distributed into MS and handling (H) groups, with their litters standardized in 4 females and 4 males. In adulthood, the male rats were submitted to PSD or control condition, being redistributed afterwards in modafinil- or vehicle-treatment immediately after the training session of object recognition task. PSD did not potentiate the cognitive deficit due to MS. However, modafinil was able to recover memory impairments associated to PSD and also to MS in the neonatal period. This study demonstrates for the first time that modafinil ameliorates cognitive deficits associated to MS and to PSD in adulthood, independent from MS in the neonatal period.


Medicare APMs at a crossroads.
Reaching the goals set by the Health Care Payment and Learning Action Network requires an unyielding and unrelenting focus on encouraging providers to adopt advanced alternative payment models (APMs). Many of these models will continue to be voluntary because they either are in early stages or have not yet proven their effectiveness. The models that have proven their effectiveness should become permanent, comprising the new way that providers are paid in the Medicare program. Either way, getting today's high performers into those programs and keeping them engaged to continue to innovate and set new benchmarks is as important as attracting and improving the performance of poorer performers. That will require a shift in Medicare's policy on pricing and evaluating APMs.


Performance-based comparison of neonatal intubation training outcomes: simulator and live animal.
The purpose of this article was to establish psychometric validity evidence for competency assessment instruments and to evaluate the impact of 2 forms of training on the abilities of clinicians to perform neonatal intubation. To inform the development of assessment instruments, we conducted comprehensive task analyses including each performance domain associated with neonatal intubation. Expert review confirmed content validity. Construct validity was established using the instruments to differentiate between the intubation performance abilities of practitioners (N = 294) with variable experience (novice through expert). Training outcomes were evaluated using a quasi-experimental design to evaluate performance differences between 294 subjects randomly assigned to 1 of 2 training groups. The training intervention followed American Heart Association Pediatric Advanced Life Support and Neonatal Resuscitation Program protocols with hands-on practice using either (1) live feline or (2) simulated feline models. Performance assessment data were captured before and directly following the training. All data were analyzed using analysis of variance with repeated measures and statistical significance set at P < .05. Content validity, reliability, and consistency evidence were established for each assessment instrument. Construct validity for each assessment instrument was supported by significantly higher scores for subjects with greater levels of experience, as compared with those with less experience (P = .000). Overall, subjects performed significantly better in each assessment domain, following the training intervention (P = .000). After controlling for experience level, there were no significant differences among the cognitive, performance, and self-efficacy outcomes between clinicians trained with live animal model or simulator model. Analysis of retention scores showed that simulator trained subjects had significantly higher performance scores after 18 weeks (P = .01) and 52 weeks (P = .001) and cognitive scores after 52 weeks (P = .001). The results of this study demonstrate the feasibility of using valid, reliable assessment instruments to assess clinician competency and self-efficacy in the performance of neonatal intubation. We demonstrated the relative equivalency of live animal and simulation-based models as tools to support acquisition of neonatal intubation skills. Retention of performance abilities was greater for subjects trained using the simulator, likely because it afforded greater opportunity for repeated practice. Outcomes in each assessment area were influenced by the previous intubation experience of participants. This suggests that neonatal intubation training programs could be tailored to the level of provider experience to make efficient use of time and educational resources. Future research focusing on the uses of assessment in the applied clinical environment, as well as identification of optimal training cycles for performance retention, is merited.


Neuroimaging of Intracerebral Hemorrhage.
Intracerebral hemorrhage (ICH) accounts for 10% to 20% of strokes worldwide and is associated with high morbidity and mortality rates. Neuroimaging is indispensable for rapid diagnosis of ICH and identification of the underlying etiology, thus facilitating triage and appropriate treatment of patients. The most common neuroimaging modalities include noncontrast computed tomography (CT), CT angiography (CTA), digital subtraction angiography, and magnetic resonance imaging (MRI). The strengths and disadvantages of each modality will be reviewed. Novel technologies such as dual-energy CT/CTA, rapid MRI techniques, near-infrared spectroscopy, and automated ICH detection hold promise for faster pre- and in-hospital ICH diagnosis that may impact patient management.


Predicting community violence from patients discharged from acute mental health units in England.
To investigate the validity of risk factors and established risk measures in predicting community violence in an acute mental health sample up to 20 weeks post-discharge. Prospective cohort follow-up study conducted between January 2006 and August 2007. Baseline assessments were conducted while participants were inpatients. The measures were rated following interview with the participants, record review and speaking to someone who knows the person well (e.g. friend, relative, carer). Baseline measures were then compared with frequency and severity of violence in the community post-discharge at 20 weeks. In the 20-week period post-discharge, 29 (25.4%) of the 114 participants were violent. All the risk measures and measures of impulsiveness and anger were predictive of violence where p < 0.05. The HCR-20 total, psychopathy and clinical factors were strongly correlated with the frequency of violence where p < 0.05. The risk factors and risk measures that have been found to be predictive in forensic samples are also predictive in acute mental health samples, although the effects are not as large. Future research needs to be conducted with a larger sample to include investigation of differences in risk factors based on gender and social support. Services and clinicians need to consider how to integrate findings into useful frameworks to support decisions and contribute to managing risk. This should assist in identifying interventions aimed at preventing community violence.


Leukotriene B4: an inflammatory mediator with vascular actions in vivo.
Leukotriene B4 (LTB4) is a 5, 12-dihydroxy derivative of arachidonic acid generated by a variety of inflammatory cells via the lipoxygenase enzyme system. In vitro leukotriene B4 is a potent chemotactic and aggregatory agent; enhances neutrophil complement receptors; stimulates membrane calcium changes and causes contraction of lung parenchyma. In vivo LTB4 is a potent stimulator of vascular permeability in rats, rabbits, guinea-pigs and man particularly in the presence of a vasodilator such as PGE2. LTB4 causes a profound transient neutropenia and massive accumulation of neutrophils when injected into the dermis (rabbit and man), skin chambers (rabbit and man) or body cavities (guinea-pig, rat).


Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events.
Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR). Neurodegenerative effects of proteasome inhibitors were assessed in an in vitro model utilizing a differentiated neuronal cell line. Secondary targets of both inhibitors were identified by a multifaceted approach involving candidate screening, profiling with an activity-based probe, and database mining. Secondary target activity was measured in rats and patients receiving both inhibitors. Despite equivalent levels of proteasome inhibition, only bortezomib reduced neurite length, suggesting a nonproteasomal mechanism. In cell lysates, bortezomib, but not carfilzomib, significantly inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies near or equivalent to that for the proteasome. Inhibition of CatG was detected in splenocytes of rats receiving bortezomib and in peripheral blood mononuclear cells derived from bortezomib-treated patients. Levels of HtrA2/Omi, which is known to be involved in neuronal survival, were upregulated in neuronal cells exposed to both proteasome inhibitors but was inhibited only by bortezomib exposure. These data show that bortezomib-induced neurodegeneration in vitro occurs via a proteasome-independent mechanism and that bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which may play a role in its clinical ADR profile.


Structured measurement error in nutritional epidemiology: applications in the Pregnancy, Infection, and Nutrition (PIN) Study.
Preterm birth, defined as delivery before 37 completed weeks' gestation, is a leading cause of infant morbidity and mortality. Identifying factors related to preterm delivery is an important goal of public health professionals who wish to identify etiologic pathways to target for prevention. Validation studies are often conducted in nutritional epidemiology in order to study measurement error in instruments that are generally less invasive or less expensive than "gold standard" instruments. Data from such studies are then used in adjusting estimates based on the full study sample. However, measurement error in nutritional epidemiology has recently been shown to be complicated by correlated error structures in the study-wide and validation instruments. Investigators of a study of preterm birth and dietary intake designed a validation study to assess measurement error in a food frequency questionnaire (FFQ) administered during pregnancy and with the secondary goal of assessing whether a single administration of the FFQ could be used to describe intake over the relatively short pregnancy period, in which energy intake typically increases. Here, we describe a likelihood-based method via Markov Chain Monte Carlo to estimate the regression coefficients in a generalized linear model relating preterm birth to covariates, where one of the covariates is measured with error and the multivariate measurement error model has correlated errors among contemporaneous instruments (i.e. FFQs, 24-hour recalls, and/or biomarkers). Because of constraints on the covariance parameters in our likelihood, identifiability for all the variance and covariance parameters is not guaranteed and, therefore, we derive the necessary and suficient conditions to identify the variance and covariance parameters under our measurement error model and assumptions. We investigate the sensitivity of our likelihood-based model to distributional assumptions placed on the true folate intake by employing semi-parametric Bayesian methods through the mixture of Dirichlet process priors framework. We exemplify our methods in a recent prospective cohort study of risk factors for preterm birth. We use long-term folate as our error-prone predictor of interest, the food-frequency questionnaire (FFQ) and 24-hour recall as two biased instruments, and serum folate biomarker as the unbiased instrument. We found that folate intake, as measured by the FFQ, led to a conservative estimate of the estimated odds ratio of preterm birth (0.76) when compared to the odds ratio estimate from our likelihood-based approach, which adjusts for the measurement error (0.63). We found that our parametric model led to similar conclusions to the semi-parametric Bayesian model.


Prediagnostic level of fatty acids in serum phospholipids: omega-3 and omega-6 fatty acids and the risk of prostate cancer.
Ecological and case-control studies have demonstrated a positive correlation between consumption of fat and the risk of prostate cancer. Two recent human studies have focused on alpha-linolenic acid as a risk factor for prostate cancer. Animal experiments have shown that dietary omega-6 polyunsaturated fatty acids have generally stimulated tumour development, whereas omega-3 polyunsaturated fatty acids have diminished it. The aim of our study was to investigate the association between these fatty acids and the subsequent risk of prostate cancer. Blood donors to the Janus serum data bank in Norway, who later developed prostate cancer, were matched to blood donors without prostate cancer (141 matched sets); the proportional level of fatty acids measured before diagnosis in the donors' serum was examined. The risk of later prostate cancer was analysed by conditional logistic regression. Increasing risk for prostate cancer was found with increasing quartiles of palmitoleic, palmitic and alpha-linolenic acid. An inverse risk association was found with increasing levels of tetracosanoic acid, for the ratios of linoleic to alpha-linolenic acid and arachidonic to eicosapentaenoic acid. There was no clear association between the risk effect of total omega-3 and total omega-6 fatty acids. There were no indications of a relationship between fatty acids and more aggressive cancers. Our results verify recent findings of a positive association between alpha-linolenic acid and a negative association between the ratio of linoleic to alpha-linolenic acid and the risk of prostate cancer.


Edge Computing Resource Allocation for Dynamic Networks: The DRUID-NET Vision and Perspective.
The potential offered by the abundance of sensors, actuators, and communications in the Internet of Things (IoT) era is hindered by the limited computational capacity of local nodes. Several key challenges should be addressed to optimally and jointly exploit the network, computing, and storage resources, guaranteeing at the same time feasibility for time-critical and mission-critical tasks. We propose the DRUID-NET framework to take upon these challenges by dynamically distributing resources when the demand is rapidly varying. It includes analytic dynamical modeling of the resources, offered workload, and networking environment, incorporating phenomena typically met in wireless communications and mobile edge computing, together with new estimators of time-varying profiles. Building on this framework, we aim to develop novel resource allocation mechanisms that explicitly include service differentiation and context-awareness, being capable of guaranteeing well-defined Quality of Service (QoS) metrics. DRUID-NET goes beyond the state of the art in the design of control algorithms by incorporating resource allocation mechanisms to the decision strategy itself. To achieve these breakthroughs, we combine tools from Automata and Graph theory, Machine Learning, Modern Control Theory, and Network Theory. DRUID-NET constitutes the first truly holistic, multidisciplinary approach that extends recent, albeit fragmented results from all aforementioned fields, thus bridging the gap between efforts of different communities.


Phenotypic evolution of dispersal-enhancing traits in insular voles.
Evolutionary theory predicts that in metapopulations subject to rapid extinction-recolonization dynamics, natural selection should favour evolution of traits that enhance dispersal and recolonization ability. Metapopulations of field voles (Microtus agrestis) on islands in the Stockholm archipelago, Sweden, are characterized by frequent local extinction and recolonization of subpopulations. Here, we show that voles on the islands were larger and had longer feet than expected for their body size, compared with voles from the mainland; that body size and size-specific foot length increased with increasing geographical isolation and distance from mainland; and that the differences in body size and size-specific foot length were genetically based. These findings provide rare evidence for relatively recent (less than 1000 years) and rapid (corresponding to 100-250 darwins) evolution of traits facilitating dispersal and recolonization in island metapopulations.


Predators in the plant-soil feedback loop: aboveground plant-associated predators may alter the outcome of plant-soil interactions.
Plant-soil feedback (PSF) can structure plant communities, promoting coexistence (negative PSF) or monodominance (positive PSF). At higher trophic levels, predators can alter plant community structure by re-allocating resources within habitats. When predator and plant species are spatially associated, predators may alter the outcome of PSF. Here, I explore the influence of plant-associated predators on PSF using a generalised cellular automaton model that tracks nutrients, plants, herbivores and predators. I explore key contingencies in plant-predator associations such as whether predators associate with live vs. senesced vegetation. Results indicate that plant-associated predators shift PSF to favour the host plant when predators colonise live vegetation, but the outcome of PSF will depend upon plant dispersal distance when predators colonise dead vegetation. I apply the model to two spider-associated invasive plants, finding that spider predators should shift PSF dynamics in a way that inhibits invasion by one forest invader, but exacerbates invasion by another.


Mammalian DNA demethylation: multiple faces and upstream regulation.
DNA cytosine methylation is a reversible epigenetic mark regulating gene expression. Aberrant methylation profiles are concomitant with developmental defects and cancer. Numerous studies in the past decade have identified enzymes and pathways responsible for active DNA demethylation both on a genome-wide as well as gene-specific scale. Recent findings have strengthened the idea that 5-methylcytosine oxidation catalyzed by members of the ten-eleven translocation (Tet1-3) oxygenases in conjunction with replication-coupled dilution of the conversion products causes the majority of genome-wide erasure of methylation marks during early development. In contrast, short and long patch DNA excision repair seems to be implicated mainly in gene-specific demethylation. Growth arrest and DNA damage-inducible protein 45 a (Gadd45a) regulates gene-specific demethylation within regulatory sequences of limited lengths raising the question of how such site specificity is achieved. A new study identified the protein inhibitor of growth 1 (Ing1) as a reader of the active chromatin mark histone H3 lysine 4 trimethylation (H3K4me3). Ing1 binds and directs Gadd45a to target sites, thus linking the histone code with DNA demethylation.


RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3.
Despite advances in diagnosis and treatment, prostate cancer is the most prevalent cancer in males and the second highest cause of cancer-related mortality. We identified an RNA helicase gene, DDX3 (DDX3X), which is overexpressed in prostate cancers, and whose expression is directly correlated with high Gleason scores. Knockdown of DDX3 in the aggressive prostate cancer cell lines DU145 and 22Rv1 resulted in significantly reduced clonogenicity. To target DDX3, we rationally designed a small molecule, RK-33, which docks into the ATP-binding domain of DDX3. Functional studies indicated that RK-33 preferentially bound to DDX3 and perturbed its activity. RK-33 treatment of prostate cancer cell lines DU145, 22Rv1, and LNCaP (which have high DDX3 levels) decreased proliferation and induced a G1 phase cell-cycle arrest. Conversely, the low DDX3-expressing cell line, PC3, exhibited few changes following RK-33 treatment. Importantly, combination studies using RK-33 and radiation exhibited synergistic effects both in vitro and in a xenograft model of prostate cancer demonstrating the role of RK-33 as a radiosensitizer. Taken together, these results indicate that blocking DDX3 by RK-33 in combination with radiation treatment is a viable option for treating locally advanced prostate cancer. Cancer Res; 76(21); 6340-50. ©2016 AACR.


Identification of genetically mediated cortical networks: a multivariate study of pediatric twins and siblings.
Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.


Phytotoxicity of 4,8-dihydroxy-1-tetralone isolated from Carya cathayensis Sarg. to various plant species.
The aqueous extract from Carya cathayensis Sarg. exocarp was centrifuged, filtered, and separated into 11 elution fractions by X-5 macroporous resin chromatography. A phenolic compound, 4,8-dihydroxy-1-tetralone (4,8-DHT) was isolated from the fractions with the strongest phytotoxicity by bioassy-guided fractionation, and investigated for phytotoxicity on lettuce (Latuca sativa L.), radish (Raphanus sativus L.), cucumber (Cucumis sativus L.), onion (Allium cepa L.) and wheat (Triticum aestivum L.). The testing results showed that the treatment with 0.6 mM 4,8-DHT could significantly depress the germination vigor of lettuce and wheat, reduce the germination rate of lettuce and cucumber, and also inhibit radicle length, plumule length, and fresh weight of seedlings of lettuce and onion, but could significantly promote plumule length and fresh weight of seedlings of cucumber (p < 0.05). For the tested five plants, the 4,8-DHT was the most active to the seed germination and seedling growth of lettuce, indicating that the phytotoxicity of 4,8-DHT had the selectivity of dosage, action target (plant type) and content (seed germination or seedling growth).


A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania.
A significant number of mania patients fail to respond to current pharmacotherapy, thereby there is need for novel augmentation strategies. The results of some early studies showed the effectiveness of cholinomimetics in the treatment of mania. One open case series suggested the efficacy of donepezil in the treatment of bipolar disorder. Our aim was to explore whether an oral cholinesterase inhibitor, donepezil, administered during a 4-week treatment period, would benefit patients with acute mania. We conducted a 4-week double-blind, placebo-controlled trial of donepezil as an adjunctive treatment to lithium in patients with acute mania. Eligible subjects were randomly assigned to receive donepezil or placebo in addition to lithium. Donepezil was started at 5 mg/day, and increased to 10 mg/day in the first week. Patients were rated with the Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) at baseline, day 1, week 1, week 2, and week 4. Out of the 30 patients who were enrolled, 15 were on donepezil and 15 were on placebo. All patients completed the 4-week trial. On the first day, there was a difference of 1.97 units on the psychomotor symptoms scale of the YMRS in the donepezil group as compared to the placebo group (t = 2.39, P = 0.02). There was a difference of 0.57 units (t = 2.09, P = 0.04) in the speech item and a difference of 0.29 units in the sexual interest item (t = 2.11, P = 0.04) in the donepezil group as compared to the placebo group. The total YMRS difference on the first day approached the conventional significance level (1.97 units, t = 1.84, P = 0.07). Over the course of 4 weeks, we failed to find that donepezil produced any significant difference in the YMRS (6.71 units difference, t = -1.44, P = 0.16) or the BPRS scale (1.29 units difference, t = -0.33, P = 0.75) as compared to placebo. Ten subjects (66.67%) in both groups met the criteria for clinical response (Fisher's exact P = 1.00). Five subjects (33.33%) in the donepezil group met the criteria for clinical remission while nine subjects (60.00%) in the placebo group met the remission criteria (Fisher's exact P = 0.27). Use of the oral anticholinergic donepezil had some benefit in the augmentation of lithium treatment on the first day, but did not provide any significant benefits in the long-term.


Identification of Escherichia coli isolated from flies (Insecta: Diptera) that inhabit the environment of dairy farms harboring extraintestinal virulence markers.
We investigate extraintestinal pathogenic genes (ExPEC) related to virulence of Escherichia coli in flies from the dairy environment. We collected 217 flies from nine dairy farms, which were submitted to microbiological culture. Fifty-one E. coli were identified using mass spectrometry. Eleven dipteran families were identified, with a predominance of Muscidae, and a minor frequency of Tachinidae, Drosophilidae, Sphaeroceridae, Ulidiidae, Syrphidae, Chloropidae, Calliphoridae, Sarcophagidae, and Piophilidae. A panel of 16 virulence-encoding genes related to ExPEC infections were investigated, which revealed predominance of serum resistance (traT, 31/51 = 60.8%; ompT, 29/51 = 56.9%), iron uptake (irp2, 17/51 = 33.3%, iucD 11/51 = 21.6%), and adhesins (papC, 6/51 = 11.8%; papA, 5/51 = 9.8%). Our findings reveal Dipterans from milking environment carrying ExPEC virulence-encoding genes also identified in clinical bovine E. coli-induced infections.


Hoyaspectatissima (Gentianales, Apocynaceae), a new species from Yunnan, China.
Hoyaspectatissima, a new species from Yunnan Province, China, is described and illustrated. Hoyaspectatissima is morphologically similar to H.lyi, but can be easily distinguished from the latter by its succulent leaves that are 2‒4.5 cm long (vs. coriaceous leaves that are up to 9 cm long), corolla that is pink to pale pink (vs. yellowish-white) and corona lobes that are sub-rhombic in top view (vs. ovoid in top view).


The effect of high vacuum on oxidative reactions in bacteria and the activity of certain enzymes.
Among the physical factors which might influence micro-organisms one of the most potentially interesting is high vacuum. The effect of high vacuum is less studied as compared with other physical factors. It is impossible to achieve, under laboratory conditions, a vacuum of the order 10(-16) mm Hg which is probably characteristic of space. Earlier, the effect of high vacuum was studied on different bacteria, yeasts, molds and algae. It appeared that spores and fungal conidia were not killed by high vacuum. Later, the effect of high vacuum on physiological processes in micro-organisms was studied. The ability to oxidize glucose or ethanol was studied with Sarcina flava and Bacillus simplex cells after they were subjected for 72 hr to vacuum (10(-8) to 10(-9) mm Hg). The oxidation rate was followed polarographically. The oxidative ability of S. flava cells diminished [correction of dimished] after their subjection to vacuum, while B. simplex spores were unchanged in that respect. The following crystalline enzymes were subjected for 72 hr to the same vacuum: alpha-amylase, catalase, ribonuclease, trypsine and urease. Then the activity of the above enzymes was tested on corresponding substrates. Not a single enzyme was totally inactivated. About 50% of activity was lost with alpha-amylase; 25--35% of activity with catalase, ribonuclease and urease. Trypsine retained its total activity. Thus, high vacuum cannot be listed among factors rapidly inactivating enzymes of micro-organisms.


Multicenter experience with balloon mitral commissurotomy. NHLBI Balloon Valvuloplasty Registry Report on immediate and 30-day follow-up results. The National Heart, Lung, and Blood Institute Balloon Valvuloplasty Registry Participants.
Balloon mitral commissurotomy can increase mitral valve areas and reduce symptoms in selected patients with mitral stenosis. The National Heart, Lung, and Blood Institute Balloon Valvuloplasty Registry was organized to address concerns regarding differences in patient selection and technique and to report the current clinical outcome. In 24 cooperating centers, 738 patients had balloon mitral commissurotomy. Baseline clinical, echo Doppler, and cardiac catheterization data, procedure details, and hemodynamic and 30-day clinical outcome were reported. Overall, 81% of the patients were women (mean age, 54 +/- 15 years), and 24% had moderate or severe other valvular lesions. When single- and double-balloon procedures were compared, the final mitral valve area was larger (1.7 +/- 0.7 versus 2.0 +/- 0.8 cm2, p = 0.0009), increase in mitral regurgitation was similar (4% versus 12%, p = 0.08), and interatrial shunts occurred more frequently (2% versus 12%, p = 0.04) after double-balloon procedures. Increase in mitral valve area was weakly related to mitral valve morphology as assessed by an echo score (r = -0.15). Multivariate predictors of improved clinical status at 30 days were cases performed in larger-volume centers, baseline mitral valve area greater than 0.5 cm2, and age less than 70 years. At 30-day follow-up, 4% of the patients with completed procedures had mitral valve surgery, 3% had died, and 83% had their overall condition improved. Patients with mixed mitral stenosis or regurgitation and isolated mitral stenosis had a similar course, but fewer patients with multivalve disease became asymptomatic. Balloon mitral commissurotomy, as practiced in a broad range of experienced centers, produced significant short-term hemodynamic and clinical improvements. Balloon mitral commissurotomy can be considered an effective treatment option in patients with symptomatic mitral stenosis.


[Blade auricular septostomy].
We describe the first case of BAS in our country in a three months old child with transposition of the great arteries, restrictive atrial septal defect (RASD) and intact interventricular septum. When he was 15 days old, we performed a balloon atrial septostomy. He had temporal improvement and six weeks later his cyanosis increased, and a new catheterization showed systemic arterial oxygen saturation of 30%, RASD and an interatrial pressure gradient of 2.1 mmHg (left atrium LA: 3.9 and right atrium RA: 1.8). We decided to perform a new septostomy with Park's blade atrial septostomy catheter. After the procedure the interatrial pressure gradient decreased to 0.2 mmHg (RA: 4.3 and LA: 4.5), the angiography shunt and atrial pressures increased. Five months later the child is alive and the systemic arterial oxygen saturation is 51.3%. The technique, advantages and complications are described.


Boolean logic algebra driven similarity measure for text based applications.
In Information Retrieval (IR), Data Mining (DM), and Machine Learning (ML), similarity measures have been widely used for text clustering and classification. The similarity measure is the cornerstone upon which the performance of most DM and ML algorithms is completely dependent. Thus, till now, the endeavor in literature for an effective and efficient similarity measure is still immature. Some recently-proposed similarity measures were effective, but have a complex design and suffer from inefficiencies. This work, therefore, develops an effective and efficient similarity measure of a simplistic design for text-based applications. The measure developed in this work is driven by Boolean logic algebra basics (BLAB-SM), which aims at effectively reaching the desired accuracy at the fastest run time as compared to the recently developed state-of-the-art measures. Using the term frequency-inverse document frequency (TF-IDF) schema, the K-nearest neighbor (KNN), and the K-means clustering algorithm, a comprehensive evaluation is presented. The evaluation has been experimentally performed for BLAB-SM against seven similarity measures on two most-popular datasets, Reuters-21 and Web-KB. The experimental results illustrate that BLAB-SM is not only more efficient but also significantly more effective than state-of-the-art similarity measures on both classification and clustering tasks.


Substance Use among Belgian Higher Education Students before and during the First Wave of the COVID-19 Pandemic.
The COVID-19 pandemic prompted many countries to issue far-reaching policy measures that may have led to increased substance use. Higher education students may have been disproportionally affected due to the rearrangement of educational life and their susceptibility to psychosocial distress and substance use. The current study examined associations between pandemic-related stressors, psychosocial distress, and self-reported alcohol, tobacco, and cannabis use before and during the first wave of the pandemic. Data were collected in Belgium as part of the COVID-19 International Student Well-being Study (C19 ISWS) and analyzed using multinomial logistic regression analyses. The sample contained 18,346 higher education students aged 17 to 24 (75% women). Overall use of alcohol, tobacco, and cannabis as well as binge drinking decreased during the pandemic, perhaps due to limited social gatherings. Moving back to the parental home was associated with decreased substance use, while depressive symptoms were associated with increased substance use. Perceived threat and academic stress were associated with increased binge drinking among heavy bingers and increased tobacco use. Decreases among students who moved back to their parental home may be explained by increased informal social control. Increased substance use was associated with a number of stressors and psychosocial distress, which suggests that some students may have been self-medicating to manage their mental health amidst the pandemic. Public health policy concerning substance use may prove to be less effective if not tailored to particular subgroups within the student population.


Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies.
Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains. The method can be applied across Igs to design Fc heterodimers and bsAbs. We investigated interfaces from human IgA CH3, IgD CH3, IgG1 CH3, IgM CH4, T-cell receptor (TCR) α/β, and TCR γ/δ constant domain pairs, and we found that they successfully drive human IgG1 CH3 or IgM CH4 heterodimerization to levels similar to or above those of reference methods. A comprehensive interface exchange between the TCR α/β constant domain pair and the IgG1 CH3 homodimer was evidenced by X-ray crystallography and used to engineer examples of bsAbs for cancer therapy. Parental antibody pairs were rapidly reformatted into scalable bsAbs that were free of homodimer traces by combining interface exchange, asymmetric Protein A binding, and the scFv × Fab format. In summary, we successfully built several new CH3- or CH4-based heterodimers that may prove useful for designing new bsAb-based therapeutics, and we anticipate that our approach could be broadly implemented across the Ig constant domain family. To our knowledge, CH4-based heterodimers have not been previously reported.


In vivo detection and quantification of tetracycline by use of a whole-cell biosensor in the rat intestine.
An Escherichia coli biosensor strain, harboring the plasmid pTGFP2, was introduced into the gastrointestinal tract of gnotobiotic rats that continuously received drinking water containing tetracycline. Plasmid pTGFP2 contains a transcriptional fusion between a green fluorescent protein (GFP) gene and a tetracycline-regulated promoter and was shown to produce a proportional GFP signal in response to exposure to various tetracycline concentrations when harbored by an E. coli strain. The plasmid was highly unstable in the host bacteria colonizing the intestinal system of the animals, and rapid plasmid loss was observed. Reintroduction of the E. coli MC4100/pTGFP2 strain into animals already colonized by the plasmid-free E. coli strain the day before euthanasia made it possible to extract and analyze the biosensors from intestinal samples. The induction of GFP in the biosensor cells extracted from the animals was estimated on a single-cell basis by use of flow cytometry, and the mean induction of GFP in the samples was compared to a standard curve prepared from known tetracycline concentrations. The results showed that the bioavailable tetracycline concentration within the bacterial growth habitat of the intestine was proportional to the concentration of tetracycline in drinking water but represented only approximately 0.4% of the intake concentration. This is a significant finding which will help to clarify antimicrobial therapy in the intestinal environment.


[An overview of the pulmonary sensory receptors].
The optimum realization to respiratory function depends on varied sensory feedbacks from ensemble of the sources of the body. Pulmonary sensory receptors are the initiating sites for lung reflexes. The information arriving from lungs and airways information is one of the most important feedbacks that provide the adaptation of the respiratory centre for producing of the pattern optimal in terms of work and force of breathing. In article the review of data existing currently about morphology and functional characteristics of three types of the pulmonary structures is presented: slowly adapting stretch receptors, rapidly adapting receptors, C-fiber receptors and neuroepithelial bodies.


[Hypophyseal-thyroid system function of animals in the early periods after tumor transplantation].
The signs of disintegration of hypophyseal-thyroid system function with predominant iodine uptake by thyroid gland cells are detected in the animals during the first 3 days after sarcoma M-1 inoculation. Dissimilar changes in magnesium ion levels are seen in the peripheral blood plasma and thyroid tissue homogenate of the animals with inoculated tumor and injected with non-specific antigenic stimulant.


An Atlas of the base inter-RNA stacks involved in bacterial translation.
Nucleobase-specific noncovalent interactions play a crucial role in translation. Herein, we provide a comprehensive analysis of the stacks between different RNA components in the crystal structures of the bacterial ribosome caught at different translation stages. Analysis of tRNA||rRNA stacks reveals distinct behaviour; both the A-and E-site tRNAs exhibit unique stacking patterns with 23S rRNA bases, while P-site tRNAs stack with 16S rRNA bases. Furthermore, E-site stacks exhibit diverse face orientations and ring topologies-rare for inter-chain RNA interactions-with higher average interaction energies than A or P-site stacks. This suggests that stacking may be essential for stabilizing tRNA progression through the E-site. Additionally, mRNA||rRNA stacks reveal other geometries, which depend on the tRNA binding site, whereas 16S rRNA||23S rRNA stacks highlight the importance of specific bases in maintaining the integrity of the translational complex by linking the two rRNAs. Furthermore, tRNA||mRNA stacks exhibit distinct geometries and energetics at the E-site, indicating their significance during tRNA translocation and elimination. Overall, both A and E-sites display a more diverse distribution of inter-RNA stacks compared to the P-site. Stacking interactions in the active ribosome are not simply accidental byproducts of biochemistry but are likely invoked to compensate and support the integrity and dynamics of translation.


A computational drug-target network for yuanhu zhitong prescription.
Yuanhu Zhitong prescription (YZP) is a typical and relatively simple traditional Chinese medicine (TCM), widely used in the clinical treatment of headache, gastralgia, and dysmenorrhea. However, the underlying molecular mechanism of action of YZP is not clear. In this study, based on the previous chemical and metabolite analysis, a complex approach including the prediction of the structure of metabolite, high-throughput in silico screening, and network reconstruction and analysis was developed to obtain a computational drug-target network for YZP. This was followed by a functional and pathway analysis by ClueGO to determine some of the pharmacologic activities. Further, two new pharmacologic actions, antidepressant and antianxiety, of YZP were validated by animal experiments using zebrafish and mice models. The forced swimming test and the tail suspension test demonstrated that YZP at the doses of 4 mg/kg and 8 mg/kg had better antidepressive activity when compared with the control group. The anxiolytic activity experiment showed that YZP at the doses of 100 mg/L, 150 mg/L, and 200 mg/L had significant decrease in diving compared to controls. These results not only shed light on the better understanding of the molecular mechanisms of YZP for curing diseases, but also provide some evidence for exploring the classic TCM formulas for new clinical application.


Associations between individual cognitive factors, mode of exposure and depression symptoms in practitioners working with aversive crime material.
Background: There is extensive literature on front-line officers and investigators exposure to trauma and its negative impact on them. However, there are analytical practitioners in law enforcement who indirectly work with the traumatic experiences of other people daily, but are seldom the focus of academic research.Objective: Our goal was to conduct the first international study with these practitioners to identify the risk of depression symptoms and establish whether potentially modifiable risk factors (belief in a just world, mental imagery and thought suppression) and work-related characteristics (medium of exposure) are associated with depression.Method: 99 analysts and secondary investigators employed in police and law enforcement organizations from the UK, Europe and Canada participated in the study. The online survey was advertised to employees via their employers but hosted without employer access. Multiple regression was used to analyze the data.Results: After controlling for age, gender, ethnicity, previous exposure to trauma, and marital status, four potential risk factors were identified. Analytical practitioners with vivid mental imagery, those exposed to crime material via auditory and visual means, those who suppressed intrusive thoughts, and those who believed in a just world reported more depressive symptoms.Conclusions: The majority of our sample reported clinical levels of depressive symptoms. Four potential risk factors accounted for just under half of the variance in depression scores. We consider strategies that can be used to mitigate the potential negative influence of these factors and suggest that these are established as risk factors for depression symptoms via future longitudinal research.


A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development.
Understanding how the timing of exposure to endogenous hormones influences cancer development is critical to elucidating disease etiology. Prolactin increases proliferation and cell motility, processes important in later stage tumor development, suggesting that levels proximate (versus distant) to diagnosis may better predict risk. Thus, we calculated relative risks (RR) and 95% confidence intervals (CI) for prolactin levels on samples collected <10 (proximate) versus ≥10 (distant) years before diagnosis in the Nurses' Health Study (NHS) and NHSII with breast cancer risk, including in a subset of NHS women providing two samples 10 years apart. We measured prolactin via immunoassay in cases diagnosed from 1990 to 2010 (NHS) and 1999 to 2009 (NHSII) and matched controls. Overall, 2,468 cases and 4,021 controls had prolactin measured <10 years and 953 cases and 1,339 controls >10 years before diagnosis/reference date. There was an increased risk for higher proximate prolactin levels [RR, >15.7 vs. ≤8.1 ng/mL (i.e., top vs. bottom quartiles) = 1.20; 95% CI, 1.03-1.40; Ptrend = 0.005], but not for distant levels (RR = 0.97; Ptrend = 0.94); results were similar among women with two blood samples (Pinteraction, proximate vs. distant = 0.07). The positive association was stronger for ER(+) disease (RR = 1.28; Ptrend = 0.003) and postmenopausal women (RR = 1.37; Ptrend = 0.0002). Among postmenopausal women, the association was strongest for ER(+) disease (RR = 1.52) and lymph node-positive cases (RR = 1.63). Our data suggest that prolactin levels measured <10 years before diagnosis are most strongly associated with postmenopausal breast cancer risk, especially for ER(+) tumors and metastatic disease. This corresponds with biologic data that prolactin is etiologically important in tumor promotion.


Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up.
To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension. Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months. The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4). Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.


Adding depth to overlapping displays can improve visual search performance.
Standard models of visual search have focused upon asking participants to search for a single target in displays where the objects do not overlap one another, and where the objects are presented on a single depth plane. This stands in contrast to many everyday visual searches wherein variations in overlap and depth are the norm, rather than the exception. Here, we addressed whether presenting overlapping objects on different depths planes to one another can improve search performance. Across 4 different experiments using different stimulus types (opaque polygons, transparent polygons, opaque real-world objects, and transparent X-ray images), we found that depth was primarily beneficial when the displays were transparent, and this benefit arose in terms of an increase in response accuracy. Although the benefit to search performance only appeared in some cases, across all stimulus types, we found evidence of marked shifts in eye-movement behavior. Our results have important implications for current models and theories of visual search, which have not yet provided detailed accounts of the effects that overlap and depth have on guidance and object identification processes. Moreover, our results show that the presence of depth information could aid real-world searches of complex, overlapping displays. (PsycINFO Database Record


Phytoestrogens and breast cancer: a complex story.
Genistein is an isoflavone with oestrogenic activity that is present in a variety of soy products as a constituent of complex mixtures of bioactive compounds, whose matrix profiles play an important role in determining the overall oestrogenic bioactivity of genistein. We review data on how the profile of soy bioactive compounds can modulate genistein-stimulated oestrogen-dependent tumour growth. Our research has focused on the effects of dietary genistein on the growth of oestrogen (E)-dependent mammary tumours both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumour growth. In a similar manner, dietary genistein stimulates tumour growth in the chemically-induced (NMU) mammary cancer rodent model. Genistin, the glycoside of genistein, simulates growth similar to that of genistein and withdrawal of either genistein or genistin results in tumour regression. The extent of soy processing modulates the effects of dietary genistein in vivo as soy protein isolate, a highly purified and widely used source of protein that is processed to contain low, medium, and high amounts of isoflavones, stimulate the growth of the E-dependent mammary tumours in a dose dependent manner. In contrast to the more purified diets, studies with soy flour of equivalent genistein levels did not stimulate the growth of E-dependent breast cancer tumours in vivo. However, the size of these tumours also did not regress as is observed in control groups in which oestrogen and genistein have been withdrawn. The expression of the oestrogen-target genes of pS2, progesterone receptor, and cyclin D1 correlates with the growth of E-dependent tumours and has been consistently observed to be induced in response to treatment with dietary genistein. To evaluate whether dietary genistein interacts with current anti-oestrogen breast cancer therapies such as tamoxifen (TAM), we implanted E-dependent tumours into ovariectomized athymic mice and administered oestradiol, oestradiol plus TAM, or oestradiol, TAM, and dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM on E-stimulated tumour growth. In summary, genistein can act as an oestrogen agonist resulting in proliferation of E-dependent human breast cancer tumours in vivo and its activity can be modulated by the presence of other bioactive components in complex soy foods. Additionally, dietary genistein can negate the inhibitory effects of TAM on E-stimulated growth of MCF-7 cell tumours implanted into ovariectomized athymic mice.


POZ domain transcription factor, FBI-1, represses transcription of ADH5/FDH by interacting with the zinc finger and interfering with DNA binding activity of Sp1.
The POZ domain is a protein-protein interaction motif that is found in many transcription factors, which are important for development, oncogenesis, apoptosis, and transcription repression. We cloned the POZ domain transcription factor, FBI-1, that recognizes the cis-element (bp -38 to -22) located just upstream of the core Sp1 binding sites (bp -22 to +22) of the ADH5/FDH minimal promoter (bp -38 to +61) in vitro and in vivo, as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ADH5/FDH minimal promoter is potently repressed by the FBI-1. Glutathione S-transferase fusion protein pull-down showed that the POZ domains of FBI-1, Plzf, and Bcl-6 directly interact with the zinc finger DNA binding domain of Sp1. DNase I footprinting assays showed that the interaction prevents binding of Sp1 to the GC boxes of the ADH5/FDH promoter. Gal4-POZ domain fusions targeted proximal to the GC boxes repress transcription of the Gal4 upstream activator sequence-Sp1-adenovirus major late promoter. Our data suggest that POZ domain represses transcription by interacting with Sp1 zinc fingers and by interfering with the DNA binding activity of Sp1.


What Role Does Patient Gratitude Play in the Relationship Between Relationship Quality and Patient Loyalty?
The environment in health care organizations is becoming increasingly competitive. Therefore, to improve patient return rates, health care organizations need to examine how to enhance the physician-patient relationship. In particular, the role of patient gratitude on the physician-patient relationship in health care organizations is still ambiguous. The specific role of patient gratitude in the medical service industry needs to be identified. Therefore, this study aimed to investigate physician-patient interactions with reference to relationship marketing and to further understand the relationships among relationship quality, patient gratitude, and patient loyalty. The potential effects of patient gratitude on the physician-patient relationship were examined by testing mediation effect. The results demonstrated that patient gratitude had a notable effect on the association between relationship quality and patient loyalty. To improve the physician-patient relationship in the medical service industry, health care managements should not ignore the 3 relationship quality tactics perceived by patients, specially the role of the potential effect of patient gratitude on relational building.


Neuroendoscopic fenestration of glioependymal cysts to the ventricle: report of 3 cases.
Glioependymal cysts are rare congenital lesions of the central nervous system. Reported surgical treatments of these lesions have varied and yielded mixed results, and the optimal surgical strategy is still controversial. The authors here report the clinical and surgical outcomes for three adult patients successfully treated with neuroendoscopic fenestration into the ventricular system. The patients had presented with symptomatic glioependymal cysts in the period from 2013 to 2016 at the authors' institution. All underwent minimally invasive neuroendoscopic fenestration of the glioependymal cyst into the lateral ventricle via a stereotactically guided burr hole. Presenting clinical and radiological findings, operative courses, and postintervention outcomes were evaluated.All three patients initially presented with symptoms related to regional mass effect of the underlying glioependymal cyst, including headaches, visual disturbances, and hemiparesis. All patients were successfully treated with endoscopic fenestration of the cyst wall into the lateral ventricle, where the wall was thinnest. Postoperatively, all patients reported improvement in their presenting symptoms, and neuroimaging demonstrated decompression of the cyst. Clinical follow-up ranged from 4 months to 5 years without evidence of reexpansion of the cyst or shunt requirement.Compared to open resection and shunting of the cyst contents, minimally invasive endoscopic fenestration of a glioependymal cyst into the ventricular system is a safe and effective surgical option. This approach is practical, is less invasive than open resection, and appears to provide a long-term solution.


Impact of Plasmodium falciparum infection on DNA methylation of circulating immune cells.
The regulation of immune cell responses to infection is a complex process that involves various molecular mechanisms, including epigenetic regulation. DNA methylation has been shown to play central roles in regulating gene expression and modulating cell response during infection. However, the nature and extent to which DNA methylation is involved in the host immune response in human malaria remains largely unknown. Here, we present a longitudinal study investigating the temporal dynamics of genome-wide in vivo DNA methylation profiles using 189 MethylationEPIC 850 K profiles from 66 children in Burkina Faso, West Africa, sampled three times: before infection, during symptomatic parasitemia, and after malaria treatment. The results revealed major changes in the DNA methylation profiles of children in response to both Plasmodium falciparum infection and malaria treatment, with widespread hypomethylation of CpGs upon infection (82% of 6.8 K differentially methylated regions). We document a remarkable reversal of CpG methylation profiles upon treatment to pre-infection states. These changes implicate divergence in core immune processes, including the regulation of lymphocyte, neutrophil, and myeloid leukocyte function. Integrative DNA methylation-mRNA analysis of a top differentially methylated region overlapping the pro-inflammatory gene TNF implicates DNA methylation of TNF cis regulatory elements in the molecular mechanisms of TNF regulation in human malaria. Our results highlight a central role of epigenetic regulation in mounting the host immune response to P. falciparum infection and in response to malaria treatment.


Biomechanical insights into ankle instability: a finite element analysis of posterior malleolus fractures.
Posterior malleolus fractures are known to be associated with ankle instability. The complexities involved in obtaining precise laboratory-based spatial pressure measurements of the ankle highlight the significance of exploring the biomechanical implications of these fractures. Finite element analysis was utilized to examine the stress distribution across the contact surface of the ankle joint, both in its natural state and under varied sagittal fracture line angles. The study aimed to identify stress concentration zones and understand the influence of sagittal angles on stress distribution. Three distinct stress concentration zones were identified on the ankle's contact surface: the anterolateral tibia, the anteromedial tibia, and the fracture line. The most significant stress was observed at the fracture line when a fracture occurs. Stress at the fracture line notably spikes as the sagittal angle decreases, which can potentially compromise ankle stability. Larger sagittal angles exhibited only minor stress variations at the contact surface's three vertices. It was inferred that sagittal angles below 60° might pose risks to ankle stability. The research underscores the potential implications of fractures on the stress profile of the ankle joint, emphasizing the role of the contact surface in ensuring stability. The identification of three zones of stress concentration and the influence of sagittal angles on stress distribution offers a valuable reference for therapeutic decision-making. Further, the study reinforces the importance of evaluating sagittal fracture angles, suggesting that angles below 60° may compromise ankle stability.


A multi-agent model to study epidemic spreading and vaccination strategies in an urban-like environment.
Worldwide urbanization calls for a deeper understanding of epidemic spreading within urban environments. Here, we tackle this problem through an agent-based model, in which agents move in a two-dimensional physical space and interact according to proximity criteria. The planar space comprises several locations, which represent bounded regions of the urban space. Based on empirical evidence, we consider locations of different density and place them in a core-periphery structure, with higher density in the central areas and lower density in the peripheral ones. Each agent is assigned to a base location, which represents where their home is. Through analytical tools and numerical techniques, we study the formation mechanism of the network of contacts, which is characterized by the emergence of heterogeneous interaction patterns. We put forward an extensive simulation campaign to analyze the onset and evolution of contagious diseases spreading in the urban environment. Interestingly, we find that, in the presence of a core-periphery structure, the diffusion of the disease is not affected by the time agents spend inside their base location before leaving it, but it is influenced by their motion outside their base location: a strong tendency to return to the base location favors the spreading of the disease. A simplified one-dimensional version of the model is examined to gain analytical insight into the spreading process and support our numerical findings. Finally, we investigate the effectiveness of vaccination campaigns, supporting the intuition that vaccination in central and dense areas should be prioritized.


Acute pancreatitis in pregnancy with Ascaris infestation.
Two cases of acute pancreatitis in pregnancy occurred among Vietnamese evacuees in Arkansas. In both cases, Ascaris lumbricoides seemed the likely cause. In endemic areas including the rural southeastern United States, a high index of suspicion for ascariasis is needed because these worms may cause a variety of abdominal disorders including pancreatitis, cholecystitis, and bowel obstruction. In appropriate settings, a therapeutic trial with antihelminthics is indicated.


Assessment of Antioxidant Capacity and Putative Healthy Effects of Natural Plant Products Using Soybean Lipoxygenase-Based Methods. An Overview.
In the last decades, increasing demand of antioxidant-rich foods and growing interest in their putative role in prevention of degenerative diseases have promoted development of methods for measuring Antioxidant Capacity (AC). Nevertheless, most of these assays use radicals and experimental conditions far from the physiological ones, and are able to estimate only one or a few antioxidant mechanisms. On the other hand, the novel LOX/RNO and LOX⁻FL methods, based on secondary reactions between the soybean lipoxygenase (LOX)-1 isoenzyme and either 4-nitroso-N,N-dimethylaniline (RNO) or fluorescein (FL), may provide a more comprehensive AC evaluation. In fact, they are able to detect simultaneously many antioxidant functions (scavenging of some physiological radical species, iron ion reducing and chelating activities, inhibition of the pro-oxidant apoenzyme) and to highlight synergism among phytochemicals. They are applied to dissect antioxidant properties of several natural plant products: food-grade antioxidants, cereal and pseudocereal grains, grain-derived products, fruits. Recently, LOX⁻FL has been used for ex vivo AC measurements of human blood samples after short- and long-term intakes of some of these foods, and the effectiveness in improving serum antioxidant status was evaluated using the novel Antioxidant/Oxidant Balance (AOB) parameter, calculated as an AC/Peroxide Level ratio. An overview of data is presented.


Maternal mortality in women aged 35 years or older: United States.
To examine maternal mortality among women aged 35 years or older, we used death certificates from the United States for 1974 through 1978. There were 425 maternal deaths, corresponding to a mortality rate of 58.3 deaths per 100,000 live births. This rate was higher than the rate for women 20 through 34 years of age (race-adjusted relative risk [RR] = 4.0; 95% confidence interval [CI], 3.6 to 4.4). The leading causes of death were obstetric hemorrhage and embolism. Black women had higher mortality rates than white women for deaths without abortive outcomes (RR = 3.3; CI, 2.7 to 4.1) and with abortive outcomes (RR = 9.4; 95% CI, 5.8 to 15.3), and the latter difference was largely due to a higher rate of deaths associated with ectopic pregnancy among black women. From 1974 through 1978, compared with 1982, maternal mortality rates for women aged 35 years or older reported by the National Center for Health Statistics declined approximately 50%. Among white women, changes in age and parity accounted for less than half of this decrease, suggesting that improvements have occurred in age- and parity-specific mortality for women aged 35 years or older.


Simultaneous separation of jasmonic acid conjugates with amino acids by MEKC.
Jasmonic acid (JA) conjugates with amino acids (AAs) are a group of plant hormone in the family of jasmonates. The separation of stereoisomers of JA-AA conjugates is a very challenging work since these stereoisomers have similar chromatographic and electrophoretic behavior. Simultaneous separation of ten (±)-JA conjugates with five AAs including L-Tyr (tyrosine), L-leucine, L-Ile (isoleucine), L-valine, and L-phenylalanine and their stereoisomers has been achieved by MEKC with diode array detector in this work. Optimum separation of the analytes was obtained on a 61.5 cm × 75 μm id capillary using a running buffer containing 80 mM SDS and 50 mM phosphates (pH 7.0) at +18 kV applied voltage and capillary temperature of 35°C. Ten stereoisomers of JA conjugates with five AAs are completely separated in 13 min. The RSDs of the migration times and peak areas of the ten stereoisomers were in the range of 0.48-1.03% and 1.03-2.07%, respectively. In the tested concentration range, good linear relationships (correlation coefficients above 99%) between peak areas and concentrations of the analytes were observed. The proposed method has been successfully applied to the analysis of spiked rice floret sample and original reaction solution of (±)-JA-Ile conjugate and (±)-JA-Tyr conjugate. The recoveries ranged from 91.7 to 107.6% for the rice floret sample and 92.9 to 107.2% for the original reaction solution.


Honey and Cancer: Current Status and Future Directions.
Cancer is a leading cause of death worldwide and poses a challenge to treatment. With overwhelming evidence of the role played by diet and lifestyle in cancer risk and prevention, there is a growing interest into the search for chemopreventative or chemotherapeutic agents derived from natural products. Honey is an important source of bioactive compounds derived from plants and recent years have seen an increased interest in its anticancer properties. This review examines the role of honey in targeting key hallmarks of carcinogenesis, including uncontrolled proliferation, apoptosis evasion, angiogenesis, growth factor signalling, invasion, and inflammation. The evidence for honey as an adjunct to conventional cancer therapy is also presented. The review also highlights gaps in the current understanding and concludes that, before translation of evidence from cell culture and animal studies into the clinical setting, further studies are warranted to examine the effects of honey at a molecular level, as well as on cells in the tumour environment.


Modes of late mortality in patients with a Fontan circulation.
The mechanisms of attrition of the Fontan population have been poorly characterised and it is unclear whether some of the deaths are potentially preventable. We analysed the circumstances of late death in patients with a Fontan circulation, with a special focus on identifying lesions amenable to intervention that may have contributed to the decline of their circulation. Between 1975 and 2018, a total of 105 patients from a Bi-National Registry died beyond 1 year after Fontan completion, at a median age of 18.6 (IQR 13.8-26.0) years old, 12.7 (IQR 6.0-19.3) years after Fontan completion. A total of 105 patients died-63 patients (60%) with an atriopulmonary (AP) Fontan, 21 patients (20%) with a lateral tunnel (LT) and 21 patients (20%) with an extracardiac conduit (ECC). 72 patients (69%) were reviewed within 2 years preceding death, with 32% (23/72) deemed to be clinically well. Fontan circulatory failure was the most common cause of death in 42 patients (45%). Other causes of death included sudden death/arrhythmia (19%), perioperative death (12%), neurological complication (7%) and thromboembolism (7%). All patients with an LT or ECC who died from Fontan failure had at least one surgical defect that was amenable to intervention at time of death. Conventional clinical surveillance has been insensitive in detecting a significant proportion of patients at risk of late death. Fontan circulatory failure contributes to half of the late deaths. Patients with an LT or ECC Fontan who died with a clinical picture of circulation failure may have potentially correctable lesions.


Surfactant micelles: model systems for flow instabilities of complex fluids.
Complex fluids such as emulsions, colloidal gels, polymer or surfactant solutions are all characterized by the existence of a "microstructure" which may couple to an external flow on time scales that are easily probed in experiments. Such a coupling between flow and microstructure usually leads to instabilities under relatively weak shear flows that correspond to vanishingly small Reynolds numbers. Wormlike micellar surfactant solutions appear as model systems to study two examples of such instabilities, namely shear banding and elastic instabilities. Focusing on a semidilute sample we show that two-dimensional ultrafast ultrasonic imaging allows for a thorough investigation of unstable shear-banded micellar flows. In steady state, radial and azimuthal velocity components are recovered and unveil the original structure of the vortical flow within an elastically unstable high shear rate band. Furthermore thanks to an unprecedented frame rate of up to 20,000 fps, transients and fast dynamics can be resolved, which paves the way for a better understanding of elastic turbulence.


Trichuris trichiura in a post-Colonial Brazilian mummy.
Trichuris trichiura is a soil-transmitted helminth which is prevalent in warm, moist, tropical and subtropical regions of the world with poor sanitation. Heavy whipworm can result either in Trichuris dysenteric syndrome - especially in children - or in a chronic colitis. In heavy infections, worms can spread proximally and may cause ileitis. Here we provide first microscopic evidence for a T. trichiura adult worm embedded in the rectum of a post-Colonial Brazilian adult mummy. During Colonial and post-Colonial times, many European chroniclers described a parasitic disease named Maculo whose symptomatology coincides with heavy helminthiasis. Based on our findings and on comparison of ancient textual evidence with modern description of heavy whipworm, we feel confident in considering that the two syndromes are expressions of the same pathological condition.


Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children.
Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.


Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells.
Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies.


Oxidative stress induced in rat brain by a combination of 3-nitropropionic acid and global ischemia.
In our investigation, we describe the complex model of brain oxidative stress consisted of combination of experimental brain ischemia and energy metabolism violation induced by irreversible inhibitor of mitochondrial succi-nate dehydrogenase, 3-nitropropionate (3-NPA). 3-NPA causes selective degeneration of striatum neurons, which is extremely sensitive to energy deficit. This complex model allows revealing not only biochemical but also neurological symptoms in experimental animals that permits proper estimation of protective effect of different drugs on animal status. Combination of global ischemia induced by 3-vessel occlusion of major arteries supplys rat brain and subsequent 5-day reperfusion with intraperitoneal injection of 3-nitropropionic acid induces vigorous oxidative stress in brain tissues accompanied by evident neurological symptoms in Wistar rats. Such a combination of damaging factors may be considered as a new complex experimental model of brain oxidative stress permitting the evaluation of neuroprotective effect of potential therapeutic agents. Using this model, protective effect of neuropeptide carnosine was demonstrated which is in agreement with previous data.


Meta-analysis: rectal indomethacin for the prevention of post-ERCP pancreatitis.
Despite initial evidence in the literature, nonsteroidal anti-inflammatory drugs (NSAIDs) have not been widely used to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). To complete a meta-analysis of high-quality RCTs that included the latest available literature published after past meta-analytical efforts A comprehensive electronic literature search was carried out for RCTs comparing peri-procedural rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed by the Cochrane risk of bias tool. Fixed model Mantel-Haenszel meta-analysis, Q test and I(2) index were used. Several subgroup and sensitivity analyses were planned. A total of four of 61 retrieved trials between 2007 and 2012 (n = 1470) were included. No significant publication bias existed. All studies used similar criteria to detect pancreatitis. The pooled proportion estimate of the rate of pancreatitis was 5.1% with indomethacin and 10.3% with placebo. After excluding the high-risk patients, the rates were 3.9% and 7.9% respectively. Fixed model meta-analysis showed that the rate of pancreatitis was significantly lower using indomethacin as compared with placebo [OR = 0.49(0.34-0.71); P = 0.0002]. Number needed to treat was 20. There was no significant statistical or clinical heterogeneity. In subgroup analysis, the difference remained unchanged for average-risk population [OR = 0.49(0.28-0.85); P = 0.01] or in preventing severe PEP [OR = 0.41(0.21-0.78); P = 0.007]. The result of the main outcome remained robust in multiple sensitivity analyses. Rectal indomethacin used immediately before or after ERCP significantly reduces the risk of PEP to half in both low- and high-risk patients, and with both statistically and clinically significant conclusions. These results suggest that a possible change in routine practice for patients at both low and high risk of developing PEP should be advocated.


Insights into the sodiation mechanism of hard carbon-like materials from electrochemical impedance spectroscopy.
To render the sodium ion battery (SIB) competitive among other technologies, the processes behind sodium storage in hard carbon anodes must be understood. For this purpose, electrochemical impedance spectroscopy (EIS) is usually undervalued, since fitting the spectra with equivalent circuit models requires an a priori knowledge about the system at hand. The analysis of the distribution of relaxation times (DRT) is an alternative, which refrains from fitting arbitrarily nested equivalent circuits. In this paper, the sodiation and desodiation of a hard carbon anode is studied by EIS at different states of charge (SOC). By reconstructing the DRT function, highly resolved information on the number and relative contribution of individual electrochemical processes is derived. During the sloping part of the sodiation curve, mass transport is found to be the most dominant source of resistance but rapidly diminishes when the plateau phase is reached. An equivalent circuit model qualitatively reproducing the experimental data of the sloping region was built upon the DRT results, which is particularly useful for future EIS studies on hard carbon SIB anodes. More importantly, this work contributes to establish EIS as a practical tool to directly study electrode processes without the bias of a previously assumed model.


Gene expression in the cos region of the Streptomyces temperate actinophage phi C31.
A transcription map of a 5.12 kb region containing the cos ends of actinophage phi C31 was determined using RNA prepared from induced and uninduced cultures of the temperature-sensitive lysogen, Streptomyces coelicolor A3(2) (phi C31cts1). In induced cultures, RNA synthesis was detected only late in the lytic cycle. A late operon initiated downstream of the int gene on the right-hand end of the genome traversed the cos ends and extended at least 3.6 kb along the left-hand end. Shorter, possibly processed, mRNAs were also present. The map was superimposed on the DNA sequence of 2.8 kb of the region, part of which had been determined previously and part of which is presented here. The late-expressed transcripts contained a tRNA(Thr)-like gene and four ORFs (1, 2, 3 and 5) detected on the basis of codon bias. Analysis of the putative protein products showed that one of the ORFs could encode a lysis protein and at least one may be involved in DNA maturation. Transcription mapping of RNA from uninduced cultures demonstrated a 620 nt transcript, xRNA1, of ORF6. So far this is the only gene in phi C31 found to be expressed right to left with respect to the standard map of phi C31; its function during lysogenic growth could not be deduced from database searches.


Towards a human oral vaccine for anthrax: the utility of a Salmonella Typhi Ty21a-based prime-boost immunization strategy.
We previously demonstrated the ability of an orally administered attenuated Salmonella enterica serovar Typhimurium strain expressing the protective antigen (PA) of Bacillus anthracis to confer protection against lethal anthrax aerosol spore challenge [Stokes MG, Titball RW, Neeson BN, et al. Oral administration of a Salmonella enterica-based vaccine expressing Bacillus anthracis protective antigen confers protection against aerosolized B. anthracis. Infect Immun 2007;75(April (4)):1827-34]. To extend the utility of this approach to humans we constructed variants of S. enterica serovar Typhi Ty21a, an attenuated typhoid vaccine strain licensed for human use, which expressed and exported PA via two distinct plasmid-based transport systems: the Escherichia coli HlyA haemolysin and the S. Typhi ClyA export apparatus. Murine immunogenicity studies confirmed the ability of these constructs, especially Ty21a expressing the ClyA-PA fusion protein, to stimulate strong PA-specific immune responses following intranasal immunization. These responses were further enhanced by a subsequent boost with either parenterally delivered recombinant PA or the licensed US human alum-adsorbed anthrax vaccine (AVA). Anthrax toxin neutralizing antibody responses using this prime-boost regimen were rapid, vigorous and broad in nature. The results of this study demonstrate the feasibility of employing a mucosal prime with a licensed Salmonella Typhi vaccine strain followed by a parenteral protein boost to stimulate rapid protective immunity against anthrax.


Intercellular Resistance to BRAF Inhibition Can Be Mediated by Extracellular Vesicle-Associated PDGFRβ.
Treatment of BRAF mutant melanoma with kinase inhibitors has been associated with rapid tumor regression; however, this clinical benefit is short-lived, and most patients relapse. A number of studies suggest that the extracellular environment promotes BRAF inhibitor resistance and tumor progression. Extracellular vesicles, such as exosomes, are functional mediators in the extracellular environment. They are small vesicles known to carry a concentrated group of functional cargo and serve as intercellular communicators not only locally but also systemically. Increasingly, it is reported that extracellular vesicles facilitate the development of drug resistance in cancer; however, their role in BRAF inhibitor resistance in melanoma is unclear. Here we investigated if extracellular vesicles from BRAF inhibitor-resistant melanoma could influence drug sensitivity in recipient melanoma cells. We demonstrate that the resistance driver, PDGFRβ, can be transferred to recipient melanoma cells via extracellular vesicles, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from MAPK pathway BRAF inhibition. These data suggest that the BRAF inhibitor-sensitive phenotype of metastatic melanoma can be altered by delivery of PDGFRβ by extracellular vesicles derived from neighboring drug-resistant melanoma cells.


The smallest vertebrate, teleost fish, can utilize synthetic dipeptide-based diets.
In vitro studies of brush-border intestinal transport of dipeptides and cytoplasmic hydrolysis in fish suggest that these processes could be key mechanisms in the absorption and utilization of nutrients for growth. However, in vivo experimentation to study the nutritional importance of these processes was needed. We compared three dietary formulations based on free, peptide and protein sources of amino acids. Our results were the first to show that a synthetic dipeptide (PP)-based diet could support growth in the early stages of ontogenesis of a teleost fish, rainbow trout (Oncorhynchus mykiss), whereas a free amino acid (FAA)-based diet failed. We found that fish fed an FAA-based diet had an increased rate of ammonia excretion [1.78 +/- 0.19 mmol NH(3)-N/(kg body wt.h)], compared with fish fed a PP-based diet [1.25 +/- 0.07 mmol NH(3)-N/(kg body wt.h)], suggesting that deamination is involved in the metabolism of dietary FAA. Teleost fish are known to obtain a high proportion of total energy from protein, compared with higher vertebrates. However, we found that feeding trout alevins a PP-based diet increased postprandial oxygen consumption for 2 to 24 h, whereas other treatments decreased 24-h postprandial metabolism. This may indicate that peptide metabolism is less efficient than protein metabolism. Juvenile rainbow trout differed from alevins in their response to FAA- and PP-based diets. These observations strongly suggest that intestinal dietary peptide transport and hydrolysis could support protein synthesis and growth in vertebrates that respond poorly to FAA-based diets. We conclude that nutrient administration may be improved by manipulating dietary peptide composition and peptide/protein ratios, leading to better utilization of synthetic peptides, with nutritional and therapeutic implications for all vertebrates.


Temporal coding of visual information in the thalamus.
The amount of information a sensory neuron carries about a stimulus is directly related to response reliability. We recorded from individual neurons in the cat lateral geniculate nucleus (LGN) while presenting randomly modulated visual stimuli. The responses to repeated stimuli were reproducible, whereas the responses evoked by nonrepeated stimuli drawn from the same ensemble were variable. Stimulus-dependent information was quantified directly from the difference in entropy of these neural responses. We show that a single LGN cell can encode much more visual information than had been demonstrated previously, ranging from 15 to 102 bits/sec across our sample of cells. Information rate was correlated with the firing rate of the cell, for a consistent rate of 3.6 +/- 0.6 bits/spike (mean +/- SD). This information can primarily be attributed to the high temporal precision with which firing probability is modulated; many individual spikes were timed with better than 1 msec precision. We introduce a way to estimate the amount of information encoded in temporal patterns of firing, as distinct from the information in the time varying firing rate at any temporal resolution. Using this method, we find that temporal patterns sometimes introduce redundancy but often encode visual information. The contribution of temporal patterns ranged from -3.4 to +25.5 bits/sec or from -9.4 to +24.9% of the total information content of the responses.


Anthropometric parameters of nutritional assessment as predictive factors of the Mini Nutritional Assessment (MNA) of hospitalized elderly patients.
The objective of this study was to identify nutritional indicators that predict MNA (mini nutritional assessment) classification in hospitalized elderly patients. This cross-sectional study assessed the nutritional status of 109 elderly patients at the beginning of their hospital stay with anthropometric and laboratory indicators and the MNA. Habitual energy intake (HEI) was also determined. The assessed nutritional indicators were investigated by univariate and multivariate logistic regression analysis to verify if they can predict MNA classification. The odds ratio (OR) and its respective confidence interval (CI) of 95% were also calculated, and the significance level was set at 5% (p < 0.05). The nutritional status of most patients (61.47%) was appropriate but 30.28% were at risk of malnourishment and 8.26% were malnourished. Statistical differences were found for those aged more than 70 years and for arm circumference, body mass index, calf circumference, triceps skinfold thickness and mid-arm muscle circumference. Initially, the predictive factors identified by univariate logistic regression were body mass index (BMI) (p=0.0001; OR=0.825), calf circumference (CC) (p=0.0026; OR=0.832), arm circumference (AC) (p < 0.0001; OR=0.787), triceps skinfold thickness (TST) (p=0.0014; OR=0.920) and mid-arm muscle circumference (MAMC) (p=0.0003; OR=0.975); later, multiple logistic regression analyses revealed that first AC (p=0.0025; OR=0.731 (0.597 - 0.895)), then BMI (p= < 0.0001; OR=10.909 (3.298 - 36.085)) and finally TST (p=0.0040; OR=0.924 (0.876 - 0.975)) and MAMC (p=0.0010; OR=0.976 (0.962 - 0.990)) were factors that predict MNA classification. In the conditions of this study, first AC, then BMI and finally TST and MAMC together were capable of predicting MNA classification.