Assessing relationships between chemical exposure, parasite infection, fish health, and fish ecological status: a case study using chub (Leuciscus cephalus) in the Bílina River, Czech Republic.
Multiple stressor scenarios, as they are relevant in many watersheds, call for approaches extending beyond conventional chemical-focused approaches. The present study, investigated the fish population, represented by chub (Leuciscus cephalus), in the Bílina River (Czech Republic), which is impacted by various pollution sources and might pose a risk on the fish population. To confirm or reject this hypothesis it was examined whether there exists an association between abundance of chub and exposure to toxic chemicals as well as natural stressors, represented by parasites, and whether health-related suborganismal traits, namely, organ indices, tissue histopathology, and immune parameters, would help in revealing relationships between stressor impact and population status. Toxic pressure was assessed by the toxic unit approach, which gives an integrative estimate of toxic effect concentrations and by measuring the biomarkers cytochrome P4501A and vitellogenin, which indicate exposure to bioavailable arylhydrocarbon- or estrogen receptor ligands. Parasite pressure was estimated by determining abundance and species composition of ecto- and endoparasites of chub. Chub abundance was high upstream in the Bílina, low to zero in the middle stretches, and increased again downstream. Toxic pressure increased in the downstream direction, while parasite intensity decreased in this direction. Health status of chub did not differ clearly between up-, middle-, and downstream sites. Thus, it appears that neither toxic pressure nor parasite pressure nor their combination translates into a change of chub health status. By using varied assessment tools, this study provides evidence against a presumed causative role of toxicants impairing the fish ecological status of the Bílina River.


Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort.
Adolescents with human immunodeficiency virus (HIV) infection are at increased risk for tuberculosis (TB), underscoring the importance of early identification of TB infection. The goals of this study were to assess the factors associated with the completion of evaluations for TB in a cohort of HIV-positive adolescents and young adults and to describe the prevalence of Mycobacterium tuberculosis infection and adherence to antituberculous treatment regimens. A retrospective chart review was done for all HIV-positive adolescents and young adults, ages 13 to 21 years (n = 49), seen in a comprehensive care program from January 1991 through December 1992. Data collected included CD4 cell count, HIV clinical status, living situation, substance use history, and the completion of an annual evaluation for TB infection. The evaluation consisted of a tuberculin skin test (Mantoux test), using an intraepidermal injection of 0.1 mL of 5 tuberculin units of purified protein derivative (PPD) and a simultaneous Merieux multitest anergy panel. Chi-square analysis was used to assess the association between the completion of the evaluation for TB and both living status and substance use. Thirty-one (63%) of 49 patients completed evaluations for TB. Of the 31 completed evaluations, 18 were assessed by clinic staff on site, and 13 were assessed by other medical or trained nonmedical observers through community networking efforts. Neither homelessness nor illicit substance use were factors in the completion of the evaluation. Six (19%) of the 31 patients had positive PPD skin test results. Three had medical histories and chest radiographs suggesting active TB, and all were hospitalized for at least 2 weeks. Two had positive cultures for M tuberculosis, although the third also responded clinically to antituberculous therapy. All three were otherwise asymptomatic for HIV infection, with only moderately depressed CD4 cell counts. All three were homeless and used crack cocaine. After the initial treatment as inpatients, none completed treatment within the prescribed time period. The completions of the evaluations for TB were greatly facilitated by community networking, but innovative strategies to enhance both screening and treatment programs, such as training youth service providers in the community to read PPD skin tests, expansion of directly observed therapy services, and youth-centered programs for housing and substance use, need further development. The high prevalence of TB in the cohort underscores the need for providers to increase efforts to identify cases of TB infection among adolescents and young adults and to incorporate HIV risk assessment, counseling, and testing into their practices routinely.


Can Altering Grip Technique and Bag Size Optimize Volume Delivered with Bag-Valve-Mask by Emergency Medical Service Providers?
Emergency Medical Services (EMS) professionals rely on the bag-valve-mask (BVM) to provide life-saving positive-pressure ventilation in the prehospital setting. Multiple emergency medicine and critical care studies have shown that lung-protective ventilation protocols reduce morbidity and mortality. A recent study has shown that the volumes typically delivered by EMS professionals with the adult BVM are often higher than recommended by lung-protective ventilation protocols. Our primary objective was to determine if a group of EMS professionals could reduce the volume delivered by adjusting the way the BVM was held. Secondary objectives included 1) if the adjusted grip allowed for volumes more consistent with lung-protection ventilation strategies and 2) comparing volumes to similar grip strategies used with a smaller BVM. A patient simulator of a head and thorax was used to record respiratory rate, tidal volume, peak pressure, and minute volume delivered by participants for 1 minute each across 6 different scenarios: 3 different grips (using the thumb and either 3 fingers, 2 fingers, or one finger) with 2 different sized BVMs (adult and pediatric). Trials were randomized by blindly selecting a paper with the scenario listed. A convenience sample of EMS providers was used based on EMS provider and research staff availability. We enrolled 50 providers from a large, busy, urban hospital-based EMS agency a mean 8.60 (SD = 9.76) years of experience. Median volumes for each scenario were 836.0 mL, 834.5 mL, and 794 mL for the adult BMV (p = 0.003); and 576.0 mL, 571.5 mL, and 547.0 mL for the pediatric BVM (p < 0.001). Across all 3 grips, the pediatric BVM provided more breaths within the recommended volume range for a 70 kg patient (46.4% vs. 0.4%; p < 0.001) with only a 1.1% of breaths below the recommended tidal volume. The study suggests that it is possible to alter the volume provided by the BVM by altering the grip on the BVM. The tidal volumes recorded with the pediatric BVM were above recommended range in 2 of the 3 grips. The volumes of the pediatric BVM were overall more consistent with lung-protective ventilation volumes when compared to all 3 finger-grips of the adult BVM.


Chronologic analysis of variations in retinal damage in two strains of rats after short-term illumination.
In order to determine whether an optimal period existed for evaluating retinal photodamage in rats, a chronologic analysis was made of quantifiable changes in the outer nuclear layer (ONL) and retinal thicknesses in Sprague-Dawley (SD) and Wag/Rij rats after a single, 24 hr exposure to fluorescent light. A gradual reduction in ONL and retinal thicknesses occurred between postexposure days 0 and 10 and appeared to stabilize by day 14 in both strains. The percent difference in both ONL and retinal thickness in unexposed and exposed rats was greater in Wag/Rij than in SD rats. That the superior hemisphere of the retina was more susceptible to photodamage than the inferior was substantiated, and the difference was greater in the Wag/Rij than in SD rats. This finding emphasizes a significant variability between rat strains and is possibly a manifestation of the slowly progressing genetic retinopathy in the Wag/Rij rats. Results indicated that the optimal period for assessing photodamage under these experimental conditions was not sooner than 10 to 14 days after exposure. Quantifiable analyses prior to that time would not provide an accurate evaluation of the total influence of a short-tern exposure period.


The Mortality Response to Absolute and Relative Temperature Extremes.
While the impact of absolute extreme temperatures on human health has been amply studied, far less attention has been given to relative temperature extremes, that is, events that are highly unusual for the time of year but not necessarily extreme relative to a location's overall climate. In this research, we use a recently defined extreme temperature event metric to define absolute extreme heat events (EHE) and extreme cold events (ECE) using absolute thresholds, and relative extreme heat events (REHE) and relative extreme cold events (RECE) using relative thresholds. All-cause mortality outcomes using a distributed lag nonlinear model are evaluated for the largest 51 metropolitan areas in the US for the period 1975-2010. Both the immediate impacts and the cumulative 20-day impacts are assessed for each of the extreme temperature event types. The 51 metropolitan areas were then grouped into 8 regions for meta-analysis. For heat events, the greatest mortality increases occur with a 0-day lag, with the subsequent days showing below-expected mortality (harvesting) that decreases the overall cumulative impact. For EHE, increases in mortality are still statistically significant when examined over 20 days. For REHE, it appears as though the day-0 increase in mortality is short-term displacement. For cold events, both relative and absolute, there is little mortality increase on day 0, but the impacts increase on subsequent days. Cumulative impacts are statistically significant at more than half of the stations for both ECE and RECE. The response to absolute ECE is strongest, but is also significant when using RECE across several southern locations, suggesting that there may be a lack of acclimatization, increasing mortality in relative cold events both early and late in winter.


Prospects for cannabinoid therapies in basal ganglia disorders.
Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ(9) -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation.


Percutaneous coronary intervention in the context of systemic inflammation: more injury and worse outcome.
Minor myocardial injury (MMI), identified by elevated serum levels of cardiac markers, is not uncommon after successful, uncomplicated elective percutaneous coronary intervention (PCI) in patients with stable angina. Serum cardiac troponin, especially cardiac troponin I (cTnI), are more sensitive than serum creatine kinase - MB in detecting MMI. Occlusion of small side-branch vessels, visualized by angiography, may explain the mechanism of the MMI in some, but not all patients. Occlusion of small intramyocardial vessels, not visualized by angiography, might be the mechanism of MMI in these patients. Recent reports have shown that cardiac troponin I elevation after successful, uncomplicated elective PCI in patients with stable angina may be a marker of adverse long-term outcome. Also, it has recently been reported that increased serum C-Reactive protein (CRP) is common in patients with stable angina and is a significant and independent determinant of MMI after uncomplicated elective PCI, indicating involvement of the systemic inflammatory state in the etiology of this periprocedural myocardial injury. An intense inflammatory response is expected following PCI in patients with increased baseline CRP levels, which can cause small vessel occlusion and/or microembolization that will lead to troponin elevation. With these findings in mind, and with the observation that increased risk associated with systemic inflammation can be reduced with certain preventive therapies, CRP may help to identify those who would benefit most from these pharmacological therapies before coronary interventions.


Prognosis by measurements of left ventricular function during exercise. Duke Noninvasive Research Working Group.
This study was performed to determine whether gated equilibrium radionuclide angiogram measurements of left ventricular function during rest and exercise add independent information to clinical and catheterization data in predicting cardiac death. The study population consisted of 863 consecutive patients undergoing exercise gated equilibrium radionuclide angiography within 90 days of cardiac catheterization with data prospectively entered into the Duke Cardiovascular Database. All patients were symptomatic, medically treated, with significant coronary artery disease and had undergone follow-up for < or = 6 yr. A univariable and multivariable Cox regression analysis was utilized to evaluate the independent power in predicting 147 (17.0%) cardiac deaths. This risk-adjusted analysis revealed that only rest and exercise ejection fraction as well as maximum workload contained independent prognostic information; the nuclear variables contributed 63% of the total information within the model. A multivariable model including exercise ejection fraction and clinical history variables provided slightly more prognostic information than the combination of cardiac catheterization and clinical data. Multigated equilibrium radionuclide angiography is a key predictor of cardiac death when compared to clinical and cardiac catheterization data in patients with symptomatic, medically treated coronary artery disease. Thus, long-term outcome for patients may be determined by utilizing this noninvasive tool even when clinical and cardiac catheterization data are also available.


Glycoprotein C Gene of Caprine Herpesvirus Type 1 Contains Short Sequence Repeats (SSR).
Caprine herpesvirus 1 (CpHV-1) is responsible for vaginal and respiratory disease in goats. Infection by vaginal route is usually restricted to the genital tract whereas by nasal route the virus can spread throughout the body. In order to evaluate genomic diversity, nucleotide sequences of glycoprotein C (gC) of 13 (n.8 vaginal, n.5 nasal) CpHV-1 strains were analyzed. Amino acid (aa) sequences showed a variable number of short sequence repeats (SSR). Nucleotide and amino acid sequences of amplified products showed to contain a variable number of short sequence repeats among the examined strains. These results indicated that CpHV-1 isolates had genetic diversity in the gC gene regarding the number of SSR: 4 SSR of 60 bp in one strain, 2 SSR of 30 bp in seven strains and 1 SSR of 15 bp in three strains. Two strains had no SSR.


Constrained iterative reconstruction by the conjugate gradient method.
The conjugate gradient method incorporating the object-extent constraint is applied to image reconstruction of a three-dimensional object using an incomplete projection-data set. The missing information is recovered by constraining the solution with the knowledge of the outer boundary of the object-extent which may be a priori measured or known. The algorithm is derived from the least-squares criterion as an advanced version of conventional iterative reconstruction algorithms such as SIRT (Simultaneous Iterative Reconstruction Technique) and ILST (Iterative Least Squares Technique). In the case of reconstruction from noisy projection data, a method based on the minimum mean-square error criterion is also proposed. Computer simulated reconstruction images of a phantom using limited angle and number of views are presented. The result shows that the conjugate gradient method incorporating the object-extent constraining provides the fastest convergence and the least error.


Revisiting metric sex estimation of burnt human remains via supervised learning using a reference collection of modern identified cremated individuals (Knoxville, USA).
This study aims to increase the rate of correctly sexed calcined individuals from archaeological and forensic contexts. This is achieved by evaluating sexual dimorphism of commonly used and new skeletal elements via uni- and multi-variate metric trait analyses. Twenty-two skeletal traits were evaluated in 86 individuals from the William M. Bass donated cremated collection of known sex and age-at-death. Four different predictive models, logistic regression, random forest, neural network, and calculation of population specific cut-off points, were used to determine the classification accuracy (CA) of each feature and several combinations thereof. An overall CA of ≥ 80% was obtained for 12 out of 22 features (humerus trochlea max., and lunate length, humerus head vertical diameter, humerus head transverse diameter, radius head max., femur head vertical diameter, patella width, patella thickness, and talus trochlea length) using univariate analysis. Multivariate analysis showed an increase of CA (≥ 95%) for certain combinations and models (e.g., humerus trochlea max. and patella thickness). Our study shows metric sexual dimorphism to be well preserved in calcined human remains, despite the changes that occur during burning. Our study demonstrated the potential of machine learning approaches, such as neural networks, for multivariate analyses. Using these statistical methods improves the rate of correct sex estimations in calcined human remains and can be applied to highly fragmented unburnt individuals from both archaeological and forensic contexts.


The significance of light chain-restricted bone marrow plasma cells after peripheral blood stem cell transplantation for multiple myeloma.
While plasmacytosis is a common occurrence in early post-bone marrow transplantation biopsy specimens, the significance of plasma cells in such specimens from patients with multiple myeloma (MM) is unknown. We attempted to retrospectively determine, by morphologic assessment of plasma cell percentage, immunohistologic assessment of plasma cell light chain ratio (LCR), and correlation with clinical outcome, the prevalence and significance of plasmacytosis in the posttransplantation bone marrow biopsy specimens of 25 patients with MM who underwent autologous peripheral blood stem cell transplantation (PBSCT). No pre-PBSCT morphologic or immunologic characteristics were significantly associated with the post-PBSCT outcome in this group of patients. While 9% of all biopsy specimens and 25% of hypocellular biopsy specimens obtained during the first 60 days after the PBSCT contained more than 10% plasma cells, 34% of all biopsy specimens obtained during this period had elevated LCRs. The dominant light chain in all cases with high LCRs was the same as that of the original tumors, implying that these plasma cells represent a portion of the patients' original tumors. However, the presence of tumoral plasma cells during the early post-PBSCT period was not associated with outcome (P>.5 at 30 days and 60 days after transplantation). Histologic features of recurrent MM and elevated LCR occurring at day 90 or later are correlated with progression of disease (P=.02 and P=.0001, respectively). We conclude that the presence of tumoral plasma cells in the early post-PBSCT period likely represents residual tumor and should not be regarded as indicating imminent relapse, while the presence of tumor as assessed by histologic or immunohistochemical evaluation during the late post-PBSCT period should raise the concern of relapse and disease progression.


PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis.
Adhesin proteins are used by Plasmodium parasites to bind and invade target cells. Hence, characterising molecules that participate in reticulocyte interaction is key to understanding the molecular basis of Plasmodium vivax invasion. This study focused on predicting functionally restricted regions of the P. vivax GPI-anchored micronemal antigen (PvGAMA) and characterising their reticulocyte binding activity. The pvgama gene was initially found in P. vivax VCG-I strain schizonts. According to the genetic diversity analysis, PvGAMA displayed a size polymorphism very common for antigenic P. vivax proteins. Two regions along the antigen sequence were highly conserved among species, having a negative natural selection signal. Interestingly, these regions revealed a functional role regarding preferential target cell adhesion. To our knowledge, this study describes PvGAMA reticulocyte binding properties for the first time. Conserved functional regions were predicted according to natural selection analysis and their binding ability was confirmed. These findings support the notion that PvGAMA may have an important role in P. vivax merozoite adhesion to its target cells.


Translational profiling of B cells infected with the Epstein-Barr virus reveals 5' leader ribosome recruitment through upstream open reading frames.
The Epstein-Barr virus (EBV) genome encodes several hundred transcripts. We have used ribosome profiling to characterize viral translation in infected cells and map new translation initiation sites. We show here that EBV transcripts are translated with highly variable efficiency, owing to variable transcription and translation rates, variable ribosome recruitment to the leader region and coverage by monosomes versus polysomes. Some transcripts were hardly translated, others mainly carried monosomes, showed ribosome accumulation in leader regions and most likely represent non-coding RNAs. A similar process was visible for a subset of lytic genes including the key transactivators BZLF1 and BRLF1 in cells infected with weakly replicating EBV strains. This suggests that ribosome trapping, particularly in the leader region, represents a new checkpoint for the repression of lytic replication. We could identify 25 upstream open reading frames (uORFs) located upstream of coding transcripts that displayed 5' leader ribosome trapping, six of which were located in the leader region shared by many latent transcripts. These uORFs repressed viral translation and are likely to play an important role in the regulation of EBV translation.


Adverse events and adherence to HIV post-exposure prophylaxis: a cohort study at the Korle-Bu Teaching Hospital in Accra, Ghana.
There is strong evidence that post-exposure prophylaxis (PEP) with antiretroviral drugs in the timely management of occupational exposures sustained by healthcare workers decreases the risk of HIV infection and PEP is now widely used. Antiretroviral drugs have well documented toxicities and produce adverse events in patients living with HIV/AIDS. In the era of "highly active antiretroviral therapy", non-adherence to treatment has been closely linked to the occurrence of adverse events in HIV patients and this ultimately influences treatment success but the influence of adverse events on adherence during PEP is less well studied. Following the introduction of a HIV post-exposure prophylaxis program in the Korle-Bu Teaching Hospital in January 2005, the incidence of adverse events and adherence were documented in occupationally-exposed healthcare workers (HCWs) and healthcare students (HCSs). Cohort event monitoring was used in following-up on exposed HCWs/HCSs for the two study outcomes; adverse events and adherence. All adverse events reported were grouped by MedDRA system organ classification and then by preferred term according to prophylaxis regimen. Adherence was determined by the completion of prophylaxis schedule. Cox proportional regression analysis was applied to determine the factors associated with the cohort study outcomes. Differences in frequencies were tested using the Chi square test and p < 0.05 was considered statistically significant. A total of 228 exposed HCWs/HCSs were followed up during the study, made up of 101 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 3 days; 75 exposed HCWs/HCSs administered lamivudine/zidovudine (3TC/AZT) for 28 days; and 52 exposed HCWs/HCSs administered lamivudine/zidovudine/lopinavir-ritonavir (3TC/AZT/LPV-RTV) for 28 days. The frequency of adverse events was 28% (n = 28) in exposed HCWs/HCSs administered 3TC/AZT for 3 days, 91% (n = 68) in exposed HCWs/HCSs administered 3TC/AZT for 28 days and 96% (n = 50) in exposed HCWs/HCSs administered 3TC/AZT/LPV-RTV for 28 days. Nausea was the most commonly reported adverse events in all three regimens. Adherence was complete in all exposed HCWs/HCSs administered 3TC/AZT for 3days, 56% (n = 42) in exposed HCWs/HCSs administered 3TC/AZT for 28 days and 62% (n = 32) in exposed HCWs/HCSs administered 3TC/AZT/LPV-RTV for 28 days. In the Cox regression multi-variate analysis, exposed HCWs/HCSs administered 3TC/AZT for 3 days were 70% less likely to report adverse events compared with exposed HCWs/HCSs administered 3TC/AZT for 28 days (Adjusted HR = 0.30 [95% CI, 0.18-0.48], p < 0.001). Exposed HCWs/HCSs administered 3TC/AZT for 3 days were 75% more likely to adhere to the schedule compared with exposed HCWs/HCSs administered 3TC/AZT for 28 days (Adjusted HR = 1.75 [95% CI, 1.16-2.66], p = 0.008). The intolerance to adverse events was cited as the sole reason for truncating PEP, thereby indicating the need for adequate, appropriate and effective counselling, education, active follow-up (possibly through mobile /phone contact) and management of adverse events. Education on the need to complete PEP schedule (especially for exposed HCWs/HCSs on 28-day schedule) can lead to increased adherence, which is very critical in minimizing the risk of HIV sero-conversion. The present results also indicate that cohort event monitoring could be an effective pharmacovigilance tool in monitoring adverse events in exposed HCWs/HCSs on HIV post-exposure prophylaxis.


Intervention fidelity in postintensive care follow-up consultations at ten sites in the RAPIT-trial: A mixed-methods evaluation.
The aim of the study was to evaluate intervention fidelity of nurses' delivery of the RAPIT recovery program for postintensive care patients. Interventions addressing patient problems after intensive care lack description of the process of delivery and the evidence of their effectiveness. This is needed to understand how these interventions work. Multistage intervention framework in a mixed-methods design. Intervention fidelity strategies were assessed for intervention design, training, delivery, receipt, and enactment with quantitative and qualitative methods inspired by the Medical Research Council and the National Institutes of Health Fidelity Framework. Data collection was embedded in a multicenter randomized controlled trial to explore intervention fidelity of a recovery program (December 2012-February 2017). Ten Danish intensive care units participated in the RAPIT-trial including 386 patients and 27 nurses. Quantitative data covered training and delivery. Qualitative data explored design, quality of delivery, receipt, and enactment seen from nurses' and patients' perspectives. Data were analysed statistically and by systematic deductive-inductive thematic analysis. A framework for participatory enactment of a complex intervention was developed and demonstrated delivery with high consistent fidelity across sites. Low delivery doses and variations were related to the program, patient, provider nurses and context. Our study provides insight into the process of intervention fidelity of a nurse-led postintensive care recovery program and potentially enables professionals to understand key factors in cross-site implementation. Although we demonstrate consistent delivery and variations suggest that some patients may benefit more than others.


[Effects of cefpirome sulfate on male sexual development in rats].
Cefpirome sulfate (CPR) was administered subcutaneously at 200, 500, and 1000 mg/kg/day to male rats for 5 weeks from 6 through 40 days of age and examinations were made to determine whether the antibiotic caused any detrimental effects on male sexual development when administered to juvenile rats. Cefotetan (CTT) was given at 1000 mg/kg/day as a positive control. Incrustation occurred at the injection site during administration in all treated groups. The CPR groups had no compound related changes in fertility, spermatozoa, and reproductive organs, while the CTT group showed decreased testicular weight, abnormal fertility and spermatozoa, and atrophied germinal epithelium of seminiferous tubules, atrophied epididymis, and decreased number of spermatozoa. From the results of this investigation, it may be concluded that CPR had no effects on male sexual development when administered to juvenile rats.


Genetic architecture of floral traits in Iris hexagona and Iris fulva.
The formation of hybrids among closely related species has been observed in numerous plant taxa. Selection by pollinators on floral traits can act as an early reproductive isolating barrier and may be especially important when there is overlap in distribution and flowering time. In this study, we use Quantitative Trait Locus (QTL) mapping based on 293 codominant SNP markers in an F2 population (n = 328) to assess the size, magnitude, and location of the genetic regions controlling floral traits known to be important for pollinator attraction in 2 species of Lousiana Irises, Iris fulva and Iris hexagona. We also evaluate correlations among F2 traits and identify transgression in the hybrid population. Overall, we observe that differences in most floral traits between I. fulva and I. hexagona are controlled by multiple QTLs and are distributed across several linkage groups. We also find evidence of transgression at several QTL, suggesting that hybridization can contribute to generating phenotypic variation, which may be adaptive in rapidly changing environments.


Evaluating individual hospital quality through outcome statistics.
Case abstract data are routinely collected by hospital abstracting services, peer review organizations, and some state agencies. These data have proved invaluable in the analysis of patterns of performance across large numbers of hospitals and have shown, for example, the inverse relation between diagnosis- or procedure-specific volume and outcome. Routinely collected data also appear to be an attractive means for identifying hospitals, and perhaps physicians, with particularly good or poor outcomes for their patients. Unfortunately, problems of small numbers of patients and relatively low rates of poor outcomes make it difficult to be confident in the identification of individual performers. Recent data for cardiac catheterization patients are used to illustrate this problem.


Twin studies of affective illness.
In a summary of the major twin studies of affective illness, there are significant differences between monozygotic (MZ) and dizygotic (DZ) concordance rates for both unipolar and bipolar illness, indicating the importance of genetic factors in the etiology of affective illness. However, since 28% of MZ twins are discordant for bipolar illness and 60% of MZ twins are discordant for unipolar illness, environmental factors are important as well. In addition, there is a significant difference between unipolar and bipolar concordance for MZ twins (although not for DZ twins). This supports other evidence that unipolar and bipolar illness are separate entities, and it suggests the possibility that genetic factors are more important in the occurrence of bipolar illness than in unipolar illness.


Obesity and smoking habits.
A large-scale survey of steel workers in South Wales has shown a considerable difference between the body weights of smokers and of non-smokers. The difference increases with age so that men over 40 years who have never smoked are on average 13 lb (5.9 kg) heavier than smokers. Even so, smokers are about 15 lb (6.8 kg) heavier than the weight standard considered desirable by the Metropolitan Life Insurance Company, while non-smokers are nearly 30 lb (13.6 kg) heavier.About 20% of the men are attempting to give up the smoking habit. Ex-smokers who have given up smoking for more than eight years approach the body weight of men of the same age who have never smoked.Many reports have been published on the health consequences of smoking and of obesity. Because smoking and obesity are inversely related studies of the interrelation of these two health hazards and of their relative importance are needed.


Immunity-linked genes are stimulated by a membrane stress pathway linked to Golgi function and the ARF-1 GTPase.
Infection response and other immunity-linked genes (ILGs) were first named in Caenorhabditis elegans-based expression after pathogen challenge, but many are also up-regulated when lipid metabolism is perturbed. Why pathogen attack and metabolic changes both increase ILGs is unclear. We find that ILGs are activated when phosphatidylcholine (PC) levels change in membranes of secretory organelles in C. elegans. RNAi targeting of the ADP-ribosylation factor arf-1, which disrupts the Golgi and secretory function, also activates ILGs. Low PC limits ARF-1 function, suggesting a mechanism for ILG activation via lipid metabolism, as part of a membrane stress response acting outside the ER. RNAi of selected ILGs uncovered defects in the secretion of two GFP reporters and the accumulation of a pathogen-responsive complement C1r/C1s, Uegf, Bmp1 (CUB) domain fusion protein. Our data argue that up-regulation of some ILGs is a coordinated response to changes in trafficking and may act to counteract stress on secretory function.


Possible relationship between the risk of Japanese bladder cancer cases and the CYP4B1 genotype.
Cytochrome P450 4B1 (CYP4B1) is involved in the metabolism of several xenobiotics, such as 2-aminofluorene, 2-naphthylamine and benzidine. CYP4B1 allelic variants CYP4B1*1-*7 were recently identified. We thus hypothesized that CYP4B1 genotypes may modify bladder cancer risk. We examined the CYP4B1 genotypes in 169 bladder cancer cases and 190 hospital controls using a hybridization probe assay. Among the CYP4B1 genotypes observed, the most frequent genotypes in both the groups were CYP4B1*1/*1, *1/*2, *1/*3 and *2/*2. Logistic regression analysis revealed that the subjects carrying the CYP4B1*1/*2 or *2/*2 genotypes had a 1.75-fold increased risk of bladder cancer (95% CI=1.03-2.95, P = 0.038) compared with the subjects carrying the CYP4B1*1/*1 genotype. We demonstrated the first genetic study regarding the association of CYP4B1 with bladder cancer. Our results suggest that CYP4B1 genotypes might have an effect on the risk of bladder cancer.


Caspase-3-Responsive Fluorescent/Photoacoustic Imaging of Tumor Apoptosis.
Caspase-3 is an essential executor in apoptosis, and its activation has been regarded as a biomarker of cell apoptosis. The development of Caspase-3-responsive multimodal probes is a promising research prospect. Fluorescent/photoacoustic (FL/PA) imaging has attracted considerable attention due to the high sensitivity of FL as well as the high spatial resolution and penetration depth of PA. To our knowledge, there has been no tumor-targeted FL/PA probe to monitor the activity of Caspase-3 in vivo. Therefore, we developed a tumor-targeted FL/PA probe (Bio-DEVD-HCy) for Caspase-3-responsive imaging of tumor apoptosis. Ac-DEVD-HCy without tumor-targeted biotin is used as a control probe. In vitro experiments indicated that Bio-DEVD-HCy is superior to Ac-DEVD-HCy because of the higher kinetic parameter of Bio-DEVD-HCy in comparison to Ac-DEVD-HCy. Cell and tumor imaging results suggested that Bio-DEVD-HCy could enter and accumulate in tumor cells with higher FL/PA signal with the help of tumor-targeted biotin. In detail, Bio-DEVD-HCy or Ac-DEVD-HCy could image apoptotic tumor cells with 4.3-fold or 3.5-fold FL enhancement and 3.4-fold or 1.5-fold PA enhancement. Bio-DEVD-HCy or Ac-DEVD-HCy could image tumor apoptosis with 2.5-fold or 1.6-fold FL enhancement and 4.1-fold or 1.9-fold PA enhancement. We envision that Bio-DEVD-HCy will be applied for FL/PA imaging of tumor apoptosis in clinical settings.


Clustering of hepatitis C virus antibody positivity within households and communities in Punjab, India.
To better understand hepatitis C virus (HCV) epidemiology in Punjab state, India, we estimated the distribution of HCV antibody positivity (anti-HCV+) using a 2013-2014 HCV household seroprevalence survey. Household anti-HCV+ clustering was investigated (a) by individual-level multivariable logistic regression, and (b) comparing the observed frequency of households with multiple anti-HCV+ persons against the expected, simulated frequency assuming anti-HCV+ persons are randomly distributed. Village/ward-level clustering was investigated similarly. We estimated household-level associations between exposures and the number of anti-HCV+ members in a household (N = 1593 households) using multivariable ordered logistic regression. Anti-HCV+ prevalence was 3.6% (95% confidence interval 3.0-4.2%). Individual-level regression (N = 5543 participants) found an odds ratio of 3.19 (2.25-4.50) for someone being anti-HCV+ if another household member was anti-HCV+. Thirty households surveyed had ⩾2 anti-HCV+ members, whereas 0/1000 (P < 0.001) simulations had ⩾30 such households. Excess village-level clustering was evident: 10 villages had ⩾6 anti-HCV+ members, occurring in 31/1000 simulations (P = 0.031). The household-level model indicated the number of household members, living in southern Punjab, lower socio-economic score, and a higher proportion having ever used opium/bhuki were associated with a household's number of anti-HCV+ members. Anti-HCV+ clusters within households and villages in Punjab, India. These data should be used to inform screening efforts.


[Effect of oxidative phosphorylation inhibitors and uncoupling agents on cAMP activity].
Uncouplers of oxidative phosphorylation increased the speed of substrate oxidation and ATP hydrolysis and raised cAMP induced neuron membrane current. Different inhibitors decreased it. Both effects support the hypothesis that a signal of intracellular injected cAMP spreads to the neuron membrane as a mechanical signal. This signal propagated to the membrane along microtubules which according to this hypothesis serve as a sound generator with metabolic heat pumping.


Dose-dependent antioxidant responses and pathological changes in tenca (Tinca tinca) after acute oral exposure to Microcystis under laboratory conditions.
The effects of cyanobacterial cells containing microcystins (MCs), toxins from cyanobacteria, on oxidative stress biomarkers from liver and kidney of Tenca fish (Tinca tinca) were investigated under laboratory conditions. Moreover, a histopathological study of liver, kidney, heart and intestine tissues was performed. Fish were orally exposed to cyanobacterial cells dosing 0, 5, 11, 25 and 55 microg MC-LR/fish mixed with the food. Results showed a dose-dependent decrease of superoxide dismutase (SOD) activity, and also of catalase (CAT) in the liver. Glutathione levels and protein oxidation, however, were not altered by the exposure to the cyanobacterial material. The microscopic study revealed tissue alterations even at the lower cyanobacterial cells doses. Onion-like hepatocytes in the liver, glomerulopathy in the kidney, loss of myofibrils in the heart and vacuolated enterocytes in the gastrointestinal tract were the main changes observed. These findings suggest that this fresh water fish can be adversely affected by cyanobacterial blooms in their natural habitats.


Production of free glutamate in milk requires the leucine transporter LAT1.
The concentration of free glutamate (Glu) in rat's milk is ∼10 times higher than that in plasma. Previous work has shown that mammary tissue actively transports circulatory leucine (Leu), which is transaminated to synthesize other amino acids such as Glu and aspartate (Asp). To investigate the molecular basis of Leu transport and its conversion into Glu in the mammary gland, we characterized the expression of Leu transporters and [(3)H]Leu uptake in rat mammary cells. Gene expression analysis indicated that mammary cells express two Leu transporters, LAT1 and LAT2, with LAT1 being more abundant than LAT2. This transport system is sodium independent and transports large neutral amino acids. The Leu transport system in isolated rat mammary cells could be specifically blocked by the LAT1 inhibitors 2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid (BCH) and triiodothyronine (T3). In organ cultures, Glu secretion was markedly inhibited by these LAT1 inhibitors. Furthermore, the profiles of Leu uptake inhibition by amino acids in mammary cells were similar to those reported for LAT1. In vivo, concentrations of free Glu and Asp increased in milk by oral gavage with Leu at 6, 12, and 18 days of lactation. These results indicate that the main Leu transporter in mammary tissue is LAT1 and the transport of Leu is a limiting factor for the synthesis and release of Glu and Asp into milk. Our studies provide the bases for the molecular mechanism of Leu transport in mammary tissue by LAT1 and its active role on free Glu secretion in milk, which confer umami taste in suckling pups.


Improved quantification of small objects in near-infrared diffuse optical tomography.
Diffuse optical tomography allows quantification of hemoglobin, oxygen saturation, and water in tissue, and the fidelity in this quantification is dependent on the accuracy of optical properties determined during image reconstruction. In this study, a three-step algorithm is proposed and validated that uses the standard Newton minimization with Levenberg-Marquardt regularization as the first step. The second step is a modification to the existing algorithm using a two-parameter regularization to allow lower damping in a region of interest as compared to background. This second stage allows the recovery of the actual size of an inclusion. A region-based reconstruction is the final third step, which uses the estimated size and position information from step 2 to yield quantitatively accurate average values for the optical parameters. The algorithm is tested on simulated and experimental data and is found to be insensitive to object contrast and position. The percentage error between the true and the average recovered value for the absorption coefficient in test images is reduced from 47 to 27% for a 10-mm inclusion, from 38 to 13% for a 15-mm anomaly, and from 28 to 5.5% for a 20-mm heterogeneity. Simulated data with absorbing and scattering heterogeneities of 15 mm diam located in different positions show recovery with less than 15% error in absorption and 6% error in reduced scattering coefficients. The algorithm is successfully applied to clinical data from a subject with a breast abnormality to yield quantitatively increased absorption coefficients, which enhances the contrast to 3.8 compared to 1.23 previously.


Cancer Stem Cells: Devil or Savior-Looking behind the Scenes of Immunotherapy Failure.
Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.


Narrative reconstruction therapy for prolonged grief disorder - a pilot study.
Background: Prolonged grief disorder (PGD) is a chronic and disabling condition that affects approximately 10% of non-traumatically bereaved people. Narrative reconstruction (NR), originally designed for the treatment of posttraumatic stress disorder (PTSD), is a time-limited integrative therapy consisting of exposure to the loss memory, detailed written reconstruction of the loss memory narrative, and an elaboration of the personal significance of that memory for the bereaved. Objective: This pilot study examined the efficacy of NR therapy in reducing symptoms in bereaved people diagnosed with PGD. Method: Ten PGD patients participated in the study and were treated with 16 weekly sessions of NR. PGD, PTSD, and depression symptoms, as well as levels of loss integration, were assessed at pre-treatment, post-treatment, and at a 3-month follow-up. Results: Following NR, participants showed significant reductions in PGD, depression, and PTSD symptoms, and elevated levels of trauma integration. Symptoms showed further improvement at the three-month follow-up. Conclusions: These findings provide preliminary evidence for the feasibility and efficacy of NR in treating PGD. Narrative reconstruction therapy requires further evaluation in randomized controlled trials.


CEP-1347/KT7515 prevents motor neuronal programmed cell death and injury-induced dedifferentiation in vivo.
CEP-1347, also known as KT7515, a derivative of a natural product indolocarbazole, inhibited motor neuronal death in vitro, inhibited activation of the stress-activated kinase JNK1 (c-jun NH terminal kinase) in cultured spinal motor neurons, but had no effect on the mitogen-activated protein kinase ERK1 in these cells. Results reported here profile the functional activity of CEP-1347/KT7515 in vivo in models of motor neuronal death or dedifferentiation. Application of CEP-1347/KT7515 to the chorioallantoic membrane of embryonic chicks rescued 40% of the lumbar motor neurons that normally die during the developmental period assessed. Peripheral administration of low doses (0.5 and 1 mg/kg daily) of CEP-1347/KT7515 reduced death of motor neurons of the spinal nucleus of the bulbocavernosus in postnatal female rats, with efficacy comparable to testosterone. Strikingly, daily administration of CEP-1347/KT7515 during the 4-day postnatal window of motor neuronal death resulted in persistent long-term motor neuronal survival in adult animals that received no additional CEP-1347/KT7515. In a model of adult motor neuronal dedifferentiation following axotomy, local application of CEP-1347/KT7515 to the transected hypoglossal nerve substantially reduced the loss of choline acetyl transferase immunoreactivity observed 7 days postaxotomy compared to untreated animals. Results from these experiments demonstrate that a small organic molecule that inhibits a signaling pathway associated with stress and injury also reduces neuronal death and degeneration in vivo.


ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.


The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer.
Colorectal cancer is among the most lethal malignancies globally. BRAF is a member of the RAS/RAF/MEK/ERK signaling pathway. Its constitutive activation can result in increased cellular growth, development, invasion, and resistance to therapy. A mutation of the BRAF gene is present in 5-10% of metastatic colorectal cancers. BRAF mutations have been found to predict a lack of benefit to anti-EGFR therapy in metastatic CRC. Furthermore, CRC containing the BRAF V600E mutation display an innate resistance to BRAF inhibitors. The mechanisms of cell resistance can be explained at least in part by ERK dependent and ERK in-dependent pathway. Clinical trials evaluating the combinations of BRAF, PI3K, EGFR, and/or MEK inhibitors have revealed promising activity in BRAF mutant containing CRCs. There may be some benefit from future studies that focus on improving the efficacy of combined therapy in CRC with respect to the sustained effects. The aim of current review is to give an overview about the current status and prospective regarding the therapeutic potential of targeting BRAF mutant colorectal cancer.


Serotonin regulation of neurite outgrowth in identified neurons from mature and embryonic Helisoma trivolvis.
Neurite outgrowth and growth cone motility are among the many aspects of neuronal development that can be affected by specific neurotransmitters. This was first demonstrated in experiments on identified molluscan neurons that were isolated from mature ganglia and cultured under conditions that promote the regeneration of new neurites. The application of serotonin to a regenerating Helisoma neuron B19 produced an abrupt, reversible cessation of neurite outgrowth and growth cone motility. While this type of response would subsequently be demonstrated for other neurons and neurotransmitters in many different invertebrate and vertebrate species, experiments on Helisoma neurons have continued to play a pivotal role in advancing this field. In this paper, the mechanisms and sites of serotonin action and how these responses are manifested in vivo during embryonic development are discussed. Experiments primarily on neuron B19 have shown that serotonin acts on a novel serotonin receptor that is coupled to the elevation of cyclic AMP. This intracellular messenger directly activates a class of cyclic-nucleotide-gated sodium channels, leading to sodium influx, membrane depolarization, and activation of voltage-gated calcium channels. The resulting elevation of intracellular calcium acts through a calcium/calmodulin-dependent pathway to inhibit neurite outgrowth and growth cone motility. Although the final steps have yet to be completely resolved, they undoubtedly involve calcium-dependent regulation of cytoskeletal components. Regarding the sites of serotonin action, serotonin responses have been localized to growth cones and even filopodia in specific neurons. However, some studies suggest that neurite development may actually be regulated by serotonin in a paracrine, non-localized manner in a surprisingly large percentage of Helisoma neurons. Finally, experiments on Helisoma embryos have investigated how serotonin actually regulates the in vivo development of specific neurons. Pharmacological treatments that reduce the serotonin concentration in embryos affected the neurite morphology and synaptic efficacy of neuron B19 and the amount of neurite branching in embryonic neuron C1. All of these responses were consistent with the primary action of serotonin being the inhibition of neurite outgrowth, as predicted by the original cell culture studies.


Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells.
Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.


Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.
Human innate immunity against most African trypanosomes, including Trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum HDL, called trypanosome lytic factor-1 (TLF-1). This HDL contains two primate specific proteins, apolipoprotein L-1 and haptoglobin (Hp)-related protein, as well as apolipoprotein A-1. These assembled proteins provide a powerful defense against trypanosome infection. Trypanosoma brucei rhodesiense causes human African sleeping sickness because it has evolved an inhibitor of TLF-1, serum resistance-associated (SRA) protein. Trypanosoma brucei gambiense lacks the SRA gene, yet it infects humans. As transfection of T. b. gambiense (group 1) is not possible, we initially used in vitro-selected TLF-1-resistant T. b. brucei to examine SRA-independent mechanisms of TLF-1 resistance. Here we show that TLF-1 resistance in T. b. brucei is caused by reduced expression of the Hp/Hb receptor gene (TbbHpHbR). Importantly, T. b. gambiense (group 1) also showed a marked reduction in uptake of TLF-1 and a corresponding decrease in expression of T. b. gambiense Hp/Hb receptor (TbgHpHbR). Ectopic expression of TbbHpHbR in TLF-1-resistant T. b. brucei rescued TLF-1 uptake, demonstrating that decreased TbbHpHbR expression conferred TLF-1 resistance. Ectopic expression of TbgHpHbR in TLF-1-resistant T. b. brucei failed to rescue TLF-1 killing, suggesting that coding sequence changes altered Hp/Hb receptor binding affinity for TLF-1. We propose that the combination of coding sequence mutations and decreased expression of TbgHpHbR directly contribute to parasite evasion of human innate immunity and infectivity of group 1 T. b. gambiense.


Growth hormone promotes Ca(2+)-induced Ca2+ release in insulin-secreting cells by ryanodine receptor tyrosine phosphorylation.
Elevation in cytoplasmic free Ca2+ concentration ([Ca2+]i) is a common mechanism in signaling events. An increased [Ca2+]i induced by GH, has been observed in relation to different cellular events. Little is known about the mechanism underlying the GH effect on Ca2+ handling. We have studied the molecular mechanisms underlying GH-induced rise in [Ca2+]i in BRIN-BD11 insulin-secreting cells. GH (500 ng/ml, 22 nm) induced a sustained increase in [Ca2+]i. The effect of GH on [Ca2+]i was prevented in the absence of extracellular Ca2+ and was inhibited by the ATP-sensitive K(+)-channel opener diazoxide and the voltage-dependent Ca(2+)-channel inhibitor nifedipine. However, GH failed to induce any changes in Ca2+ current and membrane potential, evaluated by patch-clamp recordings and by using voltage-sensitive dyes. When the intracellular Ca2+ pools had been depleted using the Ca(2+)-ATPase inhibitor thapsigargin, the effect of GH was inhibited. In addition, GH-stimulated rise in [Ca2+]i was completely abolished by ruthenium red, an inhibitor of mitochondrial Ca2+ transport, and caffeine. GH induced tyrosine phosphorylation of ryanodine receptors. The effect of GH on [Ca2+]i was completely blocked by the tyrosine kinase inhibitors genistein and lavendustin A. Interestingly, treatment of the cells with GH significantly enhanced K(+)-induced rise in [Ca2+]i. Hence, GH-stimulated rise in [Ca2+]i is dependent on extracellular Ca2+ and is mediated by Ca(2+)-induced Ca2+ release. This process is mediated by tyrosine phosphorylation of ryanodine receptors and may play a crucial role in physiological Ca2+ handling in insulin-secreting cells.


[Cognition, schizophrenia and the effect of antipsychotics].
In this review, we conclude that cognitive impairments are as important as positive and negative symptoms in the clinical assessment and management of patients with schizophrenia. This is not a comprehensive review, considering that the new Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) model will soon provide valuable data. It is however a product of the collective efforts of a French Canadian clinical research team that proposes a synthesis of data of pragmatic interest to clinicians. Medication with improved safety and cognition profile, gene-rally lead to better outcomes by facilitating compliance with drug regimens and rehabilitation programs. In addition, measures of attention and executive function (EF) appear to improve with novel antipsychotics when compared to traditional neuroleptics. Nevertheless, evaluating cognitive performance is not a routine procedure outside the domain of research. For example, procedural learning (PL) -- an important measure of cognitive function -- refers to cognitive and motor learning processes in which execution strategies cannot be explicitly described (ie learning by doing). These actions or procedures are then progressively learned through trial and error until automation of optimal performance is established. Procedural learning is rarely assessed in clinical practice. Inconsistent findings regarding the effects of neuroleptic drugs on PL have been reported. Trials using acute administration of chlorpromazine in normal subjects induced PL deficits, suggesting the direct effect of neuroleptics, presumably via a D(2) dopamine blockade in the striatum. In a recent study by our group, schizophrenia patients, divided into three groups according to their pharmacological treatment (haloperidol, clozapine and risperidone) were compared to normal controls on two PL tasks; a visuomotor learning task (mirror drawing) and a problem solving learning task (Tower of Toronto). No deficits were detected in patients receiving clozapine, while haloperidol was associated with deleterious effects in both tasks. Risperidone, however, produced different effects depending on the task performed. Another 6-month double-blind Canadian study confirmed the beneficial effect of olanzapine on PL compared to haloperidol and risperidone. The differential effects of drugs on the striatal D(2) receptors, -irrespective of their classification as conventional or atypical neuroleptics and the specific process implicated in each of these PL tasks may explain these results. Tracer studies using radioactive benzamides (IBZM) specific to striatal D receptors determined a relationship between striatal D(2) receptor occupancy and PL performance such as the mirror drawing task. Using this method, data obtained in Montreal on schizophrenia patients receiving olanzapine and haloperidol have shown that the coefficient of determination in a visuomotor PL task varied inversely with D2 receptor saturation. This review probes the effect of impaired cognitive functions on schizophrenia patients' quality of life. Cognitive deficits found in schizophrenia affect planning, along with the aptitude to initiate and -regulate a goal-directed behaviour. These impairments have been repeatedly, yet inconclusively, attributed to frontal lobe dysfunction. Morphological findings obtained from neuroimaging studies remain inconsistent, some noting no differences between patients and controls while others observing reduced prefrontal volumes in schizophrenia patients. Conversely, functional neuroimaging (fMRI) demonstrated reduced frontal blood flow relative to global cerebral perfusion in schizophrenia patients. Overall, neuroimaging literature provides reliable evidence of frontal impairments in schizophrenia, although the average magnitude of difference between patients and controls is insufficient to defend a frontal lobe dysfunction hypo-thesis, as far as brain volume, resting cerebral metabolism or blood flow are concerned. The only measurement clearly distinguishing between patients and controls is fMRI of the frontal lobe while performing an experimentally controlled task. Here, schizophrenia patients fail to activate their frontal cortex when required. Sensitive to frontal lobe dysfunction are Neuropsychological tests of executive function. A study conducted in Montreal assessed the relation between EF impairments and difficulties in planning daily activities in schizophrenia patients scoring more than 3 on at least 4 items of the PANSS negative subscale. Performances on EF, memory and script generation were measured and compared to controls. Script production task required that subjects recite 10-20 actions that would normally be carried out for during daily life activity (going to a restaurant, buying groceries, etc.). Patients' performances were significantly lower with higher perserveration and sequencing impairments. Routine activities such as the ability to cook a meal were similarly investigated. Patients were videotaped in a kitchen while preparing a specific meal. Optimal sequence of micro- and macro-steps necessary to prepare the meal in a minimal time were measured. Sequencing errors, repetitions and omissions were significantly higher compared to controls. In addition, temporal organization was positively correlated with negative symptoms and low EF performance on neuro-psychological tasks. Thus concluding that EF impairment interferes with basic routine activities in schizophrenia patients, notably those with negative symptoms. Last but not least, we assessed the progress of patients' subjective complaints with regards to their cognitive functions using tests such as the SSTICS, specifically developed to address subjective cognitive complaints and insight. This review concludes that from now on cognitive deficit should be recognized as a major element in social and professional integration of schizophrenia patients, and should become a standardized assessment approach in clinical practice.


[Interaction of thiamine with rat brain synaptosomes].
Thiamine has been shown to be bound specifically by a synaptosomal plasmatic membrane and transported inside to the nervous ending. Apparent K[symbol: see text] and Km for processes of binding and transport have been determined as equal 2.34 +/- 0.55 MKM and 3.92 +/- 1.3 MKM, respectively. The thiamine uptake by the isolated nervous endings (synaptosomes) at its physiological concentration is reduced in presence of metabolic inhibitors and partially depends on Mg2+ and Ca2+ ions, that can testify about the interrelation between endogenic thiamine phosphorilation and its transport through the membrane. Thiamine binding with synaptosomes is inhibited by ouabain and neurotoxins such as, latrotoxin and most significantly--with veratridin; tetrodotoxin fail to be efficient practically. In the conditions of synaptic membranes depolarisation their ability to bind thiamine is reduced and output of already uptaken with synaptosomes thiamine is observed.


The kruppel-like factor (KLF) family, diseases, and physiological events.
The Kruppel-Like Factor family of regulatory proteins, which has 18 members, is transcription factors. This family contains zinc finger proteins, regulates the activation and suppression of transcription, and binds to DNA, RNA, and proteins. Klfs related to the immune system are Klf1, Klf2, Klf3, Klf4, Klf6, and Klf14. Klfs related to adipose tissue development and/or glucose metabolism are Klf3, Klf7, Klf9, Klf10, Klf11, Klf14, Klf15, and Klf16. Klfs related to cancer are Klf3, Klf4, Klf5, Klf6, Klf7, Klf8, Klf9, Klf10, Klf11, Klf12, Klf13, Klf14, Klf16, and Klf17. Klfs related to the cardiovascular system are Klf4, Klf5, Klf10, Klf13, Klf14, and Klf15. Klfs related to the nervous system are Klf4, Klf7, Klf8, and Klf9. Klfs are associated with diseases such as carcinogenesis, oxidative stress, diabetes, liver fibrosis, thalassemia, and the metabolic syndrome. The aim of this review is to provide information about the relationship of Klfs with some diseases and physiological events and to guide future studies.


Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells.
Single channel and whole cell recordings were used to study ion permeation through Ca channels in isolated ventricular heart cells of guinea pigs. We evaluated the permeability to various divalent and monovalent cations in two ways, by measuring either unitary current amplitude or reversal potential (Erev). According to whole cell measurements of Erev, the relative permeability sequence is Ca2+ greater than Sr2+ greater than Ba2+ for divalent ions; Mg2+ is not measurably permeant. Monovalent ions follow the sequence Li+ greater than Na+ greater than K+ greater than Cs+, and are much less permeant than the divalents. These whole cell measurements were supported by single channel recordings, which showed clear outward currents through single Ca channels at strong depolarizations, similar values of Erev, and similar inflections in the current-voltage relation near Erev. Information from Erev measurements stands in contrast to estimates of open channel flux or single channel conductance, which give the sequence Na+ (85 pS) greater than Li+ (45 pS) greater than Ba2+ (20 pS) greater than Ca2+ (9 pS) near 0 mV with 110-150 mM charge carrier. Thus, ions with a higher permeability, judged by Erev, have lower ion transfer rates. In another comparison, whole cell Na currents through Ca channels are halved by less than 2 microM [Ca]o, but greater than 10 mM [Ca]o is required to produce half-maximal unitary Ca current. All of these observations seem consistent with a recent hypothesis for the mechanism of Ca channel permeation, which proposes that: ions pass through the pore in single file, interacting with multiple binding sites along the way; selectivity is largely determined by ion affinity to the binding sites rather than by exclusion by a selectivity filter; occupancy by only one Ca ion is sufficient to block the pore's high conductance for monovalent ions like Na+; rapid permeation by Ca ions depends upon double occupancy, which only becomes significant at millimolar [Ca]o, because of electrostatic repulsion or some other interaction between ions; and once double occupancy occurs, the ion-ion interaction helps promote a quick exit of Ca ions from the pore into the cell.


The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells.
The role of JAK-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific small interfering RNA or JAK3 gene knockout resulted in an increase in TLR-mediated production of proinflammatory cytokines while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3K downstream effectors including Akt, mammalian target of rapamycin complex 1, glycogen synthase kinase 3β (GSK3β), and CREB. Constitutive activation of Akt or inhibition of GSK3β abrogated the capability of JAK3 inhibition to enhance proinflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS-stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-κB p65. Moreover, JAK3 inhibition correlated with an increased CD4(+) T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3 and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells.


Childhood maltreatment and response to novel face stimuli presented during functional magnetic resonance imaging in adults.
Facial cues contain important information for guiding social interactions, but not all humans are equally expert at face processing. A number of factors, both genetic and environmental, contribute to differences in face-processing ability. For example, both heritable individual differences in temperament and exposure to childhood maltreatment are associated with alterations in face processing ability and social function. Understanding the neural correlates of alterations in face-processing ability can provide insights into how genetic and environmental risk factors impair social functioning. We examined the association between childhood maltreatment and blood-oxygenation-level-dependent (BOLD) signal as measured in functional magnetic resonance imaging (fMRI) in a group of young adults with an inhibited temperament. We hypothesized that childhood maltreatment exposure would correlate positively with BOLD signal in regions subserving face processing and novelty detection during viewing of novel compared to familiar faces. Functional magnetic resonance imaging (fMRI) degree of exposure to childhood maltreatment was positively correlated with BOLD signal in the bilateral fusiform gyri and the left hippocampus. These fMRI findings suggest that young adults with an inhibited temperament and a history of maltreatment may be particularly vulnerable to neural alterations. These differences could be related to a heightened sensitivity to potential threat-for example, from new people-and may contribute to both the altered social functioning and increased incidence of anxiety disorders in these individuals.


Neural conflict-control mechanisms improve memory for target stimuli.
According to conflict-monitoring models, conflict serves as an internal signal for reinforcing top-down attention to task-relevant information. While evidence based on measures of ongoing task performance supports this idea, implications for long-term consequences, that is, memory, have not been tested yet. Here, we evaluated the prediction that conflict-triggered attentional enhancement of target-stimulus processing should be associated with superior subsequent memory for those stimuli. By combining functional magnetic resonance imaging (fMRI) with a novel variant of a face-word Stroop task that employed trial-unique face stimuli as targets, we were able to assess subsequent (incidental) memory for target faces as a function of whether a given face had previously been accompanied by congruent, neutral, or incongruent (conflicting) distracters. In line with our predictions, incongruent distracters not only induced behavioral conflict, but also gave rise to enhanced memory for target faces. Moreover, conflict-triggered neural activity in prefrontal and parietal regions was predictive of subsequent retrieval success, and displayed conflict-enhanced functional coupling with medial-temporal lobe regions. These data provide support for the proposal that conflict evokes enhanced top-down attention to task-relevant stimuli, thereby promoting their encoding into long-term memory. Our findings thus delineate the neural mechanisms of a novel link between cognitive control and memory.


[Free amino acids in the brain in moderate alcoholization of animals and administration of ethanolamine].
Content of free amino acids was studied in rat brain after moderately-acute alcohol intoxication (Ig/kg of body mass), after administration of ethanolamine (100 mg/kg), phosphoethanolamine (230 mg/kg) and/or combination of these drugs with ethanol. Ethanolamine, as distinct from phosphoethanolamine, removed the effects of alcohol. Structural similarity of ethanol and ethanolamine was apparently responsible for their antagonism.


Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells.
CD4+ T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce restricted patterns of cytokines, which are tailored to combat various microbial pathogens. Although classically viewed as distinct lineages, recent work calls into question whether helper CD4+ T cell subsets are more appropriately viewed as terminally differentiated cells or works in progress. Herein, we review recent advances that pertain to this topic and the mechanisms that contribute to helper CD4+ T cell commitment and plasticity. The therapeutic implications of these new findings are also considered.


Aerosol Jet-Printed High-Aspect Ratio Micro-Needle Electrode Arrays Applied for Human Cerebral Organoids and 3D Neurospheroid Networks.
The human brain is a complex and poorly accessible organ. Thus, new tools are required for studying the neural function in a controllable environment that preserves multicellular interaction and neuronal wiring. In particular, high-throughput methods that alleviate the need for animal experiments are essential for future studies. Recent developments of induced pluripotent stem cell technologies have enabled in vitro modeling of the human brain by creating three-dimensional brain tissue mimic structures. To leverage these new technologies, a systematic and versatile approach for evaluating neuronal activity at larger tissue depths within the regime of tens to hundreds of micrometers is required. Here, we present an aerosol-jet- and inkjet-printing-based method to fabricate microelectrode arrays, equipped with high-aspect ratio μ-needle electrodes that penetrate 3D neural network assemblies. The arrays have been successfully applied for electrophysiological recordings on interconnected neurospheroids formed on an engineered substrate and on cerebral organoids, both derived from human induced pluripotent stem cells.


Creating a community coalition to address violence.
Building a community-wide coalition to address violence evolved out of a five-year federally funded project on abuse during pregnancy. The setting for this coalition building is Haverhill, Massachusetts, a city of about 60,000, located northeast of Boston in the Merrimack River Valley. For nearly eight years, representatives of more than 30 agencies and institutions have been meeting monthly and creating programs and strategies to address violence in homes, schools, and neighborhoods, and designing interventions for children witnessing this violence. The purpose of this article is to describe the process of coalition building and provide an analysis of this work.


High-throughput chemical screening identifies AG-490 as a stimulator of aquaporin 2 membrane expression and urine concentration.
A reduction or loss of plasma membrane aquaporin 2 (AQP2) in kidney principal cells due to defective vasopressin (VP) signaling through the VP receptor causes excessive urine production, i.e., diabetes insipidus. The amount of AQP2 on the plasma membrane is regulated by a balance of exocytosis and endocytosis and is the rate limiting step for water reabsorption in the collecting duct. We describe here a systematic approach using high-throughput screening (HTS) followed by in vitro and in vivo assays to discover novel compounds that enhance vasopressin-independent AQP2 membrane expression. We performed initial chemical library screening with a high-throughput exocytosis fluorescence assay using LLC-PK1 cells expressing soluble secreted yellow fluorescent protein and AQP2. Thirty-six candidate exocytosis enhancers were identified. These compounds were then rescreened in AQP2-expressing cells to determine their ability to increase AQP2 membrane accumulation. Effective drugs were then applied to kidney slices in vitro. Three compounds, AG-490, β-lapachone, and HA14-1 increased AQP2 membrane accumulation in LLC-PK1 cells, and both AG-490 and β-lapachone were also effective in MDCK cells and principal cells in rat kidney slices. Finally, one compound, AG-490 (an EGF receptor and JAK-2 kinase inhibitor), decreased urine volume and increased urine osmolality significantly in the first 2-4 h after a single injection into VP-deficient Brattleboro rats. In conclusion, we have developed a systematic procedure for identifying new compounds that modulate AQP2 trafficking using initial HTS followed by in vitro assays in cells and kidney slices, and concluding with in vivo testing in an animal model.


Cloning of the nprA gene for neutral protease A of Bacillus thuringiensis and effect of in vivo deletion of nprA on insecticidal crystal protein.
The nprA gene, encoding Bacillus thuringiensis neutral protease A, was cloned by the use of gene-specific oligonucleotides. The size of neutral protease A deduced from the nprA sequence was 566 amino acids (60,982 Da). The cloned nprA gene was partially deleted in vitro, and the deleted allele, designated nprA3, was used to construct an nprA3 strain (neutral protease A-deficient strain) of B. thuringiensis. Growth and sporulation of the nprA3 strain were similar to those of an isogenic nprA+ strain, although the extracellular proteolytic activity of the nprA3 strain was significantly less than that of the nprA+ strain. The nprA3 strain produced insecticidal crystal proteins that were more stable than those of the isogenic nprA+ strain after solubilization in vitro, and sporulated cultures of the nprA3 strain contained higher concentrations of full-length insecticidal crystal proteins than did those of its isogenic counterpart. The absence of neutral protease A did not affect the insecticidal activity of a lepidopteran-specific crystal protein of B. thuringiensis. These results indicate that crystal protein stability and yield may be improved by deletion of specific proteases from B. thuringiensis.


5,8-Dimeth-oxy-3,9-dimethyl-3a,4,9,9a-tetra-hydro-4,9-ep-oxy-naphtho-[2,3-d]isoxazole.
The title compound, C15H17NO4, is the exo isomer with a syn arrangement of the O atom in the isoxazole ring to the methyl group of the bicyclic alkene. The dihedral angle between the isoxazole ring and the benzene ring is 7.42 (9)°. In the crystal, weak C-H⋯O hydrogen bonds link mol-ecules, forming a three-dimensional network. The isoxazole O atom is an acceptor for both weak hydrogen bonds.


Impact of Prescribed Exercise on the Physical and Cognitive Health of Adults with Down Syndrome: The MinDSets Study.
The duplication of chromosome 21, as evidenced in Down Syndrome (DS), has been linked to contraindications to health, such as chronotropic and respiratory incompetence, neuromuscular conditions, and impaired cognitive functioning. The purpose of this study was to examine the effects of eight weeks of prescribed exercise and/or cognitive training on the physical and cognitive health of adults with DS. Eighty-three participants (age 27.1 ± 8.0 years) across five continents participated. Physical fitness was assessed using a modified version of the six-minute walk test (6MWT), while cognitive and executive functions were assessed using the Corsi block test, the Sustained-Attention-To-Response Task (SART), and the Stroop task (STROOP). All were completed pre- and post-intervention. Participants were assigned to eight weeks of either exercise (EXE), 3 × 30 min of walking/jogging per week, cognitive training (COG) 6 × ~20 min per week, a combined group (COM), and a control group (CON) engaging in no intervention. 6MWT distance increased by 11.4% for EXE and 9.9% for COM (p < 0.05). For SART, there were positive significant interactions between the number of correct and incorrect responses from pre- to post-intervention when participants were asked to refrain from a response (NO-GO-trials) across all experimental groups (p < 0.05). There were positive significant interactions in the number of correct, incorrect, and timeout incompatible responses for STROOP in EXE, COG, and COM (p < 0.05). Walking generated a cognitive load attributed to heightened levels of vigilance and decision-making, suggesting that exercise should be adopted within the DS community to promote physical and cognitive well-being.


Exploring the Case for Eminent Domain of Hepatitis C Virus Treatment Patents.
Hepatitis C virus (HCV) is a silent epidemic affecting millions of patients and represents the leading indication for liver transplantation in the United States and worldwide. New direct-acting antiviral agents offer the potential to cure patients infected with HCV but it comes at a staggering cost. Given the recent attention to these high-priced HCV therapies and the impact treating individuals with HCV is having on drug expenditures in the United States, there may be a need to revisit drug patent laws and the options the federal government has to ensure patient access to care.


Cold Induced Depot-Specific Browning in Ferret Aortic Perivascular Adipose Tissue.
Brown adipose tissue is responsible for facultative thermogenesis to produce heat and increase energy expenditure in response to proper stimuli, e.g., cold. Acquisition of brown-like features (browning) in perivascular white adipose tissue (PVAT) may protect against obesity/cardiovascular disease. Most browning studies are performed in rodents, but translation to humans would benefit from a closer animal model. Therefore, we studied the browning response of ferret thoracic aortic PVAT (tPVAT) to cold. We performed global transcriptome analysis of tPVAT of 3-month-old ferrets acclimatized 1 week to 22 or 4°C, and compared the results with those of inguinal subcutaneous adipose tissue. Immunohistochemistry was used to visualize browning. Transcriptome data revealed a stronger cold exposure response of tPVAT, including increased expression of key brown/brite markers, compared to subcutaneous fat. This translated into a clear white-to-brown remodeling of tPVAT, with the appearance of multilocular highly UCP1-stained adipocytes. The pathway most affected by cold exposure in tPVAT was immune response, characterized by down-regulation of immune-related genes, with cardio protective implications. On the other hand, subcutaneous fat responded to cold by increasing energy metabolism based on increased expression of fatty acid oxidation and tricarboxylic acid cycle genes, concordant with lower inguinal adipose tissue weight in cold-exposed animals. Thus, ferret tPVAT responds to cold acclimation with a strong induction of browning and immunosuppression compared to subcutaneous fat. Our results present ferrets as an accessible translational animal model displaying functional responses relevant for obesity and cardiovascular disease prevention.


4-h Identification of Pseudomonas aeruginosa with 9-chloro-9-(4-diethylaminophenyl)-10-phenylacridan.
A total of 361 gram-negative bacilli were evaluated for their ability to grow in the presence of 9-chloro-9-(4-diethylaminophenyl)-10-phenylacridan. The minimum time required for the production of visual turbidity in brain heart infusion broth was determined to be 4 h in shake cultures at 35 degrees C. The minimal inhibitory concentration (MIC) of 9-chloro-9-(4-diethylaminophenyl)-10-phenylacridan in brain heart infusion broth was determined for 174 isolates. The MICs for all 40 Pseudomonas aeruginosa isolates tested were greater than 50 micrograms/ml. The MICs for the other 53 pseudomonads tested were less than or equal to 5 micrograms/ml. Among 81 other gram-negative bacilli tested, the MICs for 4 were 15 micrograms/ml, the MICs for 15 were 10 micrograms/ml, the MICs for 21 were 5 micrograms/ml, and the MICs for 41 were less than or equal to 1 micrograms/ml. Based on these data, 361 gram-negative bacilli were inoculated into brain heart infusion broth containing 15 micrograms of 9-chloro-9-(4-diethylaminophenyl)-10-phenylacridan per ml and incubated on a shaker for 4 h. The only bacteria that produced visual turbidity were identified as P. aeruginosa (170 of 170 isolates).


Changes in life satisfaction among middle-aged adults living alone over a 12-year span.
This secondary analysis used data collected for the Korean Longitudinal Study of Aging from 2006 to 2018 to examine changes in life satisfaction among middle-aged adults living alone in South Korea. Individuals who were over 45 years of age, lived alone at the time of the first data collection wave, and responded at least twice to the survey over the 12-year study period were included in the final linear mixed model (N = 124). Life satisfaction increased for those who had increased assets, were widowed, and had more frequent contact with acquaintances (i.e., once a month and once a week compared with once a year). Life satisfaction decreased as the number of chronic illnesses increased for underweight individuals compared with normal weight or overweight individuals and for depressed versus non-depressed individuals. This study's findings indicate that increased social support is beneficial for middle-aged marginalized individuals, including those who are economically disadvantaged, have few social interactions, are underweight, and have chronic illnesses.


Human transcriptional signature of protection after Plasmodium falciparum immunization and infectious challenge via mosquito bites.
The identification of immune correlates of protection against infectious pathogens will accelerate the design and optimization of recombinant and subunit vaccines. Systematic analyses such as immunoprofiling including serological, cellular, and molecular assessments supported by computational tools are key to not only identify correlates of protection but also biomarkers of disease susceptibility. The current study expands our previous cellular and serological profiling of vaccine-induced responses to a whole parasite malaria vaccine. The irradiated sporozoite model was chosen as it is considered the most effective vaccine against malaria. In contrast to whole blood transcriptomics analysis, we stimulated peripheral blood mononuclear cells (PBMC) with sporozoites and enriched for antigen-specific cells prior to conducting transcriptomics analysis. By focusing on transcriptional events triggered by antigen-specific stimulation, we were able to uncover quantitative and qualitative differences between protected and non-protected individuals to controlled human malaria infections and identified differentially expressed genes associated with sporozoite-specific responses. Further analyses including pathway and gene set enrichment analysis revealed that vaccination with irradiated sporozoites induced a transcriptomic profile associated with Th1-responses, Interferon-signaling, antigen-presentation, and inflammation. Analyzing longitudinal time points not only post-vaccination but also post-controlled human malaria infection further revealed that the transcriptomic profile of protected vs non-protected individuals was not static but continued to diverge over time. The results lay the foundation for comparing protective immune signatures induced by various vaccine platforms to uncover immune correlates of protection that are common across platforms.


Perspectives on oral pre-exposure prophylaxis use amongst female sex workers in Harare, Zimbabwe.
Pre-exposure prophylaxis (PrEP) could provide protection from human immunodeficiency virus (HIV) infection in sexually active persons at risk. Limited data are available in Zimbabwe with regard to the perceptions about PrEP amongst female sex workers (FSWs). The aim of this study was to evaluate the knowledge levels of oral PrEP and the likelihood of its use amongst FSWs. This was a cross-sectional study in the peri-urban areas of Harare, Zimbabwe. Human immunodeficiency virus-negative FSWs were interviewed to assess their awareness of and likelihood to use PrEP. The relative importance index was used to evaluate the levels of knowledge and the likelihood of, and barriers to, PrEP use. A set of 10 questions was designed and validated that evaluated participants' understanding of PrEP. A bivariate logistic regression model was utilised to identify predictors of PrEP use. A total of 131 FSWs with a median age of 25 years (interquartile range: 21-31) participated in this study. Of the 71 (54%) FSWs who had heard about PrEP, 46 (35%) participants had adequate knowledge of its use. A total of 102 (78%) participants revealed that they would be willing to continuously use PrEP if it was provided free of cost. Increasing age of the participants was associated with an increase in the likelihood of using PrEP (r = 0.0033, p = 0.038). More knowledge about PrEP increased the likelihood of its use (r = 0.21, p = 0.0153). This likelihood increased amongst participants with an unprotected sexual intercourse encounter in the preceding 3 months (r = 0.0448, p = 0.026). Knowledge of PrEP amongst FSWs was low. To increase the uptake of PrEP, there is a need to further sensitise FSWs about this intervention. Programmes should also promote awareness training in FSW subgroups that are less likely to use PrEP.


Apolipoprotein polymorphisms and phenotypic variability in American Samoans: Preliminary data.
Human apolipoprotein genetic variation is associated with phenotypic variability in body habitus and in lipid and glucose metabolism, interrelated aspects of human physiology. In this study, structural variation at the apolipoprotein E and H loci, documented for 67 residents of American Samoa, was investigated for associations with body habitus, plasma glucose, glycated hemoglobin, pulse rate, and blood pressure. Compared to men with the common APO E*3 allele, those with APO E*2 had higher weight, percent trunk fat, ratio of subscapular to triceps skinfold, and larger subscapular, suprailiac, and medial calf skinfolds; men with the APO E*4 allele had lower weight, body mass index (BMI), upper arm circumference, estimated arm muscle circumference, and a smaller suprailiac skinfold. Such variability by apolipoprotein E types was not observed in Samoan women nor when men and women were combined for analysis with or without statistical control for sex. At the APO H locus, little difference in aspects of body habitus was observed between men carrying the most common APO H*2 allele and the less common APO H*1 allele. Percent trunk fat and the subscapular to triceps skinfold ratio tended to be larger in women with the APO H*1 allele. Plasma glucose and glycated hemoglobin were lower in Samoans with the APO E*2 and E*4 alleles, but higher in those with the APO H*1 allele. Blood pressure and pulse rate were lower and higher, respectively, in those with the APO E*4 allele. The observed associations differ from those observed in Caucasian, Japanese, and Hispanic samples, and support suggestions that associations between apolipoprotein polymorphisms and morphological measures vary across ethnic groups. © 1993 Wiley-Liss, Inc.


Antibiotic Use and Vaccine Antibody Levels.
The majority of children are prescribed antibiotics in the first 2 years of life while vaccine-induced immunity develops. Researchers have suggested a negative association of antibiotic use with vaccine-induced immunity in adults, but data are lacking in children. From 2006 to 2016, children aged 6 to 24 months were observed in a cohort study. A retrospective, unplanned secondary analysis of the medical record regarding antibiotic prescriptions and vaccine antibody measurements was undertaken concurrently. Antibody measurements relative to diphtheria-tetanus-acellular pertussis (DTaP), inactivated polio (IPV), Haemophilus influenzae type b (Hib), and pneumococcal conjugate (PCV) vaccines were made. In total, 560 children were compared (342 with and 218 without antibiotic prescriptions). Vaccine-induced antibody levels to several DTaP and PCV antigens were lower (P < .05) in children given antibiotics. A higher frequency of vaccine-induced antibodies below protective levels in children given antibiotics occurred at 9 and 12 months of age (P < .05). Antibiotic courses over time was negatively associated with vaccine-induced antibody levels. For each antibiotic course the child received, prebooster antibody levels to DTaP antigens were reduced by 5.8%, Hib by 6.8%, IPV by 11.3%, and PCV by 10.4% (all P ≤ .05), and postbooster antibody levels to DTaP antigens were reduced by 18.1%, Hib by 21.3%, IPV by 18.9%, and PCV by 12.2% (all P < .05). Antibiotic use in children <2 years of age is associated with lower vaccine-induced antibody levels to several vaccines.


Shifts to earlier selfing in sympatry may reduce costs of pollinator sharing.
Coexisting plant congeners often experience strong competition for resources. Competition for pollinators can result in direct fitness costs via reduced seed set or indirect costs via heterospecific pollen transfer (HPT), causing subsequent gamete loss and unfit hybrid offspring production. Autonomous selfing may alleviate these costs, but to preempt HPT, selfing should occur early, before opportunities for HPT occur (i.e., "preemptive selfing hypothesis"). We evaluated conditions for this hypothesis in Collinsia sister species, C. linearis and C. rattanii. In field studies, we found virtually identical flowering times and pollinator sharing between congeners in sympatric populations. Compared to allopatric populations, sympatric C. linearis populations enjoyed higher pollinator visitation rates, whereas visitation to C. rattanii did not differ in sympatry. Importantly, the risk of HPT to each species in sympatry was strongly asymmetrical; interspecies visits comprised 40% of all flower-to-flower visits involving C. rattanii compared to just 4% involving C. linearis. Additionally, our greenhouse experiment demonstrated a strong cost of hybridization when C. rattanii was the pollen donor. Together, these results suggest that C. rattanii pays the greatest cost of pollinator sharing. Matching predictions of the preemptive selfing hypothesis, C. rattanii exhibit significantly earlier selfing in sympatric relative to allopatric populations.


Constructing High-Performance Ternary Device Using Analogous Polymer Donors.
Both ternary copolymerization and ternary blending are effective methods to fine-tune polymer structure and manipulate thin-film morphology to improve device performance. In this work, three D-A-A-A (D: donor, A: acceptor) terpolymer donors (FY1, FY2, and FY3) are synthesized by introducing BDD (1,3-bis(2-ethylhexyl)-5,7-di(thiophen-2-yl)benzo[1,2-c:4,5-c']dithiophene-4,8-dione) units into the D-A alternating copolymer PM6 backbone. Owing to the promoted conjugated planarity and excellent absorption of BDD, the obtained terpolymers display an extended absorption range and enhanced π-π stacking orientation, which is a promising third component in ternary device. As a result, the optimal FY1:PM6:BTP-eC9-based ternary device afforded an impressive power conversion efficiency (PCE) as high as 18.52%, owing to the efficient charge transport, negligible energy loss, and suitable domain size. The result provides an efficient method to obtain high-performance polymer solar cells by using analogous polymer donors in ternary device.