Warfare and wildlife declines in Africa's protected areas.
Large-mammal populations are ecological linchpins, and their worldwide decline and extinction disrupts many ecosystem functions and services. Reversal of this trend will require an understanding of the determinants of population decline, to enable more accurate predictions of when and where collapses will occur and to guide the development of effective conservation and restoration policies. Many correlates of large-mammal declines are known, including low reproductive rates, overhunting, and habitat destruction. However, persistent uncertainty about the effects of one widespread factor-armed conflict-complicates conservation-planning and priority-setting efforts. Case studies have revealed that conflict can have either positive or negative local impacts on wildlife, but the direction and magnitude of its net effect over large spatiotemporal scales have not previously been quantified. Here we show that conflict frequency predicts the occurrence and severity of population declines among wild large herbivores in African protected areas from 1946 to 2010. Conflict was extensive during this period, occurring in 71% of protected areas, and conflict frequency was the single most important predictor of wildlife population trends among the variables that we analysed. Population trajectories were stable in peacetime, fell significantly below replacement with only slight increases in conflict frequency (one conflict-year per two-to-five decades), and were almost invariably negative in high-conflict sites, both in the full 65-year dataset and in an analysis restricted to recent decades (1989-2010). Yet total population collapse was infrequent, indicating that war-torn faunas can often recover. Human population density was also correlated (positively) with wildlife population trajectories in recent years; however, we found no significant effect, in either timespan, of species body mass, protected-area size, conflict intensity (human fatalities), drought frequency, presence of extractable mineral resources, or various metrics of development and governance. Our results suggest that sustained conservation activity in conflict zones-and rapid interventions following ceasefires-may help to save many at-risk populations and species.


The protective effect of glycyrrhizin on hepatic ischemia-reperfusion injury in rats and possible related signal pathway.
To investigate the protective effect of glycyrrhizin (GL) on hepatic ischemia-reperfusion injury (HIRI). Forty SD rats were randomly divided into sham group, HIRI group, GL 100 mg/kg group, and GL 200 mg/kg group. The pathological alterations of liver tissue in each group were observed. The levels of alanine transaminase (ALT), aspartate aminotransferase (AST), endothelin-1 (ET-l), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) were detected. Western blot was used to detect the expression levels of cytoplasmic protein caspase-3, Bax, Bcl-2, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear protein Nrf2. Compared with the HIRI group, the levels of AST, ALT, ET-1, TNF-α, IL-1β, and IL-6 in GL groups were lower, serum NO content was higher, MDA content was lower, SOD and GSH-Px activities were significantly increased, apoptosis index was lower (P<0.05), which was more obvious in high-dose GL (200 mg/kg) group. The LC3-II/LC3-I ratio and Beclin-1 protein expression levels in the GL group were significantly lower than the HIRI group, but the expression levels of cytoplasmic protein HO-1 and nuclear protein Nrf2 were significantly higher than those of the HIRI group, which was more obvious in the high-dose GL group (P<0.05). GL has a protective effect on the liver of HIRI rats, and its mechanism may be related to activation of the Nrf2/HO-1 signaling pathway, inhibition of oxidative stress, inflammation, autophagy, and apoptosis.


Understanding the impact of second-hand smoke exposure on clinical outcomes in participants with COPD in the SPIROMICS cohort.
Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD. Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity. Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, β 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (β 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (β 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, β 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes. Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS. NCT01969344 (clinicaltrials.gov).


Prevalence of Common Gynecological Conditions in the Middle East: Systematic Review and Meta-Analysis.
Introduction: High prevalence of gynecological conditions in women of Middle Eastern origin is reported, likely due to regional risk factors and mediators. The objective of this systematic review and meta-analysis is to investigate the prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin. Methods: MEDLINE, EMBASE, PsycINFO, Global Health, and Google Scholar databases were searched from database inception until 14 February 2021 to identify relevant studies. Peer-reviewed research articles that reported the prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern population were written in English or Arabic. The primary outcome was the estimated pooled prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern populations. The secondary outcome was to assess the evidence in the data for the presence of heterogeneity, by conducting subtype-pooled analysis of prevalence estimates of the conditions. Total weighted prevalence was calculated via Freeman-Tukey arcsine transformation and heterogeneity through the I 2 statistic. Quality control was performed using GRADE criteria. Results: A total of 47 studies, 26 on PCOS, 12 on endometriosis, eight on uterine fibroids, and seven on adenomyosis, were included. The pooled prevalence of PCOS diagnosed according to the NIH criteria was 8.9% (95% CI: 6.5-11.7; prevalence range: 4.0-27.6%), with a higher prevalence from the Gulf Arab states (18.8%, 95% CI: 9.5-30.3; range: 12.1-27.6%). According to the Rotterdam criteria, the pooled prevalence of PCOS was 11.9% (95% CI: 7.1-17.7; range: 3.4-19.9%) with studies limited to the Persian and Levant regions. Endometriosis was diagnosed in 12.9% (95% CI: 4.2-25.4; range: 4.2-21.0%) of women undergoing laparoscopy, for any indication. Uterine fibroid and adenomyosis prevalence of women was 30.6% (95% CI: 24.9-36.7; range: 18.5-42.6%) and 30.8% (95% CI: 27.1-34.6, range: 25.6-37.7%), respectively. Heterogeneity was present between studies due to statistical and methodological inconsistencies between studies, and quality of evidence was low due to sample size and unrepresentative participant selection. Conclusion: This is the first review that has reported the prevalence of gynecological diseases in the Middle Eastern population, suggesting that gynecological morbidity is a public health concern. Due to the health disparities in women, further research is required to understand the relative roles of environmental and genetic factors in the region to serve as a benchmark for evaluation and comparative purposes with other populations.


Anti-smoking advice in general practice consultations: general practitioners' attitudes, reported practice and perceived problems.
Anti-smoking advice from general practitioners has proven efficacy. However, general practitioners do not exploit a large proportion of opportunities to discuss smoking with patients. A study aimed to explore general practitioners attitudes towards discussing smoking with patients and to assess how these influence the quantity of anti-smoking advice that general practitioners report giving during routine consultations. It also aimed to determine the extent to which general practitioners report using evidence-based interventions against smoking and to discover the problems they experience when discussing smoking with patients. A postal survey of all 468 general practitioners on the Leicestershire Family Health Services Authority list was conducted. General practitioners' attitudes were assessed by scoring 13 attitude statements using a six-point Likert-type scale. They were also asked to rank (from a list of 12 items) the five approaches that they found most productive and (from a list of 11 items) the five problems that they most commonly encountered when giving anti-smoking advice to patients. A total of 327 questionnaires (70%) were returned. Most respondents (97%) thought that their advice was more effective when linked to patients' presenting problems and 65% reported that linking their anti-smoking advice to patients' presenting complaints was one of their three most preferred approaches to discussing smoking. Advising all presenting smokers to quit was considered by 40% of respondents to be an appropriate use of time but 76% reported that patients' lack of motivation was one of the three most commonly encountered problems. An analysis of the ratings of the 13 statements suggested that general practitioners who reported the greatest smoking cessation activity during routine consultations held more positive attitudes towards discussing smoking with patients. This study suggests that general practitioners believe that their anti-smoking advice is more effective when linked to patients' presenting complaints, and this belief appears to be reflected in the way in which general practitioners approach smoking cessation with patients. The findings may indicate that general practitioners are unlikely to accept a role in a population-based anti-smoking strategy which demands that they discuss smoking with all presenting smokers.


Effect of ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus.
The combination of ribavirin and interferon alfa has potent synergistic effects in the treatment of chronic hepatitis C. The antiviral mechanism of ribavirin is unknown. We investigated whether a transient initial antiviral effect of ribavirin was sufficient to improve the response to interferon. Fifteen HCV-infected patients (ten male, five female; mean age 45.4+/-11.0 years) treated with ribavirin (1000-1200 mg) and 17 untreated patients with chronic hepatitis C (11 male, six female; mean age 45.6+/-9.9 years) were investigated. All patients were either non-responders to (n=19) or relapsed after (n=13) previous interferon treatment. Serum HCV-RNA concentrations and HCV quasispecies distribution were serially measured over 4 weeks by quantitative reverse transcription-polymerase chain reaction and single-strand conformation polymorphism analysis, respectively. In six of the 15 patients treated with ribavirin, but in none of the controls, serum alanine aminotransferase levels declined by at least 30%. Pretreatment HCV-RNA levels ranged from 5.0x10(5)-5.0x10(7) copies/ml. After initiation of ribavirin treatment, minor (0.5-1.0 log) or no changes (<0.5 log) in total hepatitis C viremia were observed in ten and five patients, respectively. In HCV-infected patients without treatment 7/17 patients had minor and 10/17 no changes in viremia. Polymerase chain reaction amplification of the hypervariable region-1 of HCV was successful in 13/15 treated and in 17/17 untreated patients. Changes in HCV quasispecies according to the single-strand conformation polymorphism band pattern occurred in only one patient treated with ribavirin and in three of the untreated patients. Ribavirin monotherapy has no initial antiviral effect on total hepatitis C viremia nor on HCV quasispecies. Unlike the rapid emergence of antiviral drug-resistant strains in HIV-infected patients, no viral escape phenomena are observed in HCV-infected patients treated with ribavirin.


Cognitive Learning, Monitoring and Assistance of Industrial Workflows Using Egocentric Sensor Networks.
Today, the workflows that are involved in industrial assembly and production activities are becoming increasingly complex. To efficiently and safely perform these workflows is demanding on the workers, in particular when it comes to infrequent or repetitive tasks. This burden on the workers can be eased by introducing smart assistance systems. This article presents a scalable concept and an integrated system demonstrator designed for this purpose. The basic idea is to learn workflows from observing multiple expert operators and then transfer the learnt workflow models to novice users. Being entirely learning-based, the proposed system can be applied to various tasks and domains. The above idea has been realized in a prototype, which combines components pushing the state of the art of hardware and software designed with interoperability in mind. The emphasis of this article is on the algorithms developed for the prototype: 1) fusion of inertial and visual sensor information from an on-body sensor network (BSN) to robustly track the user's pose in magnetically polluted environments; 2) learning-based computer vision algorithms to map the workspace, localize the sensor with respect to the workspace and capture objects, even as they are carried; 3) domain-independent and robust workflow recovery and monitoring algorithms based on spatiotemporal pairwise relations deduced from object and user movement with respect to the scene; and 4) context-sensitive augmented reality (AR) user feedback using a head-mounted display (HMD). A distinguishing key feature of the developed algorithms is that they all operate solely on data from the on-body sensor network and that no external instrumentation is needed. The feasibility of the chosen approach for the complete action-perception-feedback loop is demonstrated on three increasingly complex datasets representing manual industrial tasks. These limited size datasets indicate and highlight the potential of the chosen technology as a combined entity as well as point out limitations of the system.


Bilineal Extramedullary Blast Crisis as an Initial Presentation of Chronic Myeloid Leukemia: A Case Report and Literature Review.
BACKGROUND Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia chromosome generated by the reciprocal translocation t(9: 22)(q34;q11). CML is usually diagnosed in the chronic phase. Blast crisis represents an advanced phase of CML. Extramedullary blast crisis as the initial presentation of CML with bone marrow remaining in chronic phase is an unusual event. Further, extramedullary blast crisis with T lymphoid/myeloid bilineal phenotype as an initial presentation for CML is extremely unusual. CASE REPORT Here, we report the case of a 49-year-old male with rapidly enlarged submandibular lymph nodes. Biopsy specimen from the nodes revealed a characteristic appearance with morphologically and immunohistochemically distinct myeloblasts and T lymphoblasts co-localized in 2 adjacent regions, accompanied by chronic phase of the disease in bone marrow. The presence of the BCR/ABL1 fusion gene within both cellular populations in this case confirmed the extramedullary disease represented a localized T lymphoid/myeloid bilineal blastic transformation of CML. After 3 courses of combined chemotherapy plus tyrosine kinase inhibitor treatment, the mass was completely regressed with a 3-log decrease in BCR/ABL1 transcript from baseline. Five months after the diagnosis, the patient showed diminished vision, hand tremors, and weakness of lower extremities. Flow cytometric immunophenotyping of cerebrospinal fluid revealed the presence of myeloid blasts. An isolated central nervous system relapse of leukemia was identified. Following high-dose systemic and intrathecal chemotherapy, the patient continued to do well. CONCLUSIONS The possibility of extramedullary blast crisis as an initial presentation in patients with CML should be considered. Further, an isolated central nervous system blast crisis should be considered if neurological symptoms evolve in patients who have shown a good response to therapy.


Cellular uptake of nanoparticles: journey inside the cell.
Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell-cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano-bio interface. Recent advances in chemical synthesis have yielded new nanoscale materials with precisely defined biochemical features, and emerging analytical techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available analytical techniques to follow and track these processes.


Phase II trial of infusional cyclophosphamide, idarubicin, and etoposide in poor prognosis non-Hodgkin's lymphoma.
The purpose of this study was to determine the complete response (CR) rate, failure-free survival (FFS), and overall survival (OS) of patients with poor-prognosis intermediate-grade non-Hodgkin's lymphoma (NHL) after treatment with cyclophosphamide, idarubicin, and etoposide given as a continuous intravenous infusion (CIVI) over 96 hours (infusional CIE), including patients with relapsed/refractory disease and patients with no prior therapy but at least two poor-risk features by the age-adjusted International Prognostic Index. Forty-two patients with previously untreated NHL (N = 24) or relapsed/refractory (N = 18) NHL received cyclophosphamide (200 mg/m2/d), idarubicin (2.5-3.0 mg/m2/d) and etoposide (60 mg/m2/d) given by a 96-hour CIVI every 3 weeks for a maximum of 8 cycles. All patients also received granulocyte-colony-stimulating factor. CR occurred in 10 of 24 patients (42%; 95% confidence intervals [CI] 22%, 62%) treated with CIE as first-line therapy, and in 3 of 18 patients (17%; 95% CI 20%, 32%) treated with CIE as second-line or greater therapy. One-year FFS and OS were 42% and 64%, respectively, in patients with no prior therapy, and 17% and 56% in patients with prior therapy. Severe (grade III) or life-threatening (grade IV) toxicity included leukopenia (59%), anemia (61%), thrombocytopenia (31%), and infection (10%). Two patients (4%) died due to treatment related infectious complications. It is unlikely that infusional CIE produces a CR rate more than about 60% in poor-risk patients with intermediate-grade NHL when used as first-line therapy, or more than about 30% in patients receiving the regimen as second-line therapy. Substitution of idarubicin for doxorubicin in this setting, therefore, is not associated with an improved response rate.


The potential of intravenous immunoglobulins for cancer therapy: a road that is worth taking?
Much has been learned recently about the role of immunoglobulins as effector molecules of the adaptive immunity and as active elements in the maintenance of immune homeostasis. The increasing number of pathologies where intravenous immunoglobulins (IVIg) display a beneficial action illustrates their therapeutic relevance. Considering recent findings on the ability of IVIg to modulate macrophage polarization, herein we review evidences on the antitumoral activity of IVIg. Fragmentary and nonconclusive, available evidences are just suggestive of the potential of IVIg in antitumoral therapy, but encourage for the generation of additional evidences through well-designed clinical trials, and for additional studies to address the molecular effects of IVIg as a means to avoid the extrapolation of data gathered from animal models.


Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker.
There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus-related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus-related neoplasia and to predict neoplastic progression. Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus-related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus-related neoplasia from 321 patients in three independent cohorts. Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus-related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus-related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus-related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%. We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.


Assessing the potential of RAD-sequencing to resolve phylogenetic relationships within species radiations: The fly genus Chiastocheta (Diptera: Anthomyiidae) as a case study.
Determining phylogenetic relationships among recently diverged species has long been a challenge in evolutionary biology. Cytoplasmic DNA markers, which have been widely used, notably in the context of molecular barcoding, have not always proved successful in resolving such phylogenies. However, with the advent of next-generation-sequencing technologies and associated techniques of reduced genome representation, phylogenies of closely related species have been resolved at a much higher detail in the last couple of years. Here we examine the potential and limitations of one of such techniques-Restriction-site Associated DNA (RAD) sequencing, a method that produces thousands of (mostly) anonymous nuclear markers, in disentangling the phylogeny of the fly genus Chiastocheta (Diptera: Anthomyiidae). In Europe, this genus encompasses seven species of seed predators, which have been widely studied in the context of their ecological and evolutionary interactions with the plant Trollius europaeus (Ranunculaceae). So far, phylogenetic analyses using mitochondrial markers failed to resolve monophyly of most of the species from this recently diversified genus, suggesting that their taxonomy may need a revision. However, relying on a single, non-recombining marker and ignoring potential incongruences between mitochondrial and nuclear loci may provide an incomplete account of the lineage history. In this study, we applied both classical Sanger sequencing of three mtDNA regions and RAD-sequencing, for reconstructing the phylogeny of the genus. Contrasting with results based on mitochondrial markers, RAD-sequencing analyses retrieved the monophyly of all seven species, in agreement with the morphological species assignment. We found robust nuclear-based species assignment of individual samples, and low levels of estimated contemporary gene flow among them. However, despite recovering species' monophyly, interspecific relationships varied depending on the set of RAD loci considered, producing contradictory topologies. Moreover, coalescence-based phylogenetic analyses revealed low supports for most of the interspecific relationships. Our results indicate that despite the higher performance of RAD-sequencing in terms of species trees resolution compared to cytoplasmic markers, reconstructing inter-specific relationships among recently-diverged lineages may lie beyond the possibilities offered by large sets of RAD-sequencing markers in cases of strong gene tree incongruence.


A Network of Regulations by Small Non-Coding RNAs: The P-TEFb Kinase in Development and Pathology.
Part of the heterodimeric P-TEF-b element of the Pol II transcription machinery, the cyclin-dependent kinase 9 plays a critical role in gene expression. Phosphorylation of several residues in the polymerase is required for elongation of transcript. It determines the rates of transcription and thus, plays a critical role in several differentiation pathways, best documented in heart development. The synthesis and activity of the protein are tightly regulated in a coordinated manner by at least three non-coding RNAs. First, its kinase activity is reversibly inhibited by formation of a complex with the 334 nt 7SK RNA, from which it is released under conditions of stress. Then, heart development requires a maximal rate of synthesis during cardiomyocyte differentiation, followed by a decrease in the differentiated state. The latter is insured by microRNA-mediated translational inhibition. In a third mode of RNA control, increased levels of transcription are induced by small non-coding RNA molecules with sequences homologous to the transcript. Designated paramutation, this epigenetic variation, stable during development, and hereditarily transmitted in a non-Mendelian manner over several generations, is thought to be a response to the inactivation of one of the two alleles by an abnormal recombination event such as insertion of a transposon.


Production and Characterization of Laminates of Paper and Cellulose Nanofibrils.
A novel laminate system comprising of sheets of paper bound together using cellulose nanofibrils (CNF) is manufactured and characterized. Bonding properties of CNF were first confirmed through a series of peeling tests. Composite laminates were manufactured from sheets of paper bonded together using CNF at two different consistencies, press times, and press temperatures. Mechanical properties of the laminates in tension and bending were characterized and the results were statistically analyzed. Elastic modulus and strength results met or exceeded those of a short glass fiber reinforced polypropylene and various natural fiber-filled polypropylene composites as well as some wood and paper based laminates. Stiffness properties, assuming perfect bonding within the laminates, were successfully estimated through a classical laminated plate theory (CLPT) with only 2-10% variation compared to experimental results. Laminates, together with CNF-peeled surfaces, were observed and qualitatively analyzed by SEM imaging. Physical properties, namely, water absorption and thickness swelling were measured. Swelling was controlled by the addition of a small percentage of a cross-linking additive.


Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry.
Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV.


Harassment among university hospital physicians in four European cities. Results from a cross-sectional study in Norway, Sweden, Iceland and Italy (the HOUPE study).
The objective of this cross-national study was to identify work-related factors related to the prevalence of harassment, and identify potential similarities and differences in harassment levels and appointed perpetrators within the same professional group across four European cities. 2078 physicians working in university hospitals in Trondheim, Stockholm, Reykjavik, and Padova participated in the study. Questionnaire comprised items on direct and indirect experience of workplace harassment, appointed perpetrators, psychosocial work environment and basic socio-demographics. Harassment was found to be a relatively frequent work environment problem among physicians in all four European cities, with particular high levels in Padova. Role conflict, human resource primacy, empowerment leadership, and control over work pace were all found to be significantly related to workplace harassment. Differences in harassment prevalence and perpetrators indicated a cultural difference between the Italian and the Nordic hospitals. Harassment followed the line of command in Padova in contrast to being a horizontal phenomenon in the Scandinavian hospitals. This may be explained by national differences in organizational systems and traditions. In order to decrease harassment level and create a positive and productive work environment, each organization must employ different strategies in accordance with their harassment patterns.


Knowledge and attitudes of older adults about sexuality in ageing: a comparison of two studies.
Two studies using separate samples sought to explore differences among male and female elders on their knowledge, attitudes, and sexual behaviour using a nonexperimental approach. Two different samples from separate health and wellness groups were surveyed using the Aging Sexual Knowledge and Attitude Scale (White 1982). Additional data were collected on sexual satisfaction, sexual activity, and demographic variables. In the first study, questionnaires were mailed to the homes of 759 members of the wellness group. The second study was conducted in a similar manner, but with random selection of 400 males and 400 females. Both groups showed a moderate amount of knowledge and permissive attitudes with no significant differences observed between males and females. Reported sexual satisfaction was variable. Subjects were sexually active with activity varying from 0 to 30 times per month, with a mean of 4 times per month. Findings suggest that males and females are comparable on their knowledge and attitudes about sexuality in ageing and most are sexually active. Many are seeking further information on the impact of chronic illness and medications on sexuality.


The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites.
Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity. A similar phenomenon has been observed in mouse models of malaria, using the rodent parasite Plasmodium berghei, but it is unclear whether the P. falciparum proteins known to be involved in this process are conserved in the rodent parasite. Here we identify the P. berghei orthologues of two such key factors of P. falciparum, SBP1 and MAHRP1. Red blood cells infected with P. berghei parasites lacking SBP1 or MAHRP1a fail to bind the endothelial receptor CD36 and show reduced sequestration and virulence in mice. Complementation of the mutant P. berghei parasites with the respective P. falciparum SBP1 and MAHRP1 orthologues restores sequestration and virulence. These findings reveal evolutionary conservation of the machinery underlying sequestration of divergent malaria parasites and support the notion that the P. berghei rodent model is an adequate tool for research on malaria virulence.


Transdifferentiation in neoplastic development and its pathological implication.
Transdifferentiation is a process in which a cell committed to a particular specialization changes to another quite distinct type. It occurs during embryological development and some pathological processes, and causes the tumor cells to express a phenotype different from that of their normal progenitors. Neoplastic transdifferentiation involves pathogenesis of cancer subtype, transition between neoplastic epithelia and neuroendocrine cell, transition between neoplastic epithelia and mesenchyme, as well as transition between non-neuroectodermal and neuroectodermal cells. We propose that differentiation disturbance of cancer cells should include not only lower-, un-, or de-differentiation, but also transdifferentiation. Tumor cell transdifferentiation results from genetic instabilities. In some type of neoplastic transition, the initiation may be induced by extracellular matrix and growth factors.


Injection site reactions after subcutaneous oligonucleotide therapy.
Oligonucleotides (ONs) are short fragments of nucleic acids, currently being investigated as therapeutic agents. When administered subcutaneously (sc), ONs cause a specific local reaction originating around the injection site, such as erythema, itching, discomfort and pain, including more severe manifestations such as ulceration or necrosis. These injection site reactions (ISRs) are common, but rather poorly described in the literature. With this review, we aim to provide an overview on the extent of the problem of ISRs, based on reported incidence. A structured literature search was performed to identify reported incidence and clinical features of ISRs which yielded 70 manuscripts that contained information regarding ISRs. The data from literature was combined with data on file available at our institution. All sc administered ONs described in the literature lead to the occurrence of ISRs. The percentage of trial subjects that developed ISRs ranged from 22 to 100% depending on ON. The majority of ONs caused ISRs in more than 70% of the trial subjects. The severity of the observed reactions varied between different ONs. Occurrence rate as well as severity of ISRs increases with higher doses. For chemistry and target of the compounds, no clear association regarding ISR incidence or severity was identified. All ONs developed to date are associated with ISRs. Overcoming the problem of ISRs might add greatly to the potential success of sc-administered ONs. Knowledge of these skin reactions and their specific immunostimulatory properties should be increased in order to obtain ONs that are more suitable for long-term use and clinically applicable in a broader patient population.


Nanostructured active and photosensitive silica glass for fiber lasers with built-in Bragg gratings.
A nanostructured core silica fiber with active and photosensitive areas implemented within the fiber core is demonstrated. The photosensitivity, active and passive properties of the fiber can be independently shaped with this new approach. We show that discrete local doping with active ions in form of nanorods allow to obtain effective laser action as in case of continuous distribution of the ions in the core. Co-existing discrete photosensitive nanostructure of germanium doped silica determine single-mode performance and allow inscription of highly efficient Bragg grating over the entire core area. Each nanostructure do not degrade performance of other one since physical interaction between active and photosensitive areas are removed. As a proof of concept, we have designed and fabricated the nanostructured, ytterbium single-mode silica fiber laser with the Bragg grating inscribed in the entire core area. We demonstrated fiber laser with good quality of generated laser beam (M2=1.1) with lasing efficiency of 44% and inscribed Bragg grating with 98.5% efficiency and -18 dB contrast.


The relationship between plasma C-reactive protein levels and presence and severity of coronary stenosis in patients with stable angina.
High-sensitivity C-reactive protein (hsCRP) is an inflammation marker and potential predictor of cardiovascular events. However, there is no consensus on the relationship between plasma hsCRP levels and angiographically documented severe coronary lesions in patients with stable angina pectoris. In this study we aimed to assess whether plasma levels of hsCRP can indicate the severity of the coronary artery disease (CAD) in patients with stable angina. A total of 52 subjects, who had undergone coronary angiography were divided into two groups as follows: those with stable angina (group 1, at least one coronary arteries stenosis >50%, n = 26) and normal (group 2, n = 26). Severity of CAD was evaluated by using the Gensini score index. For each group, the levels of hsCRP were measured. HsCRP levels were compared in the subjects with normal coronary arteries, and in those with one-, two-, and three-vessel CAD, and no significant differences among the groups were found (analysis of variance, p>0.05). There was no significant correlation between hsCRP levels and Gensini score index (r = 0.278, p = 0.169). We conclude that there is no relationship between hsCRP levels and the presence and severity of CAD in patients with stable angina.


Baicalein inhibition of hydrogen peroxide-induced apoptosis via ROS-dependent heme oxygenase 1 gene expression.
In the present study, baicalein (BE) but not its glycoside, baicalin (BI), induced heme oxygenase-1 (HO-1) gene expression at both the mRNA and protein levels, and the BE-induced HO-1 protein was blocked by adding cycloheximide (CHX) or actinomycin D (Act D). Activation of ERK, but not JNK or p38, proteins via induction of phosphorylation in accordance with increasing intracellular peroxide levels was detected in BE-treated RAW264.7 macrophages. The addition of the ERK inhibitor, PD98059, (but not the p38 inhibitor, SB203580, or the JNK inhibitor, SP600125) and the chemical antioxidant, N-acetyl cysteine (NAC), significantly reduced BE-induced HO-1 protein expression by respectively blocking ERK protein phosphorylation and intracellular peroxide production. Additionally, BE but not BI effectively protected RAW264.7 cells from hydrogen peroxide (H(2)O(2))-induced cytotoxicity, and the preventive effect was attenuated by the addition of the HO inhibitor, SnPP, and the ERK inhibitor, PD98059. H(2)O(2)-induced apoptotic events including hypodiploid cells, DNA fragmentation, activation of caspase 3 enzyme activity, and a loss in the mitochondrial membrane potential with the concomitant release of cytochrome c from mitochondria to the cytosol were suppressed by the addition of BE but not BI. Blocking HO-1 protein expression by the HO-1 antisense oligonucleotide attenuated the protective effect of BE against H(2)O(2)-induced apoptosis by suppressing HO-1 gene expression in macrophages. Overexpression of the HO-1 protein inhibited H(2)O(2)-induced apoptotic events such as DNA fragmentation and hypodiploid cells by reducing intracellular peroxide production induced by H(2)O(2), compared with those events in neo-control (neo-RAW264.7) cells. In addition, CO, but not bilirubin and biliverdin, addition inhibits H(2)O(2)-induced cytotoxicity in macrophages. It suggests that CO can be responsible for the protective effect associated with HO-1 overexpression. The notion of induction of HO-1 gene expression through a ROS-dependent manner suppressing H(2)O(2)-induced cell death is identified in the present study.


Spectral Grouping of Nominally Aspergillus versicolor Microbial-Collection Deposits by MALDI-TOF MS.
Historical microbial collections often contain samples that have been deposited over extended time periods, during which accepted taxonomic classification (and also available methods for taxonomic assignment) may have changed considerably. Deposited samples can, therefore, have historical taxonomic assignments (HTAs) that may now be in need of revision, and subdivisions of previously-accepted taxa may also be possible with the aid of current methodologies. One such methodology is matrix-assisted laser-desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS). Motivated by the high discriminating power of MALDI-TOF MS coupled with the speed and low cost of the method, we have investigated the use of MALDI-TOF MS for spectral grouping of past deposits made to the Centre for Agriculture and Bioscience International (CABI) Genetic Resource Collection under the HTA Aspergillus versicolor, a common ascomycete fungus frequently associated with soil and plant material, food spoilage, and damp indoor environments. Despite their common HTA, the 40 deposits analyzed in this study fall into six clear spectral-linkage groups (containing nine, four, four, four, four, and two members, respectively), along with a group of ten spectrally-unique samples. This study demonstrates the clear resolving power of MALDI-TOF MS when applied to samples deposited in historical microbial collections.


Growth factor/matrix-induced proliferation of human adult beta-cells.
Proliferation of human beta-cells in vitro is desirable for both transplantation and biological studies. In this study, human pancreatic islets obtained from cadavers were kept in tissue culture plates that favored cell attachment. When the cells attached to the matrix produced by the rat-bladder carcinoma cell line 804G, 5'-bromo-2'-deoxyuridine (BrdU) labeling increased from 4.7 +/- 2.5 to 13.2 +/- 2.2%, while cells simultaneously labeled for insulin and BrdU increased from 0 to 32%. Addition of the growth factor hepatocyte growth factor/scatter (HGF/SF) increased BrdU labeling to 17.5 +/- 1.8 and the percentage of double positive (BrdU + insulin) cells to 69%. This is the first in vitro demonstration that human beta-cells grown in monolayer culture are able to replicate when exposed to selected matrices and growth factors. These experiments add further evidence that HGF/SF is an important mitogenic agent for human beta-cells.


Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer.
The lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival. Inhibition of tumor FAS causes both cell cycle arrest and apoptosis, indicating FAS is a promising target for cancer treatment. Here, we used gene expression profiling to conduct a global study of the cellular processes affected by siRNA mediated knockdown of FAS in MDA-MB-435 mammary carcinoma cells. The study identified 169 up-regulated genes (> or = 1.5 fold) and 110 down-regulated genes (< or = 0.67 fold) in response to knockdown of FAS. These genes regulate several aspects of tumor function, including metabolism, cell survival/proliferation, DNA replication/transcription, and protein degradation. Quantitative pathway analysis using Gene Set Enrichment Analysis software further revealed that the most pronounced effect of FAS knockdown was down-regulation in pathways that regulate lipid metabolism, glycolysis, the TCA cycle and oxidative phosphorylation. These changes were coupled with up-regulation in genes involved in cell cycle arrest and death receptor mediated apoptotic pathways. Together these findings reveal a wide network of pathways that are influenced in response to FAS knockdown and provide new insight into the role of this enzyme in tumor cell survival and proliferation.


THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice.
Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease. Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-atherogenic factors (3% O2 and TNFα) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly. THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.


A stepwise approach for surgical management of diabetic foot infections.
Diabetic foot disease frequently leads to substantial long-term complications, imposing a huge socioeconomic burden on available resources and health-care systems. Peripheral neuropathy, repetitive trauma, and peripheral vascular disease are common underlying pathways that lead to skin breakdown, often setting the stage for limb-threatening infection. Individuals with diabetes presenting with foot infection warrant optimal surgical management to affect limb salvage and prevent amputation; aggressive short-term and meticulous long-term care plans are required. In addition, the initial surgical intervention or series of interventions must be coupled with appropriate systemic metabolic management as part of an integrated, multidisciplinary team. Such teams typically include multiple medical, surgical, and nursing specialties across a variety of public and private health-care systems. This article presents a stepwise approach to the diagnosis and treatment of diabetic foot infections with emphasis on the appropriate use of surgical interventions and includes the following key elements: incision, wound investigation, debridement, wound irrigation and lavage, and definitive wound closure.


Sleep behavior and depression: Findings from the China Kadoorie Biobank of 0.5 million Chinese adults.
Mixed results have shown the association between sleep behavior and depression, but evidence relating the joint effect of sleep duration and sleep disturbances is limited, especially in Chinese population. A total of 512,891 adults aged 30-79 years from China Kadoorie Biobank (CKB) were included. Depression was defined by Composite International Diagnostic Inventory-short form (CIDI-SF). Sleep duration and sleep disturbances, including difficulty initiating and maintaining sleep (DIMS), early morning awakening (EMA), daytime dysfunction (DDF) and any sleep disturbances (ASD), were obtained by a self-reported questionnaire. Logistic regression was applied to examine the association between sleep behavior and depression. About 23.1% of participants reported short sleep duration (≤ 6h), and 5.1% reported long sleep duration (> 9h). Compared with normal sleep duration (7-9h), both groups were associated greater likelihood of having depression (short sleep: OR = 2.32, 95%CI: 2.14-2.51; long sleep: OR = 1.56, 96%CI: 1.34-1.81). Participants reported sleep disturbances were significantly associated with depression (odds ratios ranged from 3.31 to 4.17). Moreover, the associations tended to be stronger for those who reported both abnormal sleep duration and sleep disturbances (p for interactions < 0.05), especially for those who slept long. The cross-sectional nature of the study design limits the interpretation of the results. Abnormal sleep duration and sleep disturbances were associated with depression. The associations were stronger for abnormal sleep duration accompanied with sleep disturbances, especially for a long duration. More attention should be paid on these persons in clinical practice.


Efficacy of long-term sublingual immunotherapy as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma.
Although sublingual immunotherapy (SLIT) is accepted to be a viable alternative of specific-allergen immunotherapy, the efficacy of long-term SLIT in asthmatic children is not well established. The efficacy of 3 yr of SLIT in addition to pharmacotherapy was compared with pharmacotherapy alone in a prospective, open, parallel-group, controlled study. Children with asthma aged 4-16 yr, sensitive to house dust mite (HDM) were followed up for a run-in period of 1 yr and then grouped as those who would receive SLIT + pharmacotherapy (n = 62) or pharmacotherapy alone (n = 28). All patients were evaluated based on symptom-medication scores and lung function tests every 3 months, as well as skin-prick test and serum total immunoglobulin E (IgE) levels annually for 3 yr. Children in the SLIT + pharmacotherapy group demonstrated significantly lower mean daily dose and annual duration of inhaled corticosteroid (ICS) usage when compared with controls. At the end of the 3 yr, within-group comparisons revealed statistically significant decreases in the dose and duration of ICS only in the SLIT group. Furthermore, 52.4% of subjects in the SLIT + pharmacotherapy group were able to discontinue ICS treatment for at least 6 months, which was only 9.1% for the pharmacotherapy group. Three years of SLIT as an adjunct to pharmacotherapy resulted in reduction of both the duration and dose of ICSs and successful discontinuation of ICSs along with improvement in lung functions in HDM-allergic children with asthma.


High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer.
The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues. We investigated expression of LYVE-1 by immunohistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery. A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1-positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3-positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P = 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46-70%) 5-year distant disease-free survival as compared with 74% (66-83%) among those with a low peritumoral lymph vessel density (P = 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis. A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.


Poststroke seizures as stroke mimics: Clinical assessment and management.
Epileptic seizures with postictal negative symptoms represent 20% of all suspected strokes and should be considered in the differential diagnosis of stroke in any patient presenting with an acute neurological deficit, mostly in absence of convulsions. Seizures may also occur at stroke onset, and the latter need to be promptly recognized in order to timely administer reperfusion therapies and reduce the risk of irreversible brain injury. Neuroimaging is essential in differentiating between postictal negative symptoms and deficits due to stroke. After the acute phase, poststroke seizures may worsen or cause the reappearance of neurological deficits and consciousness impairment; they can be also misinterpreted as stroke recurrence and lead to delayed treatment with antiepileptic drugs. It is mandatory to maintain a low threshold for suspecting epileptic seizures, and require appropriate electroencephalographic and neuroimaging investigations to promptly ascertain the etiology of any unexplained change in the neurological status and provide the most adequate treatment. This article is part of the Special Issue "Seizures & Stroke".


The C-terminal region of the hepatitis C virus E1 glycoprotein confers localization within the endoplasmic reticulum.
Expression of the hepatitis C virus glycoprotein E1 in cultured cells localizes it to the endoplasmic reticulum, suggesting that E1 contains a signal mediating retention. Fusion of the C-terminal region of E1 to the ectodomain of CD4 prevented it from being transported to the cell surface. Fusion of this region of E1 resulted in localization of CD4 and influenza virus haemagglutinin chimeric molecules to a pre-medial Golgi compartment. This signal was present within E1 residues 311-383. Retention was not due to misfolding since the chimeric molecules did not form disulphide-linked aggregates indicative of misfolded proteins, and could be recognized by MAbs specific for conformational epitopes.


An Examination of the Role of Difficulties Regulating Positive Emotions in Posttraumatic Stress Disorder.
Emotion regulation difficulties have been theoretically and empirically linked to posttraumatic stress disorder (PTSD). Previous research, however, has focused almost exclusively on difficulties regulating negative emotions. In this study, we explored the nature of difficulties regulating positive emotions in PTSD. Participants were women who had experienced domestic violence (N = 210; 48.6% African American; Mage = 36.14 years). Higher levels of nonacceptance of positive emotions, difficulties engaging in goal-directed behaviors when experiencing positive emotions, and difficulties controlling impulsive behaviors when experiencing positive emotions were related to a higher level of PTSD symptom severity overall and for the intrusion, avoidance/emotional numbing, and hyperarousal clusters, rs = .24-.37. The presence (vs. absence) of a probable PTSD diagnosis was related to greater difficulties engaging in goal-directed behaviors, d = 0.54, and controlling impulsive behaviors, d = 0.34, when experiencing positive emotions. Results suggest the potential utility of assessing and treating difficulties regulating positive emotions among domestic violence-victimized women with PTSD.


Characterization of Estrogenic and Androgenic Activities for Bisphenol A-like Chemicals (BPs): In Vitro Estrogen and Androgen Receptors Transcriptional Activation, Gene Regulation, and Binding Profiles.
Bisphenol A (BPA) is a high production volume chemical widely used in plastics, food packaging, and many other products. It is well known that endocrine-disrupting chemicals might be harmful to human health due to interference with normal hormone actions. Recent studies report widespread usage and exposure to many BPA-like chemicals (BPs) that are structurally or functionally similar to BPA. However, the biological actions and toxicity of those BPs are still relatively unknown. To address this data gap, we used in vitro cell models to evaluate the ability of 22 BPs to induce or inhibit estrogenic and androgenic activity. BPA, Bisphenol AF (BPAF), bisphenol Z (BPZ), bisphenol C (BPC), tetramethyl bisphenol A (TMBPA), bisphenol S (BPS), bisphenol E (BPE), 4,4-bisphenol F (4,4-BPF), bisphenol AP (BPAP), bisphenol B (BPB), tetrachlorobisphenol A (TCBPA), and benzylparaben (PHBB) induced estrogen receptor (ER)α and/or ERβ-mediated activity. With the exception of BPS, TCBPA, and PHBB, these same BPs were also androgen receptor (AR) antagonists. Only 3 BPs were found to be ER antagonists. Bisphenol P (BPP) selectively inhibited ERβ-mediated activity and 4-(4-phenylmethoxyphenyl)sulfonylphenol (BPS-MPE) and 2,4-bisphenol S (2,4-BPS) selectively inhibited ERα-mediated activity. None of the BPs induced AR-mediated activity. In addition, we identify that the BPs can bind to ER or AR with varying degrees by a molecular modeling analysis. Taken together, these findings help us to understand the molecular mechanism of BPs and further consideration of their usage in consumer products.


Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by fermented soy milk.
The effect of a fermented soy milk product (FSP) on various human breast carcinoma cell lines was investigated, and it was shown to have a growth-inhibitory effect, especially on MCF-7 cells. Thus the MCF-7 cell line was used to study the mechanism of action. In female severe combined immune deficiency mice implanted with MCF-7 cells, pretreatment with FSP significantly inhibited tumor growth. The inhibitory effect of FSP on MCF-7 cells seemed to be caused by the additive effects of a wide variety of constituents. The active components of FSP are mainly in the water phase, and the lipid-soluble fraction, which includes the soy isoflavones such as genistein and daidzein, is relatively ineffective. A variety of methods were used to demonstrate that FSP caused apoptotic cell death in MCF-7 cells. FSP induced generation of reactive oxygen species (ROS). Growth inhibition and ROS generation induced by FSP could be inhibited by catalase and deferoxamine, indicating that the ROS production probably was the cause of this apoptotic cell death. This study suggests that FSP retards tumor growth in vivo and can trigger apoptosis in vitro. It may, therefore, be a potential nutritional supplement in chemotherapy.


Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery.
The hepatoprotective effect of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) has been well documented. However, reports on the role of IL-6/STAT3 in liver regeneration are conflicting probably due to the fact that the model of Stat3 knockout mice were complicated with obesity and fatty liver, which may cause some secondary effects on liver regeneration. To study the direct role of STAT3 and to circumvent the problems of obesity and fatty liver in liver regeneration, we generated conditional STAT3 knockout in the liver (L-Stat3(-/-)) using a transthyretin-driven Cre-lox method. The L-Stat3(-/-) mice were born with the expected Mendelian frequency and showed no obesity or other obvious phenotype. After partial hepatectomy, mortality in the L-Stat3(-/-) mice was significantly higher than the littermate Stat3(f/+) controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3(-/-) mice slightly decreased as compared with Stat3(f/+) mice at 40 h after partial hepatectomy, whereas similar hepatocyte DNA synthesis was found at other time points and liver mass could be completely recovered in the L-Stat3(-/-) mice. In another model of liver regeneration induced by subcutaneous injection of carbon tetrachloride (CCl(4)), hepatocyte DNA synthesis in the CCl(4)-treated L-Stat3(-/-) mice also decreased as compared with Stat3(f/+) mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl(4)-treated L-Stat3(-/-) mice compared to wild-type mice. In conclusion, STAT3 is required for survival in the acute stage after 70% hepatectomy and plays a role in inflammatory reaction after hepatocyte necrosis. However, the hepatocytic STAT3 may have limited role in liver mass recovery although DNA synthesis may be impaired.


The influence of sexual hormones on lipogenesis and lipolysis in rat fat cells.
The insulin-stimulated conversion of glucose to fatty acids (fatty acid synthesis) and the maximally norepinephrine-stimulated lipolysis were studied in isolated fat cells from normal male and female rats, ovariectomized rats and sexual hormone-treated normal and ovariectomized rats. The fatty acid synthesis and the lipolysis oscillated considerably more in fat cells from female rats than in fat cells from male rats. This was found to be due to the oestrous cycle, since the fatty acid synthesis was high in prooestrus and low in both oestrus and dioestrus, while the lipolysis was higher in oestrus and prooestrus than in dioestrus. Oestradiol treatment of both female and male rats and testosterone treatment of male rats for three days lowered the fatty acid synthesis and increased the lipolysis. The metabolic oscillation disappeared in ovariectomized rats, and the fat cells from these animals showed a metabolic pattern comparable with that found in prooestrus. Even when ovariectomized rats were treated with oestradiol or progesterone only three hours before the examination a significant lower fatty acid synthesis was found in oestradiol-treated animals compared with the progesterone-treated animals. Since these rats were fasted three hours before the experiments, the results were not due to differences in food intake. It is concluded that fat cell metabolism is influenced by sexual hormones. The results are compatible with the hypothesis that the variation in food intake due to sexual hormones is secondary to the metabolic changes.


Polyphenon E(R), a standardized green tea extract, induces endoplasmic reticulum stress, leading to death of immortalized PNT1a cells by anoikis and tumorigenic PC3 by necroptosis.
Increasing doses of Polyphenon E®, a standardized green tea extract, were given to PNT1a and PC3 prostate epithelial cells mimicking initial and advanced stages of prostate cancer (PCa), respectively. Cell death occurred in both cell lines, with PNT1a being more sensitive [half-maximal inhibitory concentration (IC50) = 35 μg/ml] than PC3 (IC50 = 145 μg/ml) to Polyphenon E®. Cell cycle arrest occurred at G0/G1 checkpoint for PNT1a, and G2/M for PC3 cells. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) occurred in both cell lines, with each exhibiting different timing in response to Polyphenon E®. Autophagy was transiently activated in PNT1a cells within 12 h after treatment as a survival response to overcome ERS; then activation of caspases and cleavage of poly (ADP ribose) polymerase 1 occurred, committing cells to anoikis death. Polyphenon E® induced severe ERS in PC3 cells, causing a dramatic enlargement of the ER; persistent activation of UPR produced strong upregulation of GADD153/CHOP, a key protein of ERS-mediated cell death. Thereafter, GADD153/CHOP activated Puma, a BH3-only protein, committing cells to necroptosis, a programmed caspase-independent mechanism of cell death. Our results provide a foundation for the identification of novel targets and strategies aimed at sensitizing apoptosis-resistant cells to alternative death pathways.


Baseline concentrations of mercury species within sediments from Qatar's coastal marine zone.
Baseline concentration of total mercury (THg), organic extractable mercury and methylmercury (CH3Hg) concentrations in sediments from the northeastern, eastern and southeastern parts of the Arabian Gulf were assessed. Surface sediments were collected from eleven stations from the coastal waters of Qatar. All analyses were performed on homogenised samples. Total mercury analysis was performed by Cold Vapour Atomic Absorption Spectrometry (CVAAS), and methylmercury was analysed by Cold Vapour Atomic Fluorescence spectrometry (CVAFS) after aqueous phase ethylation of the extracted samples. Total mercury (THg) in sediments varied from 8.0 μg/kg to 34.3 μg/kg. Methylmercury was detected in all stations and ranged from 1.46 μg/kg to 3.10 μg/kg accounting for 5.4% to 18.4% of total mercury. Total organic carbon (TOC) ranged from 0.16 to 0.72%, while Organic extractable mercury ranged from 1.55 μg/kg to 13.3 μg/kg. Analysis, the grain size within these sediments, was carried out previously paving the way for studying the influence of these parameters on the sedimentary mercury concentration. Speciation was also assessed, as were relations between the measured mercury fractions.


Differential modulation in binding of ketoprofen to bovine serum albumin in the presence and absence of surfactants: spectroscopic and calorimetric insights.
Surfactants have long been implicated in the unique static and dynamic effect on the structure and function of serum albumins. However, there is very little information on the mode of interactions of drugs to serum albumins in presence of surfactants. The importance of such studies lay in the fact that apart from binding to serum albumins, surfactants are known to radically influence the solvents' micro environment and protein structure. Thus, we have studied the binding of the racemic form of ketoprofen with bovine serum albumin at pH 7.4 in the presence and absence of hexadecyl trimethyl ammonium bromide, sodium dodecyl sulfate, Triton X-100, and NaCl. The structural studies of ketoprofen with bovine serum albumin as investigated by circular dichroism spectroscopy revealed a significant stabilization of bovine serum albumin. However, the combined presence of the surfactants, NaCl and ketoprofen, demonstrated an extremely erratic behavior in terms of stabilization. Further the values of Stern-Volmer and dynamic quenching constant suggested the binding site of ketoprofen to be scattered in the region of domain I B and II A, close to Trp 134. The results of differential scanning calorimetry revealed that the binding of ketoprofen to bovine serum albumin leads to its temperature-dependent separation into two units. The binding parameters of bovine serum albumin obtained from isothermal titration calorimetry in the combined presence of ketoprofen and surfactants/NaCl correlate well with the differential scanning calorimetry studies further confirming the localization of ketoprofen in domain I B and II A. In the combined presence of surfactants, NaCl and ketoprofen, the binding of ketoprofen to bovine serum albumin exhibited altered binding parameters far different from the binding of ketoprofen alone. Overall, the experimental findings strongly indicated positive as well as negative modulation in the binding of ketoprofen to bovine serum albumin in the presence of ligands.


The human papillomavirus type 16 E2 transcription factor binds with low cooperativity to two flanking sites and represses the E6 promoter through displacement of Sp1 and TFIID.
The E6 promoters of all genital human papillomaviruses have a characteristic alignment of transcription factor binding sites. Activation of the basic transcription complex at the TATA box depends upon a sequence-aberrant Sp1 site. Repression of E6 promoters is achieved by two binding sites for the viral E2 protein positioned between the Sp1 site and the TATA box. We have purified the human papillomavirus type 16 E2 protein after expression in Escherichia coli and studied its binding and repression properties with oligonucleotides representing the homologous promoter sequences. A Kd value of 3 x 10(-10) M indicated binding properties expected for a native protein. We found low cooperativity in the binding of two E2 dimers to flanking sites, both when these sites were separated by 3 nucleotides, as in the natural promoter, and when they were further apart. E2 protein, bound close to the distal Sp1 site, displaced the Sp1 factor even when the aberrant sequence was replaced by a typical Sp1 core recognition site. The high affinity of E2 protein for its binding site even led to Sp1 displacement at concentrations of E2 protein nearly 2 orders of magnitude lower than those of Sp1. Functional analyses of mutated E6 promoter sequences showed repression by this distal E2 binding site in the complete absence of binding to the proximal E2 binding site. From our findings and observations published by others, we conclude that each of the E2 binding sites in the E6 promoter of genital human papillomaviruses plays a separate role by displacing the transcription factors Sp1 and TFIID.


Evaluation of a well-established task-shifting initiative: the lay counselor cadre in Botswana.
Evidence supports the implementation of task shifting to address health worker shortages that are common in resource-limited settings. However, there is need to learn from established programs to identify ways to achieve the strongest, most sustainable impact. This study examined the Botswana lay counselor cadre, a task shifting initiative, to explore effectiveness and contribution to the health workforce. This evaluation used multiple methods, including a desk review, a national lay counselor survey (n = 385; response = 94%), in-depth interviews (n = 79), lay counselors focus group discussions (n = 7), lay counselors observations (n = 25), and client exit interviews (n = 47). Interview and focus group data indicate that lay counselors contribute to essentially all HIV-related programs in Botswana and they conduct the majority of HIV tests and related counseling at public health facilities throughout the country. Interviews showed that the lay counselor cadre is making the workload of more skilled health workers more manageable and increasing HIV acceptance in communities. The average score on a work-related knowledge test was 74.5%. However for 3 questions, less than half answered correctly. During observations, lay counselors demonstrated average competence for most skills assessed and clients (97.9%) were satisfied with services received. From the survey, lay counselors generally reported being comfortable with their duties; however, some reported clinical duties that extended beyond their training and mandate. Multiple factors affecting the performance of the lay counselors were identified, including insufficient resources, such as private counseling space and HIV test kits; and technical, administrative, and supervisory support. Lay counselors are fulfilling an important role in Botswana's healthcare system, serving as the entry point into HIV care, support, and treatment services. For this and other similar task shifting initiatives, it is important that lay counselors' responsibilities are clear and that training and support are adequate to optimize their effectiveness.


Nucleotide Reverse Transcriptase Inhibitors: A Thorough Review, Present Status and Future Perspective as HIV Therapeutics.
Human immunodeficiency virus type-1 (HIV-1) infection leads to acquired immunodeficiency syndrome (AIDS), a severe viral infection that has claimed approximately 658,507 lives in the US between the years 2010-2014. Antiretroviral (ARV) therapy has proven to inhibit HIV-1, but unlike other viral illness, not cure the infection. Among various Food and Drug Administration (FDA)-approved ARVs, nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) are most effective in limiting HIV-1 infection. This review focuses on NRTIs mechanism of action and metabolism. A search of PubMed (1982-2016) was performed to capture relevant articles regarding NRTI pharmacology. The current classical NRTIs pharmacology for HIV-1 prevention and treatment are presented. Finally, various novel strategies are proposed to improve the efficacy of NRTIs, which will increase therapeutic efficiency of present-day HIV-1 prevention/treatment regimen. Use of NRTIs will continue to be critical for successful treatment and prevention of HIV-1.


Evanescent waves in simulated ear canals: Experimental demonstration and method for compensation.
Evanescent waves emerge from a small sound source that radiates into a waveguide with a larger cross-sectional area, but unlike planar waves, do not propagate far from the source. Evanescent waves thus contaminate in-ear calibration of acoustic stimuli. Measurements with an otoacoustic-emission (OAE) probe inserted at the entrance of long tubes of various diameters show a decline in the evanescent wave with distance from the source when advancing a probe tube through the OAE probe and into the long tube. The amplitude of the evanescent pressure increases with frequency and depends strongly on the diameter of the long tube. Modifying the shape of the aperture of the probe's sound source, thus effectively enlarging its diameter and redirecting acoustic flow, greatly reduced evanescent waves. The reduction in evanescent-wave pressure was observed in calibration cavities used to determine the Thévenin-equivalent source pressure and impedance of the probe. Errors in source calibrations were considerably larger in the unmodified configuration. An alternative method is proposed for calculation of acoustic source parameters that models the evanescent-wave pressure and reduces its influence on the calculation. This reduction greatly improves the quality of source calibrations, which should improve the accuracy of ear-canal impedance measurements and related quantities.


An inexact multi-objective programming model for water resources management in industrial parks of Binhai New Area, China.
In recent years, Binhai New Area of Tianjin has been suffering severe water shortage due to climate change and industrial activities. Integrated and effective water resources management approaches are urgent for the sustainable development of industrial parks in Binhai New Area. However, uncertainties exist in many aspects of the water resources system and are inevitably problematic for water resources planning and policy-making. To address these uncertainties, an interval multiple-objective programming model was developed here to support the long-term planning of industrial water resources management in Binhai New Area, Tianjin, China. The model incorporated both multiple-objective programming and interval linear programming into a general programming framework. The developed model could handle the uncertainties and complexities of the water management system, and also allowed decision makers to adjust fuzzy objective control decision variables to satisfy multiple holistic and interactive objectives. The solutions are useful for planning adjustments of the existing water allocation patterns in Binhai New Area.


Parallel Transduction of Nanomechanical Motion Using Plasmonic Resonators.
We demonstrate parallel transduction of thermally driven mechanical motion of an array of gold-coated silicon nitride nanomechanical beams, by using near-field confinement in plasmonic metal-insulator-metal resonators supported in the gap between the gold layers. The free-space optical readout, enabled by the plasmonic resonances, allows for addressing multiple mechanical resonators in a single measurement. Light absorbed in the metal layer of the beams modifies their mechanical properties, allowing photothermal tuning of the eigenfrequencies. The appearance of photothermally driven parametric amplification indicates the possibility of plasmonic mechanical actuation.


Preventive care for colorectal cancer survivors: a 5-year longitudinal study.
To explore the mix of physician specialties that long-term survivors visit and how the mix relates to preventive care. Using the Surveillance, Epidemiology, and End Results-Medicare database, we conducted a retrospective, longitudinal study of stage I to III Medicare fee-for-service colorectal cancer patients diagnosed in 1997. We examined physician visits and preventive care each year for 5 years, starting 366 days postdiagnosis, and how preventive service receipt related to the physician mix seen: primary care provider (PCP) only, oncologist only, both, or neither. A total of 1,541 patients met the eligibility criteria (mean age, 76; 43% male; 85% white). During 5 years, PCP visits increased from a mean of 4.2 to 4.7 (P < .0001), and oncology visits decreased from 1.3 to 0.5 (P < .0001). Survivor care by PCPs only increased from 44% to 62%, whereas shared care by PCPs and oncologists dropped from 37% to 21% (P < .0001). Survivors who saw both PCPs and oncologists were most likely to receive influenza vaccination, mammograms, and cervical cancer screening; survivors who saw PCPs only were most likely to receive cholesterol screening and bone densitometry. Higher socioeconomic status was associated with increased influenza vaccination, mammograms, and cervical cancer screening (P < .05). Over time, there was a decrease in mammography and cervical cancer screening and an increase in influenza vaccination (P < .05). As oncologists become less involved in survivor care, cancer-related screening decreases significantly. These results support the need for survivorship care plans that explicitly outline the roles of PCPs and oncologists in sharing care for cancer survivors, and how these roles may change over time.


Changes in the spectral index of skin-surface laser Doppler signals of nude mice following the injection of CT26 tumor cells.
This study investigated microcirculatory-blood-flow responses in nude mice following the injection of CT26 tumor cells by analyzing the frequency content of skin blood-flow signals recorded on the skin surface. CT26 cells were injected subcutaneously (10^4/100 μl) into the right back flank of each 7-week-old mouse. Three-minute laser Doppler flowmetry (LDF) signals were measured in 60 nude mice. The data sequences were obtained at 1, 2, and 3 weeks after injecting CT26 cells. Mouse tissue samples were cut into sections and examined microscopically to determine the condition of cancer metastasis. Spectral analysis performed after 1 week revealed a significant decrease in the relative energy contribution of the endothelium-related frequency band, and significant increases in those of the myogenic and respiration-related frequency bands of the LDF signals in the metastasis group (n=12). To the best of our knowledge, this is the first study demonstrating the feasibility of evaluating metastasis in animal subjects based on changes in noninvasively measured LDF parameters. Changes in the LDF spectral indexes can be attributed to differences in the microcirculatory regulatory activities. The present measurements performed on the skin surface provide a noninvasive and real-time method for evaluating the microcirculatory responses induced by implanting CT26 tumor cells.


The representations of spacing and part-based information are associated for upright faces but dissociated for objects: evidence from individual differences.
Considerable evidence suggests that qualitatively different processes are involved in the perception of faces and objects. According to a central hypothesis, the extraction of information about the spacing among face parts (e.g., eyes and mouth) is a primary function of face processing mechanisms that is dissociated from the extraction of information about the shape of these parts. Here, we used an individual-differences approach to test whether the shape of face parts and the spacing among them are indeed processed by dissociated mechanisms. To determine whether the pattern of findings that we reveal is unique for upright faces, we also presented similarly manipulated nonface stimuli. Subjects discriminated upright or inverted faces or houses that differed in parts or spacing. Only upright faces yielded a large positive correlation across subjects between performance on the spacing and part discrimination tasks. We found no such correlation for inverted faces or houses. Our findings suggest that face parts and spacing are processed by associated mechanisms, whereas the parts and spacing of nonface objects are processed by distinct mechanisms. These results may be consistent with the idea that faces are special, in that they are processed as nondecomposable wholes.


Electronic health record use and the quality of ambulatory care in the United States.
Electronic health records (EHRs) have been proposed as a sustainable solution for improving the quality of medical care. We assessed the association between EHR use, as implemented, and the quality of ambulatory care in a nationally representative survey. We performed a retrospective, cross-sectional analysis of visits in the 2003 and 2004 National Ambulatory Medical Care Survey. We examined EHR use throughout the United States and the association of EHR use with 17 ambulatory quality indicators. Performance on quality indicators was defined as the percentage of applicable visits in which patients received recommended care. Electronic health records were used in 18% (95% confidence interval [CI], 15%-22%) of the estimated 1.8 billion ambulatory visits (95% CI, 1.7-2.0 billion) in the United States in 2003 and 2004. For 14 of the 17 quality indicators, there was no significant difference in performance between visits with vs without EHR use. Categories of these indicators included medical management of common diseases, recommended antibiotic prescribing, preventive counseling, screening tests, and avoiding potentially inappropriate medication prescribing in elderly patients. For 2 quality indicators, visits to medical practices using EHRs had significantly better performance: avoiding benzodiazepine use for patients with depression (91% vs 84%; P = .01) and avoiding routine urinalysis during general medical examinations (94% vs 91%; P = .003). For 1 quality indicator, visits to practices using EHRs had significantly worse quality: statin prescribing to patients with hypercholesterolemia (33% vs 47%; P = .01). As implemented, EHRs were not associated with better quality ambulatory care.


Examining the association of lung cancer and highly correlated fibre size-specific asbestos exposures with a hierarchical Bayesian model.
Asbestos is a known carcinogen. However, little is known about the differential effects of size-specific asbestos fibres. Previous research has examined the relationship with lung cancer of each fibre group in the absence of others. Attempts to model all fibre groups within a single regression model have failed due to high correlations across fibre size groups. We compare results from frequentist models for individual fibre size groups, and a hierarchical Bayesian model that included all fibre groups to estimate the relationship of size-specific asbestos fibre groups to lung cancer mortality. The hierarchical model assumes partial exchangeability of the effects of size-specific asbestos fibre groups to lung cancer, and is capable of handling the strong correlation of the exposure data. When fibre groups are modelled independently with a frequentist model, there appears to be an increase in the dose-response with increasing fibre size. However, when subject to a hierarchical structure, this trend vanishes, and the effects of distinct fibre groups appear largely similar. This is the first occasion where distinct asbestos fibre groups have been assessed in a single regression model; however, even the use of a hierarchical modelling structure does not appear to overcome all the statistical fluctuations arising from the high correlations across fibre groups. We believe these results should be compared with other occupational cohorts with similar fibre group information. Finally, results for the smallest fibre group may be suggestive of a carcinogenic potential for nanofibres.


Interferon γ-induced GTPase promotes invasion of Listeria monocytogenes into trophoblast giant cells.
Listeria monocytogenes is well known for having the ability to cross the placental barrier, leading to fetal infections and abortion. However, the mechanisms leading to infectious abortion are poorly understood. In this study, we demonstrate that interferon γ-induced GTPase (IGTP) contributes to the invasion of L. monocytogenes into trophoblast giant (TG) cells, which are placental immune cells. Knockdown of IGTP in TG cells decreased the relative efficiencies of L. monocytogenes invasion. Moreover, IGTP accumulated around infected L. monocytogenes in TG cells. Treatment of TG cells with phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors also reduced bacterial invasion. PI3K/Akt inhibitor or IGTP knockdown reduced the amount of phosphorylated Akt. Monosialotetrahexosylganglioside (GM1) gangliosides, lipid raft markers, accumulated in the membrane of L. monocytogenes-containing vacuoles in TG cells. Furthermore, treatment with a lipid raft inhibitor reduced bacterial invasion. These results suggest that IGTP-induced activation of the PI3K/Akt signaling pathway promotes bacterial invasion into TG cells.


Occurrence and Distribution of Ergot and Estimates of Seed Loss in Kentucky Bluegrass Grown for Seed in Central Oregon.
In 1991 to 1993, ergot was detected in 36, 44, and 62%, respectively, of fields of Kentucky bluegrass grown for seed in central Oregon. Relatively few fields (2 to 13%) had a high (more than 20 sclerotia/gm seed) level of ergot. Ergot severity (percent sclerotia by weight) in 1991 to 1993 was estimated at 0.85, 0.07, and 0.34%, respectively. Percent seed replaced by ergot in 1991 to 1993 was estimated at 0.22, 0.02, and 0.08, respectively. Recleaning of seed to reduce ergot contamination and to meet purity standards resulted in a 7.8% reduction in marketable seed weight. Estimated value of seed replaced by ergot in 1991, 1992, and 1993, was $75,625, $4,758, and $17,076, respectively. Estimated value of seed lost during recleaning in 1991, 1992, and 1993, was $37,669, $8,171, and $21,964, respectively. Weed grasses supporting ergot at the time of harvest of Kentucky bluegrass were species of Bromus, Secale, Festuca, and Poa. However, very few seed heads of weed grasses were infected, and they appeared to contribute little to ergot development in central Oregon. Most infested fields (with more than one sclerotium/gm seed prior to recleaning) or weed grass sites with ergot were located in the southern range of the area of study.


Developmental origins of health and disease: current knowledge and potential mechanisms.
Epidemiologic and clinical research has provided a large body of evidence supporting the developmental origins of health and disease (DOHaD), but there has been a relative dearth of mechanistic studies in humans due to the complexity of working with large, longitudinal cohorts. Nonetheless, animal models of undernutrition have provided substantial evidence for the potential epigenetic, metabolic, and endocrine mechanisms behind DOHaD. Furthermore, recent research has explored the interaction between the environment and the gastrointestinal system by investigating how the gut microbial ecology may impact the capacity for nutrient processing and absorption in a manner that may limit growth. This review presents a summary of current research that supports the concept of DOHaD, as well as potential mechanisms and interactions that explain how nutrition in utero and during early childhood influences lifelong health.


SIZ1 deficiency causes reduced stomatal aperture and enhanced drought tolerance via controlling salicylic acid-induced accumulation of reactive oxygen species in Arabidopsis.
Transpiration and gas exchange occur through stomata. Thus, the control of stomatal aperture is important for the efficiency and regulation of water use, and for the response to drought. Here, we demonstrate that SIZ1-mediated endogenous salicylic acid (SA) accumulation plays an important role in stomatal closure and drought tolerance. siz1 reduced stomatal apertures. The reduced stomatal apertures of siz1 were inhibited by the application of peroxidase inhibitors, salicylhydroxamic acid and azide, which inhibits SA-dependent reactive oxygen species (ROS) production, but not by an NADPH oxidase inhibitor, diphenyl iodonium chloride, which inhibits ABA-dependent ROS production. Furthermore, the introduction of nahG into siz1, which reduces SA accumulation, restored stomatal opening. Stomatal closure is generally induced by water deficit. The siz1 mutation caused drought tolerance, whereas nahG siz1 suppressed the tolerant phenotype. Drought stresses also induced expression of SA-responsive genes, such as PR1 and PR2. Furthermore, other SA-accumulating mutants, cpr5 and acd6, exhibited stomatal closure and drought tolerance, and nahG suppressed the phenotype of cpr5 and acd6, as did siz1 and nahG siz1. Together, these results suggest that SIZ1 negatively affects stomatal closure and drought tolerance through the accumulation of SA.


Solarium Use and Risk for Malignant Melanoma: Meta-analysis and Evidence-based Medicine Systematic Review.
There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma. A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings. Levels of evidence and grades of recommendation were determined according to guidelines of the Oxford Centre for Evidence-Based Medicine. Summary risk estimates and 95% confidence intervals for four different outcomes (ever exposure, exposure at younger age, high/low exposure vs. non-exposure) were derived from random-effects meta-analyses to account for possible heterogeneity across studies. Two cohort and twenty-nine case-control studies were eligible. Overall, quality of included studies was poor as a result of severe limitations, including possible recall and selection bias, and due to lack of interventional trials. Summary risk estimates suggested a weak association (odds ratio (OR)=1.19, 95% confidence interval (CI)=1.04-1.35, p=0.009) for ever-exposure to UV radiation from a solarium with melanoma risk. However, sensitivity analyses did not show an association for studies from Europe (OR=1.10; 95%CI=0.95-1.27, p=0.218), studies with low risk of bias (OR=1.15; 95%CI=0.94-1.41, p=0.179), and studies conducted after 1990 (OR 1.09; 95%CI=0.93-1.29, p=0.295). Moreover, moderate associations were found for first exposure to UV radiation from a solarium at younger age (<25 years) and high exposure (>10 sessions in lifetime) with melanoma risk. However, for all outcomes analyzed, overall study quality and resulting levels of evidence (3a-) and grades of recommendation (D) were low due to lack of interventional studies and severe limitations including unobserved or unrecorded confounding. Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk.


Osteoporosis: disease severity and consequent fracture management.
Osteoporosis is a systemic skeletal disease responsible for the high incidence of fractures in older subjects, particularly in postmenopausal women. The increasing prevalence with population ageing and prolonged life expectancy raises the rates of associated morbidity, loss of independence, and mortality. BMD and previous fracture history are two main risk factors associated with osteoporosis such that the presence of prior fractures can predict future fractures. Strontium ranelate is an agent developed for the management of postmenopausal osteoporosis, demonstrated to reduce vertebral, nonvertebral, major nonvertebral, and hip fractures. It has been demonstrated to be effective for a broad spectrum of patients, including women with osteopenia, osteoporosis, and severe disease.


Potentiation rather than distraction in a trace fear conditioning procedure.
Trace conditioning procedures are defined by the introduction of a trace interval between conditioned stimulus (CS, e.g. noise or light) offset and unconditioned stimulus (US, e.g. footshock). The introduction of an additional stimulus as a distractor has been suggested to increase the attentional demands of the task and to extend the usefulness of the behavioural model. In Experiment 1, the CS was noise and the distractor was provided by an intermittent light. In Experiment 2, the CS was light and the distractor was provided by an intermittent noise. In both experiments, the introduction of a 10s trace interval weakened associative learning compared with that seen in a 0s delay conditioned group. However, there was no consistent evidence of distraction. On the contrary, in Experiment 1, associative learning was stronger (in both trace and delay conditioned groups) for rats conditioned also in the presence of the intermittent light. In Experiment 2, there was no such effect when the roles of the stimuli were reversed. The results of Experiment 2 did however confirm the particular salience of the noise stimulus. The finding of increased associative learning dependent on salience is consistent with arousal-mediated effects on associative learning.


ProLoc-GO: utilizing informative Gene Ontology terms for sequence-based prediction of protein subcellular localization.
Gene Ontology (GO) annotation, which describes the function of genes and gene products across species, has recently been used to predict protein subcellular and subnuclear localization. Existing GO-based prediction methods for protein subcellular localization use the known accession numbers of query proteins to obtain their annotated GO terms. An accurate prediction method for predicting subcellular localization of novel proteins without known accession numbers, using only the input sequence, is worth developing. This study proposes an efficient sequence-based method (named ProLoc-GO) by mining informative GO terms for predicting protein subcellular localization. For each protein, BLAST is used to obtain a homology with a known accession number to the protein for retrieving the GO annotation. A large number n of all annotated GO terms that have ever appeared are then obtained from a large set of training proteins. A novel genetic algorithm based method (named GOmining) combined with a classifier of support vector machine (SVM) is proposed to simultaneously identify a small number m out of the n GO terms as input features to SVM, where m <<n. The m informative GO terms contain the essential GO terms annotating subcellular compartments such as GO:0005634 (Nucleus), GO:0005737 (Cytoplasm) and GO:0005856 (Cytoskeleton). Two existing data sets SCL12 (human protein with 12 locations) and SCL16 (Eukaryotic proteins with 16 locations) with <25% sequence identity are used to evaluate ProLoc-GO which has been implemented by using a single SVM classifier with the m = 44 and m = 60 informative GO terms, respectively. ProLoc-GO using input sequences yields test accuracies of 88.1% and 83.3% for SCL12 and SCL16, respectively, which are significantly better than the SVM-based methods, which achieve < 35% test accuracies using amino acid composition (AAC) with acid pairs and AAC with dipedtide composition. For comparison, ProLoc-GO using known accession numbers of query proteins yields test accuracies of 90.6% and 85.7%, which is also better than Hum-PLoc (85.0%) and Euk-OET-PLoc (83.7%) using ensemble classifiers with hybridization of GO terms and amphiphilic pseudo amino acid composition for SCL12 and SCL16, respectively. The growth of Gene Ontology in size and popularity has increased the effectiveness of GO-based features. GOmining can serve as a tool for selecting informative GO terms in solving sequence-based prediction problems. The prediction system using ProLoc-GO with input sequences of query proteins for protein subcellular localization has been implemented (see Availability).