Ecological speciation in European whitefish is driven by a large-gaped predator.
Lake-dwelling fish that form species pairs/flocks characterized by body size divergence are important model systems for speciation research. Although several sources of divergent selection have been identified in these systems, their importance for driving the speciation process remains elusive. A major problem is that in retrospect, we cannot distinguish selection pressures that initiated divergence from those acting later in the process. To address this issue, we studied the initial stages of speciation in European whitefish (Coregonus lavaretus) using data from 358 populations of varying age (26-10,000 years). We find that whitefish speciation is driven by a large-growing predator, the northern pike (Esox lucius). Pike initiates divergence by causing a largely plastic differentiation into benthic giants and pelagic dwarfs: ecotypes that will subsequently develop partial reproductive isolation and heritable differences in gill raker number. Using an eco-evolutionary model, we demonstrate how pike's habitat specificity and large gape size are critical for imposing a between-habitat trade-off, causing prey to mature in a safer place or at a safer size. Thereby, we propose a novel mechanism for how predators may cause dwarf/giant speciation in lake-dwelling fish species.


1,2,4-Trioxanes as potential antimalarial agents.
A number of 1,2,4-trioxanes were prepared and tested for antimalarial activity in search of a simplified analogue of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum. The most active compounds were methyl 2-(2,4a-epidioxy-4a,5,6,7,8,8a-hexahydro-5,5,8a-trimethyl-2H-1-benzop yra n-2-yl) acetate (3b), which showed IC20's of 96 and 39 ng/mL, respectively, and 2,4a-epidioxy-3,4,4a,5,6,7,8,8a-octahydro-2-[2-(benzoyloxy)propyl]-5,5,8 a- trimethyl-2H-1-benzopyran (12), which showed IC50's of 24 and 99 ng/mL, respectively. For comparison, qinghaosu exhibits an IC50 of 1 ng/mL for both strains.


Symmetry constraints on spin dynamics: Application to hyperpolarized NMR.
Spin dynamical evolution is constrained by the symmetries of the spin Hamiltonians that generate the quantum dynamics. The consequences of symmetry-induced constraints are examined for some common hyperpolarized NMR experiments, including the excitation of singlet order in spin-pair systems, and the transfer of parahydrogen-induced hyperpolarized singlet order to magnetization in systems displaying chemical and magnetic equivalence.


Design of a high-efficiency train headlamp with low power consumption using dual half-parabolic aluminized reflectors.
We propose a train headlamp system using dual half-circular parabolic aluminized reflectors. Each half-circular reflector contains five high-efficiency and small-package light-emitting diode (LED) chips, and the halves are 180° rotationally symmetric. For traffic safety, the headlamp satisfies the Code of Federal Regulations. To predict the pattern of illumination, an analytical derivation is developed for the optical path of a ray that is perpendicular to and emitted from the center of an LED chip. This ray represents the main ray emitted from the LED chip and is located at the maximum illuminance of the spot projected by the LED source onto a screen. We then analyze the design systematically to determine the locations of the LED chips in the reflector that minimize electricity consumption while satisfying reliability constraints associated with traffic safety. Compared to a typical train headlamp system with an incandescent or halogen lamp needing several hundred watts, the proposed system only uses 20.18 W to achieve the luminous intensity requirements.


Synthetic peptides containing ITIM-like domains block expression of inflammatory mediators and migration/invasion of cancer cells through activation of SHP-1 and PI3K.
Increasing evidence supports that inflammation is closely associated with the development of cancer. In an effort to develop synthetic peptides that can suppress the inflammatory activation of cancer cells, decapeptides representing immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences of immune receptor expressed on myeloid cells-1 (IREM-1) were tested for their anti-inflammatory effects in cancer cell lines. One (named TAT-YADL) out of the five synthetic peptides tested exhibited inhibitory effects on the expression of inflammatory mediators as well as invasion and migration. The inhibitory activities of the synthetic peptides required activation of SH2-containing protein tyrosine phosphatase-1 (SHP-1) and phosphoinositide 3-kinase (PI3K).


Adherens junction proteins in the hamster uterus: their contributions to the success of implantation.
The adherens junction (AJ) is important for maintaining uterine structural integrity, composition of the luminal environment, and initiation of implantation by virtue of its properties of cell-cell recognition, adhesion, and establishment of cell polarity and permeability barriers. In this study, we investigated the uterine changes of AJ components E-cadherin, beta-catenin, and alpha-catenin at their mRNA and protein levels, together with the cellular distribution of meprinbeta, phospho-beta-catenin, and active beta-catenin proteins, in hamsters that show only ovarian progesterone-dependent uterine receptivity and implantation. By in situ hybridization and immunofluorescence, we have demonstrated that uterine epithelial cells expressed three of these AJ proteins and their mRNAs prior to and during the initial phase of implantation. Immunofluorescence study showed no change in epithelial expression patterns of uterine AJ proteins from Days 1 to 5 of pregnancy. With advancement of the implantation process, AJ components were primarily expressed in cells of the secondary decidual zone (SDZ), but not in the primary decidual zone (PDZ). In contrast, we noted strong expression of beta-catenin and alpha-catenin proteins in the PDZ, but not in the SDZ, of mice. Taken together, these results suggest that AJ proteins contribute to uterine barrier functions by cell-cell adhesion to ensure protection of the embryo. In addition, cleavage of E-cadherin by meprinbeta might contribute to weakening uterine epithelial cell-cell contact for blastocyst implantation. We also report that the nuclear localization of active beta-catenin from Day 4 onward in hamsters implies that beta-catenin/Wnt-signal transduction is activated in the uterus during implantation and decidualization.


A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated.
Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.


Acute mesenteric ischemia and duodenal ulcer perforation: a unique double pathology.
Acute mesenteric ischaemia and duodenal perforation are surgical emergencies with serious consequences. Patients presenting with acute mesenteric ischaemia alone face a high mortality rate as high as 60% whereas those presenting with peptic ulcer perforation the mortality rates range from 6-14%. There are very few reported cases of patients presenting with this dual pathology. We report a unique case of a 53 year old Italian lady who presented with acute mesenteric ischaemia and duodenal perforation. This is the first report of massive bowel ischaemia and duodenal perforation with no apparent underlying common pathophysiology leading to this presentation. Early management in the intensive care unit and appropriate surgical intervention maximised the patient's chances of survival despite the poor prognosis associated with her dual pathology. The rare pathology of the patient described can be explained by two possible hypotheses: peptic ulcer disease causing duodenal ulceration, which precipitated ischaemic infarction of the small bowel. The second hypothesis is the patient developed a stress related ulcer following ischaemic bowel infarction secondary to arterial thrombosis.


The genomic landscapes of human breast and colorectal cancers.
Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.


Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma.
We describe 2 cases of malignant melanotic epithelioid renal neoplasms bearing TFE3 gene fusions. Both neoplasms occurred in children (an 11-y-old boy and a 12-y-old girl), and presented with disseminated metastatic disease including mediastinal and mesenteric adenopathy. Both neoplasms featured sheets of epithelioid cells with clear to finely granular eosinophilic cytoplasm set in a branching capillary vasculature. The neoplastic cells contained variable amounts of finely brown pigment confirmed to be melanin by histochemical stains. By immunohistochemistry, the neoplastic cells labeled for melanocytic markers HMB45 and Melan A, but not for S100 protein, MiTF, or any epithelial marker (cytokeratins, epithelial membrane antigen), renal tubular marker (CD10, PAX8, PAX2, RCC Marker) or muscle marker (actin, desmin). Both neoplasms demonstrated nuclear labeling for TFE3 protein by immunohistochemistry, and the presence of TFE3 gene fusions was confirmed by TFE3 fluorescence in situ hybridization analysis. These distinctive neoplasms combine morphologic features of perivascular epithelioid cell neoplasms (PEComas), Xp11 translocation carcinoma, and melanoma, though the phenotype most closely approaches PEComa. These neoplasms represent the first documented examples in which TFE3 gene fusions coexist with melanin production, and their identification raises the possibility that TFE3 gene fusions may underlie an aggressive subset of lesions currently classified as PEComa in young patients.


Omega-3 Supplementation Improves Pruritus in Continuous Ambulatory Peritoneal Dialysis Patients: A Crossover Randomized Pilot Clinical Trial.
Pruritus is a prevalent skin condition in end-stage renal disease patients. Omega-3 fatty acids have been shown to reduce pruritus in hemodialysis patients. Our objective was to assess the effect of 3 g/day omega-3 supplementation on pruritus among continuous ambulatory peritoneal dialysis (CAPD) patients. In this two-period, two-sequence crossover randomized clinical trial, 40 eligible subjects (CAPD patients who complained of pruritus for more than 8 weeks) were randomized to 3 g of omega-3 (n = 20) or identical placebo capsules (n = 20) for 4 weeks. After a wash-out period of 6 weeks, patients were crossed over to the alternate treatment option. Pruritus intensity was assessed using the visual analog scale (VAS) at baseline, 2-and 4-weeks post-intervention in each study period. Both patients and investigators were blinded to the study protocol. No significant carry-over effect was detected. The mean pruritus score (VAS) in the omega-3 group compared with placebo group after the first (-3.02 vs. -0.48, P < 0.001) and second (-4.09 vs. -0.43, P < 0.001) intervention periods showed higher significant decrease. In summary, omega-3 supplementation is an effective treatment for pruritus alleviation in CAPD patients. Further studies are needed to determine the mechanisms underlying antipruritic effects of omega-3.


Untangling the phenotypic heterogeneity of Diamond Blackfan anemia.
Diamond Blackfan anemia (DBA) is a lineage-selective inherited bone marrow failure syndrome characterized primarily by anemia and physical malformations. Recent advances in identifying the genetic abnormalities underlying DBA have demonstrated involvement of genes encoding both large (RPL) and small (RPS) ribosomal subunit proteins, including mutations of RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 in 50% to 60% of affected patients. Despite significant progress, identification of gene abnormalities in the remaining patients remains an important question since present data suggest that mutations in other members of the ribosomal protein gene complement do not explain those cases without an identified genetic lesion in these genes. Genetic studies have also raised new questions with the recognition of substantial variability in the manifestations of DBA, ranging from ribosomal protein mutations in otherwise asymptomatic individuals to those with classic severe red blood cell aplasia with characteristic malformations, at times within the same kindred. In this review, we summarize the genetic basis of DBA and discuss mechanisms by which the phenotype of DBA might be modified.


Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial.
Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.


Fate of Salmonella enterica and Enterohemorrhagic Escherichia coli Cells Artificially Internalized into Vegetable Seeds during Germination.
Vegetable seeds contaminated with bacterial pathogens have been linked to fresh-produce-associated outbreaks of gastrointestinal infections. This study was undertaken to observe the physiological behavior of Salmonella enterica and enterohemorrhagic Escherichia coli (EHEC) cells artificially internalized into vegetable seeds during the germination process. Surface-decontaminated seeds of alfalfa, fenugreek, lettuce, and tomato were vacuum-infiltrated with four individual strains of Salmonella or EHEC. Contaminated seeds were germinated at 25°C for 9 days, and different sprout/seedling tissues were microbiologically analyzed every other day. The internalization of Salmonella and EHEC cells into vegetable seeds was confirmed by the absence of pathogens in seed-rinsing water and the presence of pathogens in seed homogenates after postinternalization seed surface decontamination. Results show that 317 (62%) and 343 (67%) of the 512 collected sprout/seedling tissue samples were positive for Salmonella and EHEC, respectively. The average Salmonella populations were significantly larger (P < 0.05) than the EHEC populations. Significantly larger Salmonella populations were recovered from the cotyledon and seed coat tissues, followed by the root tissues, but the mean EHEC populations from all sampled tissue sections were statistically similar, except in pregerminated seeds. Three Salmonella and two EHEC strains had significantly larger cell populations on sprout/seedling tissues than other strains used in the study. Salmonella and EHEC populations from fenugreek and alfalfa tissues were significantly larger than those from tomato and lettuce tissues. The study showed the fate of internalized human pathogens on germinating vegetable seeds and sprout/seedling tissues and emphasized the importance of using pathogen-free seeds for sprout production.IMPORTANCE The internalization of microorganisms into vegetable seeds could occur naturally and represents a possible pathway of vegetable seed contamination by human pathogens. The present study investigated the ability of two important bacterial pathogens, Salmonella and enterohemorrhagic Escherichia coli (EHEC), when artificially internalized into vegetable seeds, to grow and disseminate along vegetable sprouts/seedlings during germination. The data from the study revealed that the pathogen cells artificially internalized into vegetable seeds caused the contamination of different tissues of sprouts/seedlings and that pathogen growth on germinating seeds is bacterial species and vegetable seed-type dependent. These results further stress the necessity of using pathogen-free vegetable seeds for edible sprout production.


Revisiting the Core Entrustable Professional Activities for Entering Residency.
The Core EPAs for Entering Residency Pilot project aimed to test the feasibility of implementing 13 entrustable professional activities (EPAs) at 10 U.S. medical schools and to gauge whether the use of the Core EPAs could improve graduates' performance early in residency. In this manuscript, the authors (members of the pilot institutions and Association of American Medical Colleges staff supporting the project evaluation) describe the schools' capacity to collect multimodal evidence about their students' performance in each of the Core EPAs and the ability of faculty committees to use those data to make decisions regarding learners' readiness for entrustment. In reviewing data for each of the Core EPAs, the authors reflected on how each activity performed as an EPA informed by how well it could be assessed and entrusted. For EPAs that did not perform well, the authors examined whether there are underlying practical and/or theoretical issues limiting its utility as a measure of student performance in medical school.


Leveraging the Comparative Toxicogenomics Database to Fill in Knowledge Gaps for Environmental Health: A Test Case for Air Pollution-induced Cardiovascular Disease.
Environmental health studies relate how exposures (eg, chemicals) affect human health and disease; however, in most cases, the molecular and biological mechanisms connecting an exposure with a disease remain unknown. To help fill in these knowledge gaps, we sought to leverage content from the public Comparative Toxicogenomics Database (CTD) to identify potential intermediary steps. In a proof-of-concept study, we systematically compute the genes, molecular mechanisms, and biological events for the environmental health association linking air pollution toxicants with 2 cardiovascular diseases (myocardial infarction and hypertension) as a test case. Our approach integrates 5 types of curated interactions in CTD to build sets of "CGPD-tetramers," computationally constructed information blocks relating a Chemical- Gene interaction with a Phenotype and Disease. This bioinformatics strategy generates 653 CGPD-tetramers for air pollution-associated myocardial infarction (involving 5 pollutants, 58 genes, and 117 phenotypes) and 701 CGPD-tetramers for air pollution-associated hypertension (involving 3 pollutants, 96 genes, and 142 phenotypes). Collectively, we identify 19 genes and 96 phenotypes shared between these 2 air pollutant-induced outcomes, and suggest important roles for oxidative stress, inflammation, immune responses, cell death, and circulatory system processes. Moreover, CGPD-tetramers can be assembled into extensive chemical-induced disease pathways involving multiple gene products and sequential biological events, and many of these computed intermediary steps are validated in the literature. Our method does not require a priori knowledge of the toxicant, interacting gene, or biological system, and can be used to analyze any environmental chemical-induced disease curated within the public CTD framework. This bioinformatics strategy links and interrelates chemicals, genes, phenotypes, and diseases to fill in knowledge gaps for environmental health studies, as demonstrated for air pollution-associated cardiovascular disease, but can be adapted by researchers for any environmentally influenced disease-of-interest.


Analysis Of Multiscale Corticomuscular Coupling Networks Based On Ordinal Patterns.
The coupled analysis of corticomuscular function based on physiological electrical signals can identify differences in causal relationships between electroencephalogram (EEG) and surface electromyogram (sEMG) in different motor states. The existing methods are mainly devoted to the analysis in the same frequency band, while ignoring the cross-band coupling, which plays an active role in motion control. Considering the inherent multiscale characteristics of physiological signals, a method combining Ordinal Partition Transition Networks (OPTNs) and Multivariate Variational Modal Decomposition (MVMD) was proposed in this paper. The EEG and sEMG were firstly decomposed on a time-frequency scale using MVMD, and then the coupling strength was calculated by the OPTNs to construct a corticomuscular coupling network, which was analyzed with complex network parameters. Experimental data were obtained from a self-acquired dataset consisting of EEG and sEMG of 16 healthy subjects at different sizes of constant grip force. The results showed that the method was superior in representing changes in the causal link among multichannel signals characterized by different frequency bands and grip strength patterns. Complex information transfer between the cerebral cortex and the corresponding muscle groups during constant grip force output from the human upper limb. Furthermore, the sEMG of the flexor digitorum superficialis (FDS) in the low frequency band is the hub in the effective information transmission between the cortex and the muscle, while the importance of each frequency component in this transmission network becomes more dispersed as the grip strength grows, and the increase in coupling strength and node status is mainly in the γ band (30~60Hz). This study provides new ideas for deconstructing the mechanisms of neural control of muscle movements.


A Randomised, Double-Blind, Placebo-Controlled Trial of As-Needed Naltrexone in the Treatment of Pathological Gambling.
Effective treatment strategies are needed for the treatment of pathological gambling (PG). The efficacy of as-needed naltrexone was assessed in a single-centre, randomised, double-blind, placebo-controlled trial. The participants (n = 101) received either as-needed placebo or naltrexone (50 mg) and psychosocial support for 20 weeks. The primary outcome measure was the severity of PG assessed by the Yale-Brown Obsessive Compulsive Scale adapted for PG (PG-YBOCS). Secondary gambling-related outcome measures included thoughts/urges and behaviour subscales of PG-YBOCS as well as the highest daily expenditure and gambling frequency. In addition, RAND-36 scales of emotional well-being and social functioning were used as outcomes. The results were analysed using the intention-to-treat principle and linear random effects modelling. No significant treatment group differences were found. In an exploratory analysis, emotional well-being increased in a subgroup of participants with AA genotype of opioid receptor, mu 1 (OPRM1) A118G polymorphism (p = 0.02). Overall, the as-needed naltrexone may not provide substantial additional benefit for PG patients receiving psychosocial support. Replication by larger scale studies is warranted to further evaluate naltrexone administration schedules for the treatment of PG and the role of OPRM1.


Low-voltage high-performance silicon photonic devices and photonic integrated circuits operating up to 30 Gb/s.
We present high performance silicon photonic circuits (PICs) defined for off-chip or on-chip photonic interconnects, where PN depletion Mach-Zehnder modulators and evanescent-coupled waveguide Ge-on-Si photodetectors were monolithically integrated on an SOI wafer with CMOS-compatible process. The fabricated silicon PIC(off-chip) for off-chip optical interconnects showed operation up to 30 Gb/s. Under differential drive of low-voltage 1.2 V(pp), the integrated 1 mm-phase-shifter modulator in the PIC(off-chip) demonstrated an extinction ratio (ER) of 10.5dB for 12.5 Gb/s, an ER of 9.1dB for 20 Gb/s, and an ER of 7.2 dB for 30 Gb/s operation, without adoption of travelling-wave electrodes. The device showed the modulation efficiency of V(π)L(π) ~1.59 Vcm, and the phase-shifter loss of 3.2 dB/mm for maximum optical transmission. The Ge photodetector, which allows simpler integration process based on reduced pressure chemical vapor deposition exhibited operation over 30 Gb/s with a low dark current of 700 nA at -1V. The fabricated silicon PIC(intra-chip) for on-chip (intra-chip) photonic interconnects, where the monolithically integrated modulator and Ge photodetector were connected by a silicon waveguide on the same chip, showed on-chip data transmissions up to 20 Gb/s, indicating potential application in future silicon on-chip optical network. We also report the performance of the hybrid silicon electronic-photonic IC (EPIC), where a PIC(intra-chip) chip and 0.13μm CMOS interface IC chips were hybrid-integrated.


Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate approximately 80% coverage of common variation across the region (r (2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in approximately 8,500 case subjects and 12,400 control subjects. Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.57], P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.76], P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.


An alternative early childhood caries risk surveillance methodology for public policy and practice advancements.
Early childhood caries (ECC) negatively impacts many child health outcomes and can lead to greater costs for medical and dental care as well as negatively impact future oral health wellness. ECC risk factors are rooted in many social determinants of health. Addressing ECC at the population-level is a national public health priority. The purpose of this study was to identify the South Carolina counties with the greatest risk for ECC. As policy-makers seek to address inequities stemming from early childhood caries, documenting its prevalence is essential. Since no county level ECC rates were published for South Carolina, we identified an opportunity to strengthen ECC surveillance through public use data, so as to properly equip policy-makers and pediatric providers with an evidence based understanding of the scope of the problem. As a result we sought to develop an overall county level prevalence measure for ECC risk through an ecological analysis of public use data. Ten counties with the greatest overall risk for ECC were all rural as hypothesized. Additionally, seven of the 10 highest risk counties fell into what is often referred to as the "Corridor of Shame." We have found an affordable way of measuring county level risk for ECC that allows pediatric advocates and policy-makers to develop population level interventions to reduce and measure risk with public-use data.


Extreme learning machine for regression and multiclass classification.
Due to the simplicity of their implementations, least square support vector machine (LS-SVM) and proximal support vector machine (PSVM) have been widely used in binary classification applications. The conventional LS-SVM and PSVM cannot be used in regression and multiclass classification applications directly, although variants of LS-SVM and PSVM have been proposed to handle such cases. This paper shows that both LS-SVM and PSVM can be simplified further and a unified learning framework of LS-SVM, PSVM, and other regularization algorithms referred to extreme learning machine (ELM) can be built. ELM works for the "generalized" single-hidden-layer feedforward networks (SLFNs), but the hidden layer (or called feature mapping) in ELM need not be tuned. Such SLFNs include but are not limited to SVM, polynomial network, and the conventional feedforward neural networks. This paper shows the following: 1) ELM provides a unified learning platform with a widespread type of feature mappings and can be applied in regression and multiclass classification applications directly; 2) from the optimization method point of view, ELM has milder optimization constraints compared to LS-SVM and PSVM; 3) in theory, compared to ELM, LS-SVM and PSVM achieve suboptimal solutions and require higher computational complexity; and 4) in theory, ELM can approximate any target continuous function and classify any disjoint regions. As verified by the simulation results, ELM tends to have better scalability and achieve similar (for regression and binary class cases) or much better (for multiclass cases) generalization performance at much faster learning speed (up to thousands times) than traditional SVM and LS-SVM.


Neural correlates of behavioral preference for culturally familiar drinks.
Coca-Cola (Coke) and Pepsi are nearly identical in chemical composition, yet humans routinely display strong subjective preferences for one or the other. This simple observation raises the important question of how cultural messages combine with content to shape our perceptions; even to the point of modifying behavioral preferences for a primary reward like a sugared drink. We delivered Coke and Pepsi to human subjects in behavioral taste tests and also in passive experiments carried out during functional magnetic resonance imaging (fMRI). Two conditions were examined: (1) anonymous delivery of Coke and Pepsi and (2) brand-cued delivery of Coke and Pepsi. For the anonymous task, we report a consistent neural response in the ventromedial prefrontal cortex that correlated with subjects' behavioral preferences for these beverages. In the brand-cued experiment, brand knowledge for one of the drinks had a dramatic influence on expressed behavioral preferences and on the measured brain responses.


Comparison of COMPUTED TOMOGRAPHY Image Quality Using Intravenous vs. Intraosseous Contrast Administration in Swine.
Vascular access is essential in managing patients with significant injuries. It is required for medications, fluids, blood products, and radiographic contrast administration. Generally, this is accomplished through peripheral intravenous (i.v.) cannulation. In some patients, however, i.v. cannulation may be difficult or impossible. Intraosseous (i.o.) access is an acceptable alternative for many uses during resuscitation. However, adequacy of vascular enhancement with i.o. administration of contrast has not been studied. This study was performed to assess the efficacy of i.o. administration of contrast agents for enhanced computed tomography (CT) imaging of the chest and abdomen. We carried out a crossover study in mature mini-swine with peripheral i.v. and i.o. access established. Intraosseous access was obtained in the proximal humerus with fluoroscopic confirmation. Each animal underwent two trauma-protocol CT scans successively using the i.v. or i.o. routes of contrast administration. Wash-out between studies was established. The order for route of administration was randomized. Images were evaluated for adequacy of enhancement by two blinded board-certified radiologists. All images obtained with successful administration of i.o. contrast were judged adequately enhanced, whereas two from the i.v. route were judged to be inadequate by at least one of the radiologists. Two occurrences of failed i.o. needle placement occurred. One animal had complete contrast extravasation resulting in inadequate opacification. In this model, injection of contrast through a proximal humerus i.o. resulted in adequate enhancement of trauma-protocol CT images. Our results suggest that i.o. administration of contrast merits further investigation of its potential utility in patients when i.v. access would delay diagnostic evaluation.


REM sleep, prefrontal theta, and the consolidation of human emotional memory.
Both emotion and sleep are independently known to modulate declarative memory. Memory can be facilitated by emotion, leading to enhanced consolidation across increasing time delays. Sleep also facilitates offline memory processing, resulting in superior recall the next day. Here we explore whether rapid eye movement (REM) sleep, and aspects of its unique neurophysiology, underlie these convergent influences on memory. Using a nap paradigm, we measured the consolidation of neutral and negative emotional memories, and the association with REM-sleep electrophysiology. Subjects that napped showed a consolidation benefit for emotional but not neutral memories. The No-Nap control group showed no evidence of a consolidation benefit for either memory type. Within the Nap group, the extent of emotional memory facilitation was significantly correlated with the amount of REM sleep and also with right-dominant prefrontal theta power during REM. Together, these data support the role of REM-sleep neurobiology in the consolidation of emotional human memories, findings that have direct translational implications for affective psychiatric and mood disorders.


Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables.
To assess health related quality of life of patients with congestive heart failure; to compare their quality of life with the previously characterised general population and in those with other chronic diseases; and to correlate the different aspects of quality of life with relevant somatic variables. University hospital. A German version of the generic quality of life measure (SF-36) containing eight dimensions was administered to 205 patients with congestive heart failure and systolic dysfunction. Cardiopulmonary evaluation included assessment of New York Heart Association (NYHA) functional class, left ventricular ejection fraction, peak oxygen uptake, and the distance covered during a standardised six minute walk test. Quality of life significantly decreased with NYHA functional class (linear trend: p < 0.0001). In NYHA class III, the scores of five of the eight quality of life domains were reduced to around one third of those in the general population. The pattern of reduction was different in patients with chronic hepatitis C and major depression, and similar in patients on chronic haemodialysis. Multiple regression analysis showed that only the NYHA functional class was consistently and closely associated with all quality of life scales. The six minute walk test and peak oxygen uptake added to the explanation of the variance in only one of the eight quality of life domains (physical functioning). Left ventricular ejection fraction, duration of disease, and age showed no clear association with quality of life. In congestive heart failure, quality of life decreases as NYHA functional class worsens. Though NYHA functional class was the most dominant predictor among the somatic variables studied, the major determinants of reduced quality of life remain unknown.


Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers.
Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs.


Toxicity of the essential oil of Illicium difengpi stem bark and its constituent compounds towards two grain storage insects.
During our screening program for new agrochemicals from Chinese medicinal herbs, the essential oil of Illicium difengpi stem bark was found to possess strong insecticidal activities against the maize weevil, Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae) and red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae). A total of 37 components of the essential oil of I. difengpi were identified. The main components of the essential oil were safrole (23.61%), linalool (12.93%), and germacrene D (5.35%). Bioactivities-directed chromatographic separation on repeated silica gel columns led to the isolation of two compounds: safrole and linalool. Safrole showed pronounced contact toxicity against both insect species and (LD₅₀ = 8.54 for S. zeamais; 4.67 µg/adult for T. castaneum) and was more toxic than linalool (LD₅₀ = 24.88 for S. zeamais; 8.12 µg/adult for T. castaneum). The essential oil acting against the two species of insects showed LD₅₀ values of 13.83 and 6.33 µg/adult, respectively. Linalool also possessed strong fumigant toxicity against both insect species (LC₅₀ = 10.02 for S. zeamais; 9.34 mg/L for T. castaneum) and was more toxic than safrole (LD₅₀ = 32.96 and 38.25 mg/L), while the crude essential oil acting against the two species of insects showed LC₅₀ values of 14.62 and 16.22 mg/L, respectively. These results suggest that the essential oil of I. difengpi stem bark and the two compounds may be used in grain storage to combat insect pests.


Psychological Burden of Hepatic Encephalopathy on Patients and Caregivers.
Hepatic encephalopathy (HE) is common in advanced cirrhosis and is characterized by marked neuropsychiatric abnormalities. However, despite its severity and effects on brain function, the impact of HE on psychological status of patients has not been adequately assessed. The aim of this study was to evaluate the effect of HE on psychological status of patients and their informal caregivers. Fifteen patients with cirrhosis and episodic or persistent HE and their corresponding informal caregivers were included. Semistructured interviews were performed in patients and caregivers. Quality of life (QoL) was assessed by the short-form 36 in both patients and caregivers, and the Zarit burden score was measured in caregivers. The analysis of interviews was performed using qualitative methodology. HE causes a major psychological impact on patients with HE. The first episode of HE caused a very significant impact that was reported with deep feelings, mainly of fear, anger, misery, anxiety, and sorrow, which persisted with time. Symptoms causing more psychological impact on patients were impaired ability to walk and speak. All effects were associated with a marked impairment in QoL. The psychological impact was also marked in caregivers who had a major burden, as assessed by the Zarit score. Moreover, QoL, particularly the mental component score, was markedly impaired in caregivers in intensity similar to that of patients. HE has a profound psychological impact on patients and their informal caregivers, associated with a marked negative influence on QoL. The psychological effects of HE on patients and caregivers should be evaluated and treated.


Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers.
Assessing liver fibrosis is traditionally performed by biopsy, an imperfect gold standard. Non-invasive techniques, liver stiffness measurements (LSM) and biomarkers [FibroTest(R) (FT)], are widely used in countries where they are available. The aim was to identify factors associated with LSM accuracy using FT as a non-invasive endpoint and vice versa. The proof of concept was taken using the manufacturers recommendations for excluding patients at high risk of false negative/positive. The hypothesis was that the concordance between LSM and FT, would be improved by excluding high-risk patients. Thereafter, the impact of potential variability factors was assessed by the same methods. Liver biopsy and independent endpoints were used to validate the results. Applying manufacturers' recommendations in 2,004 patients increased the strength of concordance between LSM and FT (P<0.00001). Among the 1,338 patients satisfying recommendations, the methodology identified a significant LSM operator effect (P = 0.001) and the following variability factors (all P<0.01), related to LSM: male gender, older age, and NAFLD as a cause of liver disease. Biopsy confirmed in 391 patients these results. This study has validated the concept of using the strength of concordance between non-invasive estimates of liver fibrosis for the identification of factors associated with variability and precautions of use.


Agroecosystem energy transitions in the old and new worlds: trajectories and determinants at the regional scale.
Energy efficiency in biomass production is a major challenge for a future transition to sustainable food and energy provision. This study uses methodologically consistent data on agroecosystem energy flows and different metrics of energetic efficiency from seven regional case studies in North America (USA and Canada) and Europe (Spain and Austria) to investigate energy transitions in Western agroecosystems from the late nineteenth to the late twentieth centuries. We quantify indicators such as external final energy return on investment (EFEROI, i.e., final produce per unit of external energy input), internal final EROI (IFEROI, final produce per unit of biomass reused locally), and final EROI (FEROI, final produce per unit of total inputs consumed). The transition is characterized by increasing final produce accompanied by increasing external energy inputs and stable local biomass reused. External inputs did not replace internal biomass reinvestments, but added to them. The results were declining EFEROI, stable or increasing IFEROI, and diverging trends in FEROI. The factors shaping agroecosystem energy profiles changed in the course of the transition: Under advanced organic and frontier agriculture of the late nineteenth and early twentieth centuries, population density and biogeographic conditions explained both agroecosystem productivity and energy inputs. In industrialized agroecosystems, biogeographic conditions and specific socio-economic factors influenced trends towards increased agroecosystem specialization. The share of livestock products in a region's final produce was the most important factor determining energy returns on investment.


Assessment of non-response bias in a probability household survey of male same-gender sexual behavior.
To assess non-participation bias in a survey of male sexual behavior. A household survey was carried out in 1992-1993 using a probability sampling frame in Mexico City. Demographic variables were available for all eligible men. The extent of non-participation bias was estimated using a version of the Heckman method, which utilizes two equations, one to predict participation and the other to predict reports of same-gender sexual behavior. A total of 8,068 of the 13,713 eligible men completed a face-to-face questionnaire (response rate 59%); 173 men (2.1%) reported bisexual behavior in their lifetime, and 37 (0.4%) reported only male partners. Survey participation was predicted using demographic variables: 67% of the observations were correctly predicted by a probit regression model: 82% of participants and 53% of non-participants (pseudo-r2 = 0.13). Same-gender sexual behavior was predicted by variables indicating attachment to gay/bisexual social networks, history of sexually transmitted diseases, positive attitudes towards gay and bisexual males, and lack of support from male relatives. Ninety-seven per cent of the cases was correctly predicted by the probit model (pseudo-r2 = 0.14). The correlation between these two equations was not statistically significant. These results indicate that prevalence estimates of same-gender sexual behavior among Mexico City men were not biased by selective survey participation. Careful selection and training of household interviewers may have assisted in minimizing potential bias.


Self-esteem--a psychiatric view.
The literature relating to the acquisition, maintenance, and clinical significance of self-esteem reveals theoretical differences between earlier investigators. The nature of self-esteem remains controversial, and attention is drawn to some of the problems of construct validation and measurement. Despite the difficulties, self-esteem is a concept worthy of further pursuit. This will require a measuring instrument that captures the concept more effectively than those currently available.


DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study.
Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.


DNA double-strand break repair is impaired in presenescent Syrian hamster fibroblasts.
Studies of DNA damage response are critical for the comprehensive understanding of age-related changes in cells, tissues and organisms. Syrian hamster cells halt proliferation and become presenescent after several passages in standard conditions of cultivation due to what is known as "culture stress". Using proliferating young and non-dividing presenescent cells in primary cultures of Syrian hamster fibroblasts, we defined their response to the action of radiomimetic drug bleomycin (BL) that induces DNA double-strand breaks (DSBs). The effect of the drug was estimated by immunoblotting and immunofluorescence microscopy using the antibody to phosphorylated histone H2AX (gH2AX), which is generally accepted as a DSB marker. At all stages of the cell cycle, both presenescent and young cells demonstrated variability of the number of gH2AX foci per nucleus. gH2AX focus induction was found to be independent from BL-hydrolase expression. Some differences in DSB repair process between BL-treated young and presenescent Syrian hamster cells were observed: (1) the kinetics of gH2AX focus loss in G0 fibroblasts of young culture was faster than in cells that prematurely stopped dividing; (2) presenescent cells were characterized by a slower recruitment of DSB repair proteins 53BP1, phospho-DNA-PK and phospho-ATM to gH2AX focal sites, while the rate of phosphorylated ATM/ATR substrate accumulation was the same as that in young cells. Our results demonstrate an impairment of DSB repair in prematurely aged Syrian hamster fibroblasts in comparison with young fibroblasts, suggesting age-related differences in response to BL therapy.


Lattice Boltzmann modeling of droplet condensation on superhydrophobic nanoarrays.
Droplet nucleation and growth on superhydrophobic nanoarrays is simulated by employing a multiphase, multicomponent lattice Boltzmann (LB) model. Three typical preferential nucleation modes of condensate droplets are observed through LB simulations with various geometrical parameters of nanoarrays, which are found to influence the wetting properties of nanostructured surfaces significantly. The droplets nucleated at the top of posts (top nucleation) or in the upside interpost space of nanoarrays (side nucleation) will generate a nonwetting Cassie state, while the ones nucleated at the bottom corners between the posts of nanoarrays (bottom nucleation) produce a wetting Wenzel state. The simulated time evolutions of droplet pressures at different locations are analyzed, which offers insight into the underlying physics governing the motion of droplets growing from different nucleation modes. It is demonstrated that the nanostructures with taller posts and a high ratio of post height to interpost space (H/S) are beneficial to produce the top- and side-nucleation modes. The simulated wetting states of condensate droplets on the nanostructures, having various geometrical configurations, compare reasonably well with experimental observations. The established relationship between the geometrical parameters of nanoarrays and the preferential nucleation modes of condensate droplets provides guidance for the design of nanoarrays with desirable anticondensation superhydrophobic properties.


Functional characteristics of retrognathic patients before and after mandibular advancement surgery.
The purpose of this investigation was to compare morphologic parameters and functional performance between controls and a sample of patients with mandibular retrognathia prior to surgical correction, and to examine how oral motor function adapts after treatment. Twenty-four retrognathic female patients were compared with 26 female controls before and up to 3 years after mandibular advancement surgery. Measures of skeletal morphology, mandibular range of motion, maximum isometric bite force, and levels of electromyographic activity in the anterior and posterior temporalis and masseter muscles during isometric bites were made on all subjects over time. One-way analysis of variance was used to compare the controls, the patients before surgery, and the patients after surgery. Surgical lengthening of the mandible averaged 7.3 mm, bringing most skeletal measures into the normal range. There were no significant differences in jaw muscle mechanical advantage between patients and controls before surgery, but surgery significantly reduced mechanical advantage of the anterior temporalis and masseter muscles. Jaw hypomobility was apparent at 6 weeks after surgery, but returned to normal values within 12 to 24 months. Before surgery the patients had maximum isometric bite forces less than half those of controls. Bite forces steadily increased after surgery, approaching normal values within 2 years. Before surgery the patients' muscle activity levels per unit of bite force were equivalent to those of controls or somewhat higher. After surgery some of the patients' muscles had significantly lower levels of muscle activity per unit of bite force than did controls. The results of this study suggest that correction of mandibular retrognathia by mandibular advancement surgery produces some significant functional benefits.


Evaluation of Prognostic and Predictive Significance of Circulating MicroRNAs in Ovarian Cancer Patients.
Ovarian cancer patients are recognized with poor prognosis. This study aimed to identify microRNAs in plasma for predicting response to treatment and outcome. We have investigated microRNAs in plasma from ovarian cancer patients enrolled in a large multicenter study (ICON7), investigating the effect of adding bevacizumab to standard chemotherapy in patients diagnosed with epithelial ovarian cancer. Patients with different histology, grade, and FIGO stages were included (n = 207) in this study. Screening of 754 unique microRNAs was performed in the discovery phase (n = 91) using TaqMan Low Density Arrays. The results were validated using single assays and RT-qPCR. Low levels of miR-200b, miR-1274A (tRNALys5), and miR-141 were significantly associated with better survival, confirmed with log-rank test in the validation set. The level of miR-1274A (tRNALys5) correlated with outcome was especially pronounced in the high-grade serous tumors. Interestingly, low level of miR-200c was associated with 5-month prolongation of PFS when treated with bevacizumab compared to standard chemotherapy. We found prognostic significance of miR-200b, miR-141, and miR-1274A (tRNALys5) in all histological types, where miR-1274A (tRNALys5) may be a specific marker in high-grade serous tumors. The level of miR-200c may be predictive of effect of treatment with bevacizumab. However, this needs further validation.


The decaying genome of Mycobacterium leprae.
Everything that we need to know about Mycobacterium leprae, a close relative of the tubercle bacillus, is encrypted in its genome. Inspection of the 3.27 Mb genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus identified 1,605 genes encoding proteins and 50 genes for stable RNA species. Comparison with the genome sequence of Mycobacterium tuberculosis revealed an extreme case of reductive evolution, since less than half of the genome contains functional genes while inactivated or pseudogenes are highly abundant. The level of gene duplication was approximately 34% and, on classification of the proteins into families, the largest functional groups were found to be involved in the metabolism and modification of fatty acids and polyketides, transport of metabolites, cell envelope synthesis and gene regulation. Reductive evolution, gene decay and genome downsizing have eliminated entire metabolic pathways, together with their regulatory circuits and accessory functions, particularly those involved in catabolism. This may explain the unusually long generation time and account for our inability to culture the leprosy bacillus.


Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle.
Accumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFRα) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRα(+) cells also differentiate into collagen type-I-producing cells. In fact, PDGFRα(+) cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFRα(+) cell fraction in the mdx diaphragm. Importantly, TGF-β isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRα(+) cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRα(+) cells mainly derived from pre-existing PDGFRα(+) cells and that the contribution of PDGFRα(-) cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.


Affinity, specificity, and kinetics of the interaction of the SHC phosphotyrosine binding domain with asparagine-X-X-phosphotyrosine motifs of growth factor receptors.
The phosphotyrosine binding (PTB) domain specifically binds to tyrosine-phosphorylated proteins, but differs in structure and mechanism of action from the SH2 domain family. We quantitated the affinity, specificity, and kinetics of the interaction of the SHC PTB domain with a sequence motif, asparagine-X-X-phosphotyrosine (NXX(pY)), found in several receptor tyrosine kinases and oncogenic proteins. PTB domain-mediated interaction with the NXX(pY) motif of c-ErbB2 was characterized by similar overall affinity but slower kinetics than that reported for SH2 domains. This suggested that unlike SH2 domains, PTB domains may not rapidly exchange among associated proteins. Furthermore, when directly and quantitatively compared, PTB domain binding specificity did not significantly overlap with a panel of seven SH2 domains. Thus, signaling pathways involving PTB and SH2 domain-mediated interactions can be regulated separately. Finally, our data define the minimal SHC PTB domain binding motif as NXX(pY), not NPX(pY) as suggested by other authors, and suggest a high affinity motif, hydrophobic residue-(D/E)-N-X-X-pY-(W/F), found in the Trk and ErbB receptor tyrosine kinase families. We conclude that PTB domains mediate specific protein-protein interactions independent from those mediated by SH2 domains.


Selectivity enhancement of amperometric nitric oxide detection via shape-controlled electrodeposition of platinum nanostructures.
Nitric oxide (NO) is a biologically multifunctional gaseous signaling molecule. For electrochemical NO detections, complex membranes are commonly adopted to acquire the selectivity for NO over other oxidizable biological species. In this study, we demonstrate the improved selectivity in amperometric NO measurements at nanostructured Pt. The Pt layers were electrodeposited on Au substrate electrodes at a constant potential (-0.2 V vs. Ag/AgCl) with a constant deposition charge (0.08 C). The various distinctive nanostructures of Pt deposits were obtained via either changing the precursor concentrations (from 5 to 75 mM K2PtCl4) or using a different precursor (75 mM H2PtCl6). With a higher K2PtCl4 concentration, the Pt deposition became less sharp and the smoothest Pt was deposited with 75 mM H2PtCl6. The most greatly sharp-pointed nanostructures were generated with the lowest precursor concentration (5 mM K2PtCl4) and exhibited the highest sensitivity, which was attributed to the hydrophobic property of sharply nanostructured Pt. A hydrophobic neutral gas molecule, NO, possibly has a more favorable access to the inner surface of more hydrophobic Pt deposition and eventually increases the oxidation current. NO current sensitivity was enhanced at the more hydrophobic Pt surface, whereas the oxidation currents of acetaminophen, l-ascorbic acid, nitrite and hydrogen peroxide, four oxidizable biological interfering species, were independent of the Pt nanostructure. Conclusively, the enhanced amperometric selectivity to NO was achieved by the simple electrodeposition method without any additional membranes.


Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation.
The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation. Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded that four weeks of treatment with inhaled beclomethasone dipropionate 336 microg x day(-1) was associated with significant improvements in peak flow, forced expiratory volume in one second, and rescue salbutamol use in asthmatic subjects but was not associated with large reductions in markers of eosinophilic inflammation, bronchovascular permeability, or mucus hypersecretion.


Factors associated with constipation in a community based sample of people aged 70 years and over.
The aim was to determine the prevalence and factors associated with constipation in elderly people. The study was a survey involving administration of a structured questionnaire, an interview, and a dietary assessment. The survey was community based and the population studied was drawn from the practice records of all five general practitioners serving a rural township of 13,500 people. 778 (91.8%) of the 856 people aged 70 years and over registered with the five practitioners took part. 174 subjects had symptoms of infrequent bowel motions or frequent straining at stool or used laxatives regularly. Of this group, 34 had a bowel motion only every 3 d or less frequently and were considered to have constipation. Analysis of this subgroup showed that constipation was more common in women than men, increased with age, and was associated with the use of constipating drugs. Those whose bowels moved infrequently were a more frail group who were less physically active. Low intakes of dietary fibre, fruit, vegetables, bread and cereals, or fluid were not associated with an increased occurrence of constipation. There were 151 subjects who felt they were moderately constipated, but who had a bowel motion at least every 2 d. These people were more likely than the rest of the sample to use laxatives (55.6%), were more likely to take food for their bowels, to take hynoptics, and to regard their health as poor. About one third of people aged 70 years and over have some bowel problem such as infrequency, straining at stool, or frequent laxative use. Most modify their diet accordingly but laxative use remains high.


Association between Physical Activity and Adiposity in Adolescents with Down Syndrome.
Obesity is highly prevalent among adolescents with Down syndrome (DS); however, reported associations between body composition and moderate-to-vigorous physical activity (MVPA) have been small and nonsignificant. The purpose of this study was to compare group differences between adolescents with and without DS, including dual-energy x-ray absorptiometry (DXA) measured body composition and accelerometer-measured physical activity, and then examine associations within adolescents with DS. Thirty-nine adolescents (22 with DS and 17 typically developing controls) 12-18 yr of age participated in the study. Groups had similar distributions of age, sex, and Tanner pubertal stage. Body composition was assessed by DXA, body mass index (BMI), and BMI percentile. MVPA was measured with ActiGraph GT3X+ accelerometers. Adolescents with DS had significantly higher BMI, BMI percentile, and DXA-derived percent body fat (%BF) as well as lower MVPA compared with controls (P < 0.05). Associations between MVPA and %BF in adolescents with DS were moderate (r = -0.39, P = 0.07) but substantially stronger than BMI (r = -0.19, P = 0.40). However, linear regression analyses identified Tanner stage (β = -0.77, P < 0.001) and MVPA (β = -0.34, P = 0.047) as significant predictors of %BF. No relevant associations between body composition and MVPA were observed in adolescents with typical development (P > 0.05). Our findings suggest that MVPA is associated with adiposity when measured with DXA among adolescents with DS.


Effects of neuropathy on high-voltage-activated Ca(2+) current in sensory neurones.
Voltage-dependent Ca(2+) channels (VDCCs) have emerged as targets to treat neuropathic pain; however, amongst VDCCs, the precise role of the Ca(V)2.3 subtype in nociception remains unproven. Here, we investigate the effects of partial sciatic nerve ligation (PSNL) on Ca(2+) currents in small/medium diameter dorsal root ganglia (DRG) neurones isolated from Ca(V)2.3(-/-) knock-out and wild-type (WT) mice. DRG neurones from Ca(V)2.3(-/-) mice had significantly reduced sensitivity to SNX-482 versus WT mice. DRGs from Ca(V)2.3(-/-) mice also had increased sensitivity to the Ca(V)2.2 VDCC blocker omega-conotoxin. In WT mice, PSNL caused a significant increase in omega-conotoxin-sensitivity and a reduction in SNX-482-sensitivity. In Ca(V)2.3(-/-) mice, PSNL caused a significant reduction in omega-conotoxin-sensitivity and an increase in nifedipine sensitivity. PSNL-induced changes in Ca(2+) current were not accompanied by effects on voltage-dependence of activation in either Ca(V)2.3(-/-) or WT mice. These data suggest that Ca(V)2.3 subunits contribute, but do not fully underlie, drug-resistant (R-type) Ca(2+) current in these cells. In WT mice, PSNL caused adaptive changes in Ca(V)2.2- and Ca(V)2.3-mediated Ca(2+) currents, supporting roles for these VDCCs in nociception during neuropathy. In Ca(V)2.3(-/-) mice, PSNL-induced changes in Ca(V)1 and Ca(V)2.2 Ca(2+) current, consistent with alternative adaptive mechanisms occurring in the absence of Ca(V)2.3 subunits.


Discovery and characterization of a novel picorna-like RNA virus in the cotton bollworm Helicoverpa armigera.
We characterize a novel picorna-like virus, named Helicoverpa armigera Nora virus (HaNV), with a genome length of 11,200 nts, the sequence of which was isolated from the lepidopteran host cotton bollworm Helicoverpa armigera, using RNA-Seq. Phylogenetic analysis, using the putative amino acid sequence of the conserved RNA-dependent RNA polymerase (RdRp) domain, indicated that HaNV clustered with Spodoptera exigua Nora virus, Drosophila Nora virus and Nasonia vitripennis virus-3 with a high bootstrap value (100%), which might indicate a new viral family within the order Picornavirales. HaNV was efficiently horizontally transmitted between hosts via contaminated food, and transmission was found to be dose-dependent (up to 100% efficiency with 109 viral copy number/µl). HaNV was also found to be transmitted vertically from parent to offspring, mainly through transovum transmission (virus contamination on the surface of the eggs), but having a lower transmission efficiency (around 43%). Infection distribution within the host was also investigated, with HaNV mainly found in only the gut of both adult moths and larvae (>90%). Moreover, our results showed that HaNV appears not to be an overtly pathogenic virus to its host.


Marine toxic cyanobacteria: diversity, environmental responses and hazards.
Toxic cyanobacterial blooms have been a primary concern predominantly in the plankton of freshwater bodies. Recently, however, the toxicity of benthic cyanobacteria is increasingly attracting attention of the scientific community and environmental agencies. The occurrence of toxic strains in benthic cyanobacteria is intimately linked to our understanding of the diversity and ecological responses of these organisms under field conditions. To that effect, we are engaged in combined morphotypic and genotypic characterization (polyphasic) of benthic natural populations of cyanobacteria in tropical lagoons and coral reefs, with the objective to provide a reliable reference for further comparative work. The methods of identification based on phenotypic properties and those based on molecular tools for genotypic identification are correlated. The approach is based on identifying the occurrences of cyanobacterial benthic blooms, tested for purity and analyzed by application of molecular tools. The questions addressed include the distinction between marine and freshwater taxa, between populations in geographically separate regions as well as between their potential vs. expressed toxicity.


Effects of concentrated ambient particles on heart rate, blood pressure, and cardiac contractility in spontaneously hypertensive rats during a dust storm event.
Epidemiological studies have suggested that cardiovascular mortality and morbidity increased during Asian dust events. The findings were still inconclusive though. We have shown an increased pulmonary toxicity in diseased animals during a dust storm event. However, the toxicity nature of dust storm particles remains unclear. It is our objective in this study to further investigate the cardiovascular effects of concentrated PM(2.5) on spontaneously hypertensive rats during the same dust storm event. Four spontaneously hypertensive rats were implanted with radiotelemetry transmitters at the age of 10 wk. Baseline heart rate, mean blood pressure, and cardiac contractility (measured as QA interval, QAI) data were collected 4 wk before. Exposure group received concentrated ambient particles inhalation for 6 h during a dust storm event, while the control group received room air inhalation at the same time. Self-control data were collected 4 wk after the event during the same clock hours while there was no dust storm. Gravimetric analysis showed a particle mass concentration of 315.55 microg/m(3) during the 6 h of exposure. A linear mixed-effects model revealed sigmoid increases in heart rate (to a maximum of 93.8 +/- 18.8 bpm) and mean blood pressure (to a maximum of 14.8 +/- 5.4 mm Hg), and a sigmoid decrease of QAI (to a maximum of - 3.5 +/- 1.5 ms) during the exposure after an initial incubation period. We conclude that concentrated dust storm particles, which are different from products of automobile combustion process, may cause adverse cardiovascular effects on diseased animals.


Development of a rotor-gene real-time PCR assay for the detection and quantification of Mycoplasma genitalium.
We developed and validated a real-time quantitative polymerase chain reaction (qPCR) assay to determine Mycoplasma genitalium bacterial load in endocervical swabs, based on amplification of the pdhD gene which encodes dihydrolipoamide dehydrogenase, using the Rotor-Gene platform. We first determined the qPCR assay sensitivity, limit of detection, reproducibility and specificity, and then determined the ability of the qPCR assay to quantify M. genitalium in stored endocervical specimens collected from Zimbabwean women participating in clinical research undertaken between 1999 and 2007. The qPCR assay had a detection limit of 300 genome copies/mL and demonstrated low intra- and inter-assay variability. The assay was specific for M. genitalium DNA and did not amplify the DNA from other mycoplasma and ureaplasma species. We quantified M. genitalium in 119 of 1600 endocervical swabs that tested positive for M. genitalium using the commercial Sacace M. genitalium real-time PCR, as well as 156 randomly selected swabs that were negative for M. genitalium by the same assay. The M. genitalium loads ranged between <300 and 3,240,000 copies/mL. Overall, the qPCR assay demonstrated good range of detection, reproducibility and specificity and can be used for both qualitative and quantitative analyses of M. genitalium in endocervical specimens and potentially other genital specimens.


Novel mesenchymal and haematopoietic cell isoforms of the SHP-2 docking receptor, PZR: identification, molecular cloning and effects on cell migration.
SHP-2 (Src homology phosphatase type-2) is essential for haematopoietic skeletal and vascular development. Thus the identification of its binding partners is critically important. In the present study, we describe a unique monoclonal antibody, WM78, which interacts with PZR, a SHP-2 binding partner. Furthermore, we identify two novel isoforms of PZR, PZRa and PZRb, derived by differential splicing from a single gene transcription unit on human chromosome 1q24. All are type 1 transmembrane glycoproteins with identical extracellular and transmembrane domains, but differ in their cytoplasmic tails. The PZR intracellular domain contains two SHP-2 binding immunoreceptor tyrosine-based inhibitory motifs (VIY(246)AQL and VVY(263)ADI) which are not present in PZRa and PZRb. Using the WM78 monoclonal antibody, which recognizes the common extracellular domain of the PZR isoforms, we demonstrate that the PZR molecules are expressed on mesenchymal and haematopoietic cells, being present on the majority of CD34(+)CD38(+) and early clonogenic progenitors, and at lower levels on CD34(+)CD38(-) cells and the hierarchically more primitive pre-colony forming units. Interestingly, we show by reverse transcriptase-PCR that the PZR isoforms are differentially expressed in haematopoietic, endothelial and mesenchymal cells. Both PZR and PZRb are present in CD133(+) precursors and endothelial cells, PZRb predominates in mesenchymal and committed myelomonocytic progenitor cells, and all three isoforms occur in erythroid precursor cell lines. Importantly, using SHP-2 mutant (Delta 46-110) and SHP-2 rescue of embryonic fibroblasts stably expressing the PZR isoforms, we demonstrate for the first time that PZR, but not PZRa or PZRb, facilitates fibronectin- dependent migration of cells expressing a competent SHP-2 molecule. These observations will be instrumental in determining the mechanisms whereby PZR isoforms regulate cell motility.


Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.
Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.


Carbimazole-induced agranulocytosis.
A 47 year old lady with hyperthyroidism for past 1½ years was initially on Carbimazole 20 mg orally then changed to 30 mg (during Hysterectomy) but was taking 10 mg for last 1 year. She had intermittent fever with severe B/L bifrontal headache since 3 weeks. Routine investigations showed anaemia, neutropenia, leucopenia and CRP elevation. Peripheral smear showed normocytic normochromic anaemia with Rouleaux formation, leucopenia with 2% atypical cells and mild thrombocytosis. Widal test, RA factor (Rheumatoid factor) test, Ig M (Immunoglobulin M) dengue, Ig M Lepto, TORCH infections (Toxoplasmosis, Other (Syphilis, varicella-zoster, parvovirus B19), Cytomegalovirus and Herpes infections), ANA (Antinuclear antibody) screen cANCA (Cytoplasmic antineutrophil cytoplasmic antibodies) and pANCA (Perinuclear Anti-Neutrophil Cytoplasmic Antibodies) tests were negative. Bone marrow aspiration showed normo to hypercellular marrow with 15% atypical cells and plasma cells. Multiple myeloma workup was done. Carbimazole was withheld. Drug induced agranulocytosis occurs with in 1-2 months of taking the antithyroid medication but onset delayed by 1½ year. De-challenge resulted normalization of blood parameters.


Performance characteristics of magnetic resonance imaging without contrast agents or sedation in pediatric appendicitis.
Magnetic resonance imaging (MRI) has emerged as a promising modality for evaluating pediatric appendicitis. However optimal imaging protocols, including roles of contrast agents and sedation, have not been established and diagnostic criteria have not been fully evaluated. To investigate performance characteristics of rapid MRI without contrast agents or sedation in the diagnosis of pediatric appendicitis. We included patients ages 4-18 years with suspicion of appendicitis who underwent rapid MRI between October 2013 and March 2015 without contrast agent or sedation. After two-radiologist review, we determined performance characteristics of individual diagnostic criteria and aggregate diagnostic criteria by comparing MRI results to clinical outcomes. We used receiver operating characteristic (ROC) curves to determine cut-points for appendiceal diameter and wall thickness for optimization of predictive power, and we calculated area under the curve (AUC) as a measure of test accuracy. Ninety-eight MRI examinations were performed in 97 subjects. Overall, MRI had a 94% sensitivity, 95% specificity, 91% positive predictive value and 97% negative predictive value. Optimal cut-points for appendiceal diameter and wall thickness were ≥7 mm and ≥2 mm, respectively. Independently, those cut-points produced sensitivities of 91% and 84% and specificities of 84% and 43%. Presence of intraluminal fluid (30/33) or localized periappendiceal fluid (32/33) showed a significant association with acute appendicitis (P<0.01), with sensitivities of 91% and 97% and specificities of 60% and 50%. For examinations in which the appendix was not identified by one or both reviewers (23/98), the clinical outcome was negative. Rapid MRI without contrast agents or sedation is accurate for diagnosis of pediatric appendicitis when multiple diagnostic criteria are considered in aggregate. Individual diagnostic criteria including optimized cut-points of ≥7 mm for diameter and ≥2 mm for wall thickness demonstrate high sensitivities but relatively low specificities. Nonvisualization of the appendix favors a negative diagnosis.


Myosin regulatory light chain (RLC) phosphorylation change as a modulator of cardiac muscle contraction in disease.
Understanding how cardiac myosin regulatory light chain (RLC) phosphorylation alters cardiac muscle mechanics is important because it is often altered in cardiac disease. The effect this protein phosphorylation has on muscle mechanics during a physiological range of shortening velocities, during which the heart generates power and performs work, has not been addressed. We have expressed and phosphorylated recombinant Rattus norvegicus left ventricular RLC. In vitro we have phosphorylated these recombinant species with cardiac myosin light chain kinase and zipper-interacting protein kinase. We compare rat permeabilized cardiac trabeculae, which have undergone exchange with differently phosphorylated RLC species. We were able to enrich trabecular RLC phosphorylation by 40% compared with controls and, in a separate series, lower RLC phosphorylation to 60% of control values. Compared with the trabeculae with a low level of RLC phosphorylation, RLC phosphorylation enrichment increased isometric force by more than 3-fold and peak power output by more than 7-fold and approximately doubled both maximum shortening speed and the shortening velocity that generated peak power. We augmented these measurements by observing increased RLC phosphorylation of human and rat HF samples from endocardial left ventricular homogenate. These results demonstrate the importance of increased RLC phosphorylation in the up-regulation of myocardial performance and suggest that reduced RLC phosphorylation is a key aspect of impaired contractile function in the diseased myocardium.


Confirmation of the novel association at the BTNL2 locus with ulcerative colitis.
Linkage in families and association in population case-control investigations have clearly shown that genes within the major histocompatibility complex region on chromosome 6p are relevant to the susceptibility and pathogenesis of ulcerative colitis (UC) and Crohn's disease. However, identifying the causative variants by fine mapping has not been conclusive. In this study using 58 single nucleotide polymorphisms (SNPs) with 616 UC cases, there was significant association with SNP rs2294881 of the (butyrophilin-like 2) BTNL2 gene with odds ratio (OR) = 2.80, confidence interval (CI) = 1.62-4.84 and P = 5.69 x 10(-4) (P(Bonferroni) = 3.3 x 10(-2)) and replication of SNP rs9268480. The missense SNP rs2076523 (K196E) showed novel association with a subset of UC cases with colectomy (n = 126), OR = 0.25, CI = 0.11-0.58 and P = 4.42 x 10(-4) (P(Bonferroni) = 2.56 x 10(-2)). These three associated variants within the BTNL2 gene were neither in linkage disequilibrium with each other nor correlated with the SNPs tagging the human leukocyte antigen (HLA)-DRB1*1502 and HLA-DRB1*0301 alleles.


Supramolecular Porous Organic Nanocomposites for Heterogeneous Photocatalysis of a Sulfur Mustard Simulant.
Efficient heterogeneous photosensitizing materials require both large accessible surface areas and excitons of suitable energies and with well-defined spin structures. Confinement of the tetracationic cyclophane (ExBox4+ ) within a nonporous anionic polystyrene sulfonate (PSS) matrix leads to a surface area increase of up to 225 m2 g-1 in ExBox•PSS. Efficient intersystem crossing is achieved by combining the spin-orbit coupling associated to Br heavy atoms in 1,3,5,8-tetrabromopyrene (TBP), and the photoinduced electron transfer in a TBP⊂ExBox4+ supramolecular dyad. The TBP⊂ExBox4+ complex displays a charge transfer band at 450 nm and an exciplex emission at 520 nm, indicating the formation of new mixed-electronic states. The lowest triplet state (T1 , 1.89 eV) is localized on the TBP and is close in energy with the charge separated state (CT, 2.14 eV). The homogeneous and heterogeneous photocatalytic activities of the TBP⊂ExBox4+ , for the elimination of a sulfur mustard simulant, has proved to be significantly more efficient than TBP and ExBox+4 , confirming the importance of the newly formed excited-state manifold in TBP⊂ExBox4+ for the population of the low-lying T1 state. The high stability, facile preparation, and high performance of the TBP⊂ExBox•PSS nanocomposites augur well for the future development of new supramolecular heterogeneous photosensitizers using host-guest chemistry.


A core human microbiome as viewed through 16S rRNA sequence clusters.
We explore the microbiota of 18 body sites in over 200 individuals using sequences amplified V1-V3 and the V3-V5 small subunit ribosomal RNA (16S) hypervariable regions as part of the NIH Common Fund Human Microbiome Project. The body sites with the greatest number of core OTUs, defined as OTUs shared amongst 95% or more of the individuals, were the oral sites (saliva, tongue, cheek, gums, and throat) followed by the nose, stool, and skin, while the vaginal sites had the fewest number of OTUs shared across subjects. We found that commonalities between samples based on taxonomy could sometimes belie variability at the sub-genus OTU level. This was particularly apparent in the mouth where a given genus can be present in many different oral sites, but the sub-genus OTUs show very distinct site selection, and in the vaginal sites, which are consistently dominated by the Lactobacillus genus but have distinctly different sub-genus V1-V3 OTU populations across subjects. Different body sites show approximately a ten-fold difference in estimated microbial richness, with stool samples having the highest estimated richness, followed by the mouth, throat and gums, then by the skin, nasal and vaginal sites. Richness as measured by the V1-V3 primers was consistently higher than richness measured by V3-V5. We also show that when such a large cohort is analyzed at the genus level, most subjects fit the stool "enterotype" profile, but other subjects are intermediate, blurring the distinction between the enterotypes. When analyzed at the finer-scale, OTU level, there was little or no segregation into stool enterotypes, but in the vagina distinct biotypes were apparent. Finally, we note that even OTUs present in nearly every subject, or that dominate in some samples, showed orders of magnitude variation in relative abundance emphasizing the highly variable nature across individuals.


Temporary crate opening procedure affects immediate post-opening piglet mortality and sow behaviour.
Producers are interested in utilising farrowing systems with reduced confinement to improve sow welfare. However, concerns of increased mortality may limit commercial uptake. Temporary confinement systems utilise a standard crate which is opened 3 to 7 days postpartum, providing protection for neonatal piglets at their most vulnerable age and later increased freedom of movement for sows. However, there is anecdotal evidence that piglet mortality increases immediately after the temporary crate is opened. The current study aims were to determine if piglet mortality increases post-opening, to trial different opening techniques to reduce post-opening piglet mortality and to identify how the different opening techniques influence sow behaviour. Three opening treatments were implemented across 416 sows: two involved opening crates individually within each farrowing house when each litter reached 7 days of age, in either the morning or afternoon (AM or PM), with a control of the standard method used on the farm to open all crates in each farrowing house simultaneously once the average litter age reached 7 days (ALL). Behavioural observations were performed on five sows from each treatment during the 6 h after crate opening, and during the same 6 h period on the previous and subsequent days. Across all treatments, piglet mortality was significantly higher in the post-opening than pre-opening period (P<0.0005). Between opening treatments, there were significant differences in piglet mortality during the 2 days after crate opening (P<0.05), whilst piglet mortality also tended to differ from crate opening until weaning (P=0.052), being highest in ALL and lowest in PM. Only sows in the PM treatment showed no increase in standing behaviour but did show an increased number of potentially dangerous posture changes after crate opening (P=0.01), which may be partly attributed to the temporal difference in observation periods. Sow behaviour only differed between AM and ALL on the day before crate opening, suggesting the AM treatment disrupted behaviour pre-opening. Sows in AM and PM treatments showed more sitting behaviour than ALL, and therefore may have been more alert. In conclusion, increases in piglet mortality after crate opening can be reduced by opening crates individually, more so in the afternoon. Sow habituation to disturbance before crate opening may have reduced post-opening piglet mortality, perhaps by reducing the difference in pre- and post-opening sow behaviour patterns.


Disengaging polymerase: terminating RNA polymerase II transcription in budding yeast.
Termination of transcription by RNA polymerase II requires two distinct processes: The formation of a defined 3' end of the transcribed RNA, as well as the disengagement of RNA polymerase from its DNA template. Both processes are intimately connected and equally pivotal in the process of functional messenger RNA production. However, research in recent years has elaborated how both processes can additionally be employed to control gene expression in qualitative and quantitative ways. This review embraces these new findings and attempts to paint a broader picture of how this final step in the transcription cycle is of critical importance to many aspects of gene regulation. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation.


A Scoping Review of Interventions Designed to Support Parents With Mental Illness That Would Be Appropriate for Parents With Psychosis.
The experience of psychosis can present additional difficulties for parents, over and above the normal challenges of parenting. Although there is evidence about parenting interventions specifically targeted at parents with affective disorders, anxiety, and borderline personality disorder, there is currently limited evidence for parents with psychotic disorders. It is not yet known what, if any, interventions exist for this population, or what kinds of evaluations have been conducted. To address this, we conducted a scoping review to determine (1) what parenting interventions have been developed for parents with psychosis (either specifically for, or accessible by, this client group), (2) what components these interventions contain, and (3) what kinds of evaluations have been conducted. The eligibility criteria were broad; we included any report of an intervention for parents with a mental health diagnosis, in which parents with psychosis were eligible to take part, that had been published within the last 20 years. Two reviewers screened reports and extracted the data from the included reports. Thirty-eight studies of 34 interventions were included. The findings show that most interventions have been designed either for parents with any mental illness or parents with severe mental illness, and only two interventions were trialed with a group of parents with psychosis. After noting clusters of intervention components, five groups were formed focused on: (1) talking about parental mental illness, (2) improving parenting skills, (3) long-term tailored support for the whole family, (4) groups for parents with mental illness, and (5) family therapy. Twenty-three quantitative evaluations and 13 qualitative evaluations had been conducted but only eight interventions have or are being evaluated using a randomized controlled trial (RCT). More RCTs of these interventions are needed, in addition to further analysis of the components that are the most effective in changing outcomes for both the parent and their children, in order to support parents with psychosis and their families.


Hyperinsulinemia and the aldosterone and pressor responses to angiotensin II.
To determine whether hyperinsulinemia alters angiotensin II-mediated aldosterone secretion, the increase in plasma aldosterone after intravenous angiotensin II (5, 10, and 20 ng/kg/min for 15 minutes each) was measured before and after euglycemic hyperinsulinemia in seven chronically instrumented dogs. In a random sequence on 4 successive days, dogs received either 0, 2, 4, or 8 milliunits/kg/min insulin. Euglycemic hyperinsulinemia, at all insulin doses, resulted in a significantly greater (p less than 0.01) change in the angiotensin II-stimulated increments of plasma aldosterone than was observed when angiotensin II was administered alone. However, there was no dose-dependence of insulin's effect on angiotensin II-stimulated aldosterone. The effect of weight gain on the angiotensin II response was also evaluated in five dogs. After weight gain, euglycemic hyperinsulinemia augmented angiotensin II-stimulated aldosterone to the same magnitude that was observed before weight gain. Possible mechanisms whereby insulin could increase angiotensin II-stimulated aldosterone production include: increased intracellular potassium, reduced plasma free fatty acids, and a direct action of insulin to induce increased adrenal steroidogenesis. In addition to altering the angiotensin II-aldosterone dose-response curve, hyperinsulinemia also increased the pressor action of angiotensin II. In contrast to the angiotensin II-aldosterone response, progressive hyperinsulinemia resulted in a progressive increase in the pressor response to angiotensin II. The increased pressor response is probably due to an increased activation of the sympathetic nervous system by insulin.


Structural and biomechanical basis of mitochondrial movement in eukaryotic cells.
Mitochondria serve as energy-producing organelles in eukaryotic cells. In addition to providing the energy supply for cells, the mitochondria are also involved in other processes, such as proliferation, differentiation, information transfer, and apoptosis, and play an important role in regulation of cell growth and the cell cycle. In order to achieve these functions, the mitochondria need to move to the corresponding location. Therefore, mitochondrial movement has a crucial role in normal physiologic activity, and any mitochondrial movement disorder will cause irreparable damage to the organism. For example, recent studies have shown that abnormal movement of the mitochondria is likely to be the reason for Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and schizophrenia. So, in the cell, especially in the particular polarized cell, the appropriate distribution of mitochondria is crucial to the function and survival of the cell. Mitochondrial movement is mainly associated with the cytoskeleton and related proteins. However, those components play different roles according to cell type. In this paper, we summarize the structural basis of mitochondrial movement, including microtubules, actin filaments, motor proteins, and adaptin, and review studies of the biomechanical mechanisms of mitochondrial movement in different types of cells.