The role of mTOR inhibition in augmenting radiation induced autophagy.
Radiation affects both tumor and normal tissues, limiting the total delivered radiation dose. Therefore, novel ways to exploit molecular targets and improve the therapeutic ratio are continually being investigated. Autophagy plays an important role in cancer cell death decisions, particularly in solid tumors. This is counterbalanced by its function in cellular energy preservation. Recent studies have attempted to exploit autophagy in order to improve therapeutic ratio. However, direct inhibition of autophagy has been demonstrated to promote cancer cell death or survival dependent on cell type and condition. The mammalian target of rapamycin (mTOR) also regulates autophagy, as well as cell survival and proliferation pathways. Therefore, inhibition at this level of signaling would represent an excellent therapeutic target as it would limit cell growth, decrease cell proliferation, and boost autophagocytosis. Current investigations of mTOR inhibitors in combination with radiation appear to potentiate radiation's ability to induce autophagy. Further studies are necessary to fully elucidate which tumors have the most robust induction of autophagy in response to mTOR inhibition and radiation.


Ab initio structure search and in situ 7Li NMR studies of discharge products in the Li-S battery system.
The high theoretical gravimetric capacity of the Li-S battery system makes it an attractive candidate for numerous energy storage applications. In practice, cell performance is plagued by low practical capacity and poor cycling. In an effort to explore the mechanism of the discharge with the goal of better understanding performance, we examine the Li-S phase diagram using computational techniques and complement this with an in situ (7)Li NMR study of the cell during discharge. Both the computational and experimental studies are consistent with the suggestion that the only solid product formed in the cell is Li2S, formed soon after cell discharge is initiated. In situ NMR spectroscopy also allows the direct observation of soluble Li(+)-species during cell discharge; species that are known to be highly detrimental to capacity retention. We suggest that during the first discharge plateau, S is reduced to soluble polysulfide species concurrently with the formation of a solid component (Li2S) which forms near the beginning of the first plateau, in the cell configuration studied here. The NMR data suggest that the second plateau is defined by the reduction of the residual soluble species to solid product (Li2S). A ternary diagram is presented to rationalize the phases observed with NMR during the discharge pathway and provide thermodynamic underpinnings for the shape of the discharge profile as a function of cell composition.


Identifying sex-specific differences in the carotid revascularisation literature: findings from a scoping review.
No systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in female patients. In this scoping review, we aimed to identify all randomised controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularisation, and determine whether sufficient information is reported within these studies to assess short-term and long-term outcomes in female patients. We systematically searched Medline, Embase, Pubmed and Cochrane libraries for RCTs published between 1991 and 2020 that included female patients and compared either endarterectomy with stenting, or any revascularisation (endarterectomy or stenting) with medical therapy in patients with symptomatic high-grade (>50%) carotid stenosis. From 1537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled female patients were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however, there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment are largely limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex. Only half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analyses on the results of carotid artery intervention for female patients with symptomatic stenosis are limited.


Constructing three-dimensional porous Ni/Ni3S2 nano-interfaces for hydrogen evolution electrocatalysis under alkaline conditions.
It is still a challenging issue to design earth-abundant electrocatalysts with low cost, high activity and long-term stability for the hydrogen evolution reaction (HER) based on water splitting in alkaline solutions. Here, we report a facile synthetic route for a three-dimensional, porous Ni/Ni3S2 nano-network on carbon cloth for the efficient catalysis of HER. This unique structure exposes a high proportion of Ni/Ni3S2 hetero-interfaces to the electrolyte, creating a synergetic effect between Ni and Ni3S2 that enhances HER. The synergetic effect at the interface was verified by DFT calculation and involves the interface-assisted heterolytic splitting of H2O into OH- and H+ and the subsequent expeditious H2-forming reaction caused by weakened binding between Ni and H induced by the neighboring Ni3S2. The resulting porous network shows high HER activity in alkaline media, reaching 10 mA cm-2 at 95 mV with a Tafel slope of 66 mV dec-1. This value is much smaller than that of nickel metal, which is currently used in industry.


Immunoenzymatic and morphological detection of epithelial cell apoptotic stages in gastrointestinal allografts from multivisceral transplant patients.
Acute allograft rejection (AR) is a major contributor to morbidity and mortality among patients who undergo multivisceral transplantation. Critical to the assessment of AR is detection of apoptosis in the glandular epithelium of the gastrointestinal allograft. We utilized the TUNEL stain (TdT-mediated biotin 16-dUTP nick-end labeling) to test whether this method improved detection of apoptosis compared to standard slide evaluation. TUNEL and H&E stains were performed on paraffin-embedded tissue sections to estimate the number of apoptotic bodies per 10 high power fields, as determined by independent pathologists in blinded fashion. Both methodologies showed similar numbers and distributions of apoptotic foci present among the epithelial cells. There was a correlation between the number of apoptosis and the grade of rejection (P <.001). This is the first use of the TUNEL stain in gastrointestinal allograft biopsies to our knowledge. The similarity in pattern and sensitivity of TUNEL with standard morphology confirms that biopsy assessment with routine H&E staining allows an accurate appraisal of epithelial cell apoptosis. Therefore, current staining protocols for endoscopically derived mucosal biopsies of gastrointestinal allografts are sufficiently accurate to enumerate the critical feature of epithelial apoptosis as a determinant of the grade of acute rejection.


Potential role of N-acetylcysteine in the management of substance use disorders.
There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.


Jaw-muscle architecture and mandibular morphology influence relative maximum jaw gapes in the sexually dimorphic Macaca fascicularis.
Maximum jaw gape is a performance variable related to feeding and non-feeding oral behaviors, such as canine gape displays, and is influenced by several factors including jaw-muscle fiber architecture, muscle position on the skull, and jaw morphology. Maximum gape, jaw length, and canine height are strongly correlated across catarrhine primates, but relationships between gape and other aspects of masticatory apparatus morphology are less clear. We examine the effects of jaw-adductor fiber architecture, jaw-muscle leverage, and jaw form on gape in an intraspecific sample of sexually dimorphic crab-eating macaques (Macaca fascicularis). As M. fascicularis males have relatively larger maximum gapes than females, we predict that males will have muscle and jaw morphologies that facilitate large gape, but these morphologies may come at some expense to bite force. Male crab-eating macaques have relatively longer jaw-muscle fibers, masseters with decreased leverage, and temporomandibular joint morphologies that facilitate the production of wide gapes. Because relative canine height is correlated with maximum gape in catarrhines, and males have relatively longer canines than females, these results support the hypothesis that male M. fascicularis have experienced selection to increase maximum gape. The sexes do not differ in relative masseter physiologic cross-sectional area (PCSA), but males compensate for a potential trade-off between muscle excursion versus muscle force with increased temporalis weight and PCSA. This musculoskeletal configuration is likely functionally significant for behaviors involving aggressive canine biting and displays in male M. fascicularis and provides additional evidence supporting the multifactorial nature of the catarrhine masticatory apparatus. Our results have implications for the evolution of craniofacial morphology in catarrhine primates and reinforce the importance of evaluating additional factors other than feeding behavior and diet in analyses of masticatory apparatus form, function, and evolution.


Egg forensics: an appraisal of DNA sequencing to assist in species identification of illegally smuggled eggs.
Psittaciformes (parrots and cockatoos) are charismatic birds, their plumage and capacity for learning make them highly sought after pets. The illegal trade in parrots and cockatoos poses a serious threat to the viability of native populations; in addition, species transported to non-endemic areas may potentially vector disease and genetically 'pollute' local native avifauna. To reduce the logistical difficulties associated with trafficking live birds, smugglers often transport eggs. This creates a problem for authorities in elucidating accurate species identification without the laborious task of incubation and hand rearing until a morphological identification can be made. Here, we use 99 avian eggs seized from carriers coming into and within Australia, as a result of suspected illegal trade. We investigate and evaluate the use of mitochondrial DNA (mtDNA) to accurately identify eggs to family, genus or species level. However, Identification of a species based on percentage mtDNA similarities is difficult without good representations of the inter- and intra-levels of species variation. Based on the available reference database, we were able to identify 52% of the eggs to species level. Of those, 10 species from eight genera were detected, all of which belong to the parrot (Psittacidae) and cockatoo (Cacatuidae) families. Of the remaining 48%, a further 36% of eggs were identified to genus level, and 12% identified to family level using our assignment criteria. Clearly the lack of validated DNA reference sequences is hindering our ability to accurately assign a species identity, and accordingly, we advocate that more attention needs to be paid to establishing validated, multi locus mtDNA reference databases for exotic birds that can both assist in genetic identifications and withstand legal scrutiny.


Evaluating a Widely Implemented Proprietary Deterioration Index Model Among Hospitalized COVID-19 Patients.
The Epic Deterioration Index (EDI) is a proprietary prediction model implemented in over 100 U.S. hospitals that was widely used to support medical decision-making during the COVID-19 pandemic. The EDI has not been independently evaluated, and other proprietary models have been shown to be biased against vulnerable populations. We studied adult patients admitted with COVID-19 to non-ICU care at a large academic medical center from March 9 through May 20, 2020. We used the EDI, calculated at 15-minute intervals, to predict a composite outcome of ICU-level care, mechanical ventilation, or in-hospital death. In a subset of patients hospitalized for at least 48 hours, we also evaluated the ability of the EDI to identify patients at low risk of experiencing this composite outcome during their remaining hospitalization. Among 392 COVID-19 hospitalizations meeting inclusion criteria, 103 (26%) met the composite outcome. Median age of the cohort was 64 (IQR 53-75) with 168 (43%) African Americans and 169 (43%) women. Area under the receiver-operating-characteristic curve (AUC) of the EDI was 0.79 (95% CI 0.74-0.84). EDI predictions did not differ by race or sex. When exploring clinically-relevant thresholds of the EDI, we found patients who met or exceeded an EDI of 68.8 made up 14% of the study cohort and had a 74% probability of experiencing the composite outcome during their hospitalization with a median lead time of 24 hours from when this threshold was first exceeded. Among the 286 patients hospitalized for at least 48 hours who had not experienced the composite outcome, 14 (13%) never exceeded an EDI of 37.9, with a negative predictive value of 90% and a sensitivity above this threshold of 91%. We found the EDI identifies small subsets of high- and low-risk COVID-19 patients with fair discrimination. We did not find evidence of bias by race or sex. These findings highlight the importance of independent evaluation of proprietary models before widespread operational use among COVID-19 patients.


Recent progressions in stem cell research: breakthroughs achieved and challenges faced.
Stem cell studies have been conducted to study characteristics of stem cells, to develop better techniques for patient-specific stem cell lines generation, and to explore the therapeutic potential of stem cells. Techniques that enable efficient generation of new stem cell lines would facilitate research and allow generation of patient-specific stem cell lines for transplantation therapy. Somatic-Cell Nuclear Transfer (SCNT), which involves injection of donor cell nucleus into enucleated ovum, is the standard technique for new embryonic stem (ES) cell lines generation; presently its efficiency is low. A newer technique, pluripotent stem cell induction, reprograms somatic cells into induced pluripotent stem (iPS) cells by introducing certain factors into somatic cells. While certain adult stem cell treatments have been investigated on human participants, most ES cell or iPS cell treatments were still experimented on animal models. Recently, therapeutic potential of stem cell for several disorders was demonstrated. Researchers demonstrated stem cell's potential for treating hematologic disorders by correcting sickle cell anemia in rat model with iPS cells. Its potential role in treating cardiovascular disorder was demonstrated as injection of damaged rat heart with human ES cells derived cardiomyocyte plus "prosurvival" cocktail improved heart function. It might also treat nervous system disorders; injected into brain, ES cells derived neurons replace some loss cells in stroke rats and iPS cells derived neurons improved Parkinsonian syndrome in rats. Progress was also seen in other aspects of regenerative medicine. To overcome controversies caused by embryo destruction for obtaining ES cells, single blastomer stem cell derivation, Cdx2-inactivation, and parthenogenesis were proposed. All ES cell, iPS cell, and adult stem cell research should be continued with support from all sides.


An in vitro comparison of detection methods for approximal carious lesions in primary molars.
This study aimed to compare and contrast in vitro six methods to determine the most accurate method for detecting approximal carious lesions in primary molars. Extracted primary molars (n = 140) were stored in 0.02% chlorhexidine solution and mounted in light-cured resin in pairs. The six carious lesion detection methods used by the three examiners to assess approximal carious lesions were visual inspection, digital radiography, two transillumination lights (SDI and NSK), and two laser fluorescence instruments (CDD and DDP). Five damaged teeth were discarded. The teeth (n = 135) were sectioned, serially ground, and examined under light microscopy using Downer's histological (HST) criteria as the gold standard. Intra- and inter-examiner reliability, agreement with HST, specificity, sensitivity, receiver operating characteristic (ROC) curves, and areas under the curve were calculated. This study found visual inspection to be the most accurate method when validated by histology. Transillumination with NSK light had the highest specificity, and digital radiography had the highest sensitivity for detecting enamel and/or dentinal carious lesions. Combining specificity and sensitivity into the area under ROC curves, enamel plus dentinal lesions were detected most accurately by visual inspection followed by digital radiography; dentinal lesions were detected most accurately by digital radiography followed by visual inspection. None of the four newly developed methods can be recommended as suitable replacements for visual inspection and digital radiography in detecting carious lesions on approximal surfaces of primary molars, and further developmental work is needed.


Bacterial luciferase as a reporter of circadian gene expression in cyanobacteria.
To allow continuous monitoring of the circadian clock in cyanobacteria, we previously created a reporter strain (AMC149) of Synechococcus sp. strain PCC 7942 in which the promoter of the psbAI gene was fused to Vibrio harveyi luciferase structural genes (luxAB) and integrated into the chromosome. Northern (RNA) hybridization and immunoblot analyses were performed to examine changes in abundance of the luxAB mRNA, the native psbAI mRNA, and the luciferase protein to determine whether bioluminescence is an accurate reporter of psbAI promoter activity in AMC149. Under constant light conditions, the mRNA abundances of both luxAB and psbAI oscillated with a period of approximately 24 h for at least 2 days. The expression of these two genes following the same pattern: both mRNAs peaked in the subjective morning, and their troughs occurred near the end of the subjective night. The amount of luciferase protein also oscillated with a period of approximately 24 h, and the protein rhythm is in phase with the bioluminescence rhythm. The rhythm of the luciferase mRNA phase-leads the rhythms of luciferase protein and in vivo bioluminescence by several hours. Comparable results were obtained with a short-period mutant of AMC149. Together, these results indicate that the bioluminescence rhythm in AMC149 is due primarily to circadian oscillation of psbAI promoter activity in this cyanobacterium.


Exome-based search for recurrent disease-causing alleles in Russian population.
Exomes of 27 Russian subjects were analyzed for the presence of medically relevant alleles, such as protein-truncating variants (PTVs) in known recessive disease-associated genes and pathogenic missense mutations included in the ClinVar database. 36 variants (24 PTVs and 12 amino acid substitutions) were identified and then subjected to the analysis in 897 population controls. 9/36 mutations were novel, however only two of them (POLH c.490delG associated with xeroderma pigmentosum variant (XPV) and CATSPER1 c.859_860delCA responsible for spermatogenic failure) were shown to be recurrent. 27 out of 36 pathogenic alleles were already described in prior genetic studies; seven of them occurred only in the index cases, while 20 demonstrated evidence for persistence in Russian population. In particular, non-random occurrence was revealed for SERPINA1 c.1096G > A (alpha-1 antitrypsin deficiency), C8B c.1282C > T and c.1653G > A (complement component 8B deficiency), ATP7B c.3207C > A (Wilson disease), PROP1 c.301_302delAG (combined pituitary hormone deficiency), CYP21A2 c.844G > T (non-classical form of adrenogenital syndrome), EYS c.1155T > A (retinitis pigmentosa), HADHA c.1528G > C (LCHAD deficiency), SCO2 c.418G > A (cytochrome c oxidase deficiency), OTOA c.2359G > T (sensorineural deafness), C2 c.839_866del (complement component 2 deficiency), ACADVL c.848T > C (VLCAD deficiency), TGM5 c.337G > T (acral peeling skin syndrome) and VWF c.2561 G > A (von Willebrand disease, type 2N). These data deserve to be considered in future medical genetic activities.


Psychological resilience in sport performers: a review of stressors and protective factors.
Psychological resilience is important in sport because athletes must utilise and optimise a range of mental qualities to withstand the pressures that they experience. In this article, we discuss psychological resilience in sport performers via a review of the stressors athletes encounter and the protective factors that help them withstand these demands. It is hoped that synthesising what is known in these areas will help researchers gain a deeper profundity of resilience in sport, and also provide a rigorous and robust foundation for the development of a sport-specific measure of resilience. With these points in mind, we divided the narrative into two main sections. In the first section, we review the different types of stressors encountered by sport performers under three main categories: competitive, organisational and personal. Based on our recent research examining psychological resilience in Olympics champions, in the second section we discuss the five main families of psychological factors (viz. positive personality, motivation, confidence, focus, perceived social support) that protect the best athletes from the potential negative effect of stressors. It is anticipated that this review will help sport psychology researchers examine the interplay between stressors and protective factors, which will, in turn, focus the analytical lens on the processes underlying psychological resilience in athletes.


Preliminary Examination of the Interpersonal Psychological Theory of Suicide in an Adolescent Clinical Sample.
This study offers a preliminary examination of the Interpersonal-Psychological Theory of Suicide (IPTS; Joiner 2005) in an adolescent clinical sample. The IPTS offers a nuanced framework that has many conceptual and practical merits. Although this theory has a growing base of evidence among adults, it has yet to be tested in adolescents using direct measures of its central constructs. Participants were 147 adolescents (76.2 % girls) on an inpatient psychiatric unit, who completed measures of key IPTS constructs of thwarted belongingness, perceived burdensomeness, acquired capability for suicide, as well as depression severity, hopelessness, and severity of suicidal symptoms. Our findings were largely consistent with hypotheses derived from the IPTS: perceived burdensomeness, and at a marginal level, thwarted belongingness, were independently associated with current suicidal ideation. The thwarted belongingness by perceived burdensomeness interaction marginally distinguished between adolescents with passive and active suicidal ideation. Acquired capability for suicide was associated with recent suicidal intent. Examination of all three IPTS constructs simultaneously revealed main effects of each construct (with a marginal effect of thwarted belongingness), and interaction effects for thwarted belongingness by perceived burdensomeness, and thwarted belongingness by perceived burdensomeness by acquired capability for suicide in association with suicidal symptom severity. Sex, age, depression severity, and hopelessness were controlled in all analyses. This study offers strong, albeit preliminary, support of the IPTS in a clinical adolescent sample. Assessment of IPTS constructs may be useful in determining persistent risk for suicide attempt. Prospective tests of the theory, and extensions to intervention and prevention should be considered in future IPTS research.


An assessment of the risks associated with polychlorinated biphenyls found in the stomach contents of stranded Indo-Pacific Humpback Dolphins (Sousa chinensis) and Finless Porpoises (Neophocaena phocaenoides) from Hong Kong waters.
The risks to Indo-Pacific Humpback Dolphins and Finless Porpoises associated with polychlorinated biphenyls (PCBs) were assessed. Stomach contents from twelve stranded Humpback Dolphins and sixteen stranded Finless Porpoises were collected. Concentrations of total and isomer-specific PCBs in the stomach contents were determined using dual-column gas chromatography equipped with electron capture detectors (GC-ECD). Risks due to the PCBs were assessed in three scenarios, based on total PCBs (summation of 41 PCB congeners), total toxicity equivalency (TEQs) and PCB 118, using the toxicity reference values (TRVs) as the threshold effects benchmarks. The calculated risk quotients (RQs) showed that risks due to PCBs were generally low or negligible. Specifically, RQs from total TEQs and total PCBs for Finless Porpoises are below one, suggesting that PCBs should be a low risk for the Finless Porpoise in Hong Kong waters. However, the Humpback Dolphin has RQs larger than 1 for total TEQs and total PCBs when the 95th percentile data were used in the evaluation. This indicates that further investigation may be needed to examine more closely the potential impact of toxic contaminants in the habitat of the Humpback Dolphin.


Enhancing the Adaptability of the Deep-Sea Bacterium Shewanella piezotolerans WP3 to High Pressure and Low Temperature by Experimental Evolution under H2O2 Stress.
Oxidative stresses commonly exist in natural environments, and microbes have developed a variety of defensive systems to counteract such events. Although increasing evidence has shown that high hydrostatic pressure (HHP) and low temperature (LT) induce antioxidant defense responses in cells, there is no direct evidence to prove the connection between antioxidant defense mechanisms and the adaptation of bacteria to HHP and LT. In this study, using the wild-type (WT) strain of a deep-sea bacterium, Shewanella piezotolerans WP3, as an ancestor, we obtained a mutant, OE100, with an enhanced antioxidant defense capacity by experimental evolution under H2O2 stress. Notably, OE100 exhibited better tolerance not only to H2O2 stress but also to HHP and LT (20 MPa and 4°C, respectively). Whole-genome sequencing identified a deletion mutation in the oxyR gene, which encodes the transcription factor that controls the oxidative stress response. Comparative transcriptome analysis showed that the genes associated with oxidative stress defense, anaerobic respiration, DNA repair, and the synthesis of flagella and bacteriophage were differentially expressed in OE100 compared with the WT at 20 MPa and 4°C. Genetic analysis of oxyR and ccpA2 indicated that the OxyR-regulated cytochrome c peroxidase CcpA2 significantly contributed to the adaptation of WP3 to HHP and LT. Taken together, these results confirmed the inherent relationship between antioxidant defense mechanisms and the adaptation of a benthic microorganism to HHP and LT.IMPORTANCE Oxidative stress exists in various niches, including the deep-sea ecosystem, which is an extreme environment with conditions of HHP and predominantly LT. Although previous studies have shown that HHP and LT induce antioxidant defense responses in cells, direct evidence to prove the connection between antioxidant defense mechanisms and the adaptation of bacteria to HHP and LT is lacking. In this work, using the deep-sea bacterium Shewanella piezotolerans WP3 as a model, we proved that enhancement of the adaptability of WP3 to HHP and LT can benefit from its antioxidant defense mechanism, which provided useful insight into the ecological roles of antioxidant genes in a benthic microorganism and contributed to an improved understanding of microbial adaptation strategies in deep-sea environments.


Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells.
Naive T cells spend most of their time scanning the surface of dendritic cells (DCs), indicating that self-MHC/T cell receptor (TCR) interactions between these immune cells occur routinely in peripheral organs during the steady state. Peripheral self-MHC recognition on DCs drives seemingly opposing effects in the absence of inflammatory stimuli such as deletion of certain self-reactive T cells as well as maintenance of the T cell responsiveness to antigen, both of which shape the T cell repertoire and regulate T cell responses. Here we review recent data on the role of self-MHC recognition on steady-state DCs in the periphery and propose that interactions between T cells and steady-state DCs display an analogy with selection processes that occur in the thymus: high affinity TCR/self-MHC interactions in the periphery result in T cell deletion, while low/intermediate affinity interactions result in tonic TCR signalling that is required to keep T cells responsive to antigen.


Cluster-based segmentation of dual-echo ultra-short echo time images for PET/MR bone localization.
Magnetic resonance (MR)-based attenuation correction is a critical component of integrated positron emission tomography (PET)/MR scanners. It is generally achieved by segmenting MR images into tissue classes with known attenuation properties (e.g., bone, fat, soft tissue, lung, air). Ultra-short echo time (UTE) have been proposed in the past to locate bone tissue. In this study, tri-modality computed tomography data was used to develop an improved algorithm for the localization of bone in the head and neck. Twenty patients were scanned using a tri-modality setup. A UTE acquisition with 22-cm transaxial and 24-cm axial field of view was acquired, with a resolution of 1.5 × 1.5 × 2.0 mm(3). The sequence consisted of two echoes (30 μs, 1.7 ms) with a flip angle of 10° and 125-kHz bandwidth. The CT images of all patients were classified by thresholding and used to compute maps of the posterior probability of each tissue class, given a pair of UTE echo values. The Jaccard distance was used to compare with CT the bone masks obtained when using this information to segment the UTE datasets. The results show the desired bony structures as a cluster pattern in the space of dual-echo measurements. The clusters obtained for the tissue classes are strongly overlapped, indicating that the MR data will not, regardless of the chosen space partition, be able to completely differentiate the bony and soft structures. The classification obtained by maximizing the posterior probability compared well to previously published methods, providing a more intuitive and robust choice of the final classification threshold. The distance between MR- and CT-based bone masks was 59% on average (0% being a perfect match), compared to 76% and 69% for two previously published methods. The study of tri-modality datasets shows that improved bone tissue classification can be achieved by estimating maps of the posterior probability of voxels belonging to a particular tissue class, given a measured pair of UTE echoes.


Acute Consumption of Blueberries and Short-Term Blueberry Supplementation Improve Glucose Management and Insulin Levels in Sedentary Subjects.
Blueberries are polyphenol-rich fruits with antioxidant and anti-inflammatory properties. Polyphenols from berries act by blocking digestive enzymes, reshaping gastrointestinal microbiota, and affecting the release of gastrointestinal hormones to regulate insulin dynamics and glucose management. However, most studies use fruit extracts instead of fresh fruit. We aimed to evaluate postprandial glucose management and antioxidant capacity of fresh blueberries consumed acutely or as a six-day supplementation in 10 sedentary subjects. To evaluate the effect of acute blueberry intake, 150 g of blueberries were consumed together with 150 g of white bread by the subject and blood samples were collected at 0, 30, 60, 90 and 120 min to measure glucose, insulin, and plasma antioxidant capacity. To evaluate supplementation, 150 g of blueberries were provided daily for six days and sample collection was performed at day 7. Acute consumption of blueberries decreased postprandial glucose area under the curve (AUC) and increased insulin levels at 15 min timepoint. Supplementation did not affect glucose levels but decreased insulin levels at 120 min. No changes in antioxidant capacity were observed. Consumption of fresh blueberries improves postprandial glucose management presumably due to actions on the gastrointestinal tract, while supplementation improves insulin sensitivity, probably due antioxidant and anti-inflammatory effects.


Rural health service planning: the need for a comprehensive approach to costing.
The precipitous closure of rural maternity services in industrialized countries over the past two decades is underscored in part by assumptions of efficiencies of scale leading to cost-effectiveness. However, there is scant evidence to support this and the costing evidence that exists lacks comprehensiveness. To clearly understand the cost-effectiveness of rural services we must take the broadest societal perspective to include not only health system costs, but also those costs incurred at the family and community levels. We must consider manifest costs (hard, easily quantifiable costs, both direct and indirect) and latent costs (understood as what is sacrificed or lost), and take into account cost shifting (reallocating costs to different parts of the system) and cost downloading (passing costs on to women and families). Further, we must compare the costs of having a rural maternity service to those incurred by not having a service, a comparison that is seldom made. This approach will require determining a methodological framework for weighing all costs, one which will likely involve attention to the rich descriptions of those experiencing loss.


Randomized trial of supported employment integrated with assertive community treatment for rural adults with severe mental illness.
Urban-based randomized clinical trials of integrated supported employment (SE) and mental health services in the United States on average have doubled the employment rates of adults with severe mental illness (SMI) compared to traditional vocational rehabilitation. However, studies have not yet explored if the service integrative functions of SE will be effective in coordinating rural-based services that are limited, loosely linked, and geographically dispersed. In addition, SE's ability to replicate the work outcomes of urban programs in rural economies with scarce and less diverse job opportunities remains unknown. In a rural South Carolina county, we designed and implemented a program blending Assertive Community Treatment (ACT) with an SE model, Individual Placement and Support (IPS). The ACT-IPS program operated with ACT and IPS subteams that tightly integrated vocational with mental health services within each self-contained team. In a 24-month randomized clinical trial, we compared ACT-IPS to a traditional program providing parallel vocational and mental health services on competitive work outcomes for adults with SMI (N = 143; 69% schizophrenia, 77% African American). More ACT-IPS participants held competitive jobs (64 versus 26%; p < .001, effect size [ES] = 0.38) and earned more income (median [Mdn] = 549 US dollars, interquartile range [IQR] = 0-5,145 US dollars, versus Mdn = 0 US dollars, IQR = 0-40 US dollars; p < .001, ES = 0.70) than comparison participants. The competitive work outcomes of this rural ACT-IPS program closely resemble those of urban SE programs. However, achieving economic self-sufficiently and developing careers probably require increasing access to higher education and jobs imparting marketable technical skills.


Bioengineered 3D platform to explore cell-ECM interactions and drug resistance of epithelial ovarian cancer cells.
The behaviour of cells cultured within three-dimensional (3D) structures rather than onto two-dimensional (2D) culture plastic more closely reflects their in vivo responses. Consequently, 3D culture systems are becoming crucial scientific tools in cancer cell research. We used a novel 3D culture concept to assess cell-matrix interactions implicated in carcinogenesis: a synthetic hydrogel matrix equipped with key biomimetic features, namely incorporated cell integrin-binding motifs (e.g. RGD peptides) and the ability of being degraded by cell-secreted proteases (e.g. matrix metalloproteases). As a cell model, we chose epithelial ovarian cancer, an aggressive disease typically diagnosed at an advanced stage when chemoresistance occurs. Both cell lines used (OV-MZ-6, SKOV-3) proliferated similarly in 2D, but not in 3D. Spheroid formation was observed exclusively in 3D when cells were embedded within hydrogels. By exploiting the design flexibility of the hydrogel characteristics, we showed that proliferation in 3D was dependent on cell-integrin engagement and the ability of cells to proteolytically remodel their extracellular microenvironment. Higher survival rates after exposure to the anti-cancer drug paclitaxel were observed in cell spheroids grown in hydrogels (40-60%) compared to cell monolayers in 2D (20%). Thus, 2D evaluation of chemosensitivity may not reflect pathophysiological events seen in patients. Because of the design flexibility of their characteristics and their stability in long-term cultures (28 days), these biomimetic hydrogels represent alternative culture systems for the increasing demand in cancer research for more versatile, physiologically relevant and reproducible 3D matrices.


Modifier genes in humans: strategies for identification.
A number of genetic disorders exhibit inter- and intra-familial variability. Understanding the factors that control the expression of disease genes should provide insight into the fundamental disease processes and will have implications for counselling patients. Different mechanisms can account for this variability, including environmental factors, genotype-phenotype correlations and imprinting. There is also evidence that, in a number of genetic diseases, gene expression is under the control of modifier loci. In cases where the biological basis of the genetic disease is understood, any genes involved in the pathogenic process represent candidate modifier genes which can easily be evaluated. Alternatively, modifiers can be identified through approaches such as mouse models. Since modifier genes will generally be common and because of confounding environmental influences, linkage analyses in humans will generally be based upon affected or discordant sib pairs. Discordant sib pairs represent an attractive option for linkage studies, because recurrence rates are high and the reduced survival characteristics associated with severe phenotypes will make the likelihood of obtaining clinical material from two living cases difficult. Furthermore, the use of discordant siblings will select for those siblings which possess sufficient dissimilarity at the modifier locus to overcome any shared environmental influence.


Magnetically Sensitive Radical Photochemistry of Non-natural Flavoproteins.
It is a remarkable fact that ∼50 μT magnetic fields can alter the rates and yields of certain free-radical reactions and that such effects might be the basis of the light-dependent ability of migratory birds to sense the direction of the Earth's magnetic field. The most likely sensory molecule at the heart of this chemical compass is cryptochrome, a flavin-containing protein that undergoes intramolecular, blue-light-induced electron transfer to produce magnetically sensitive radical pairs. To learn more about the factors that control the magnetic sensitivity of cryptochromes, we have used a set of de novo designed protein maquettes that self-assemble as four-α-helical proteins incorporating a single tryptophan residue as an electron donor placed approximately 0.6, 1.1, or 1.7 nm away from a covalently attached riboflavin as chromophore and electron acceptor. Using a specifically developed form of cavity ring-down spectroscopy, we have characterized the photochemistry of these designed flavoprotein maquettes to determine the identities and kinetics of the transient radicals responsible for the magnetic field effects. Given the gross structural and dynamic differences from the natural proteins, it is remarkable that the maquettes show magnetic field effects that are so similar to those observed for cryptochromes.


Perceptions of neighborhood safety and physical activity among youth: the CLAN study.
The purpose of this study was to examine associations between perceptions of neighborhood safety and physical activity among youth. We completed a cross-sectional study of children age 8 to 9 years (n = 188) and adolescents age 13 to 15 years (n = 346) in areas of varying socioeconomic status in Melbourne, Australia. Parents and adolescents completed questionnaires on perceptions of neighborhood safety. Scores were computed for perceptions of road safety, incivilities, and personal safety of the child or adolescent. Moderate-to-vigorous physical activity (MVPA) before or after school, on evenings, and on weekends was recorded using accelerometers. There were no associations between parental perceptions of neighborhood safety and children's MVPA outside school hours. Parental perception of personal safety was positively associated with adolescent boys' MVPA after school. Adolescent girls' concern about road safety was negatively associated with their MVPA during evenings and outside school hours. Perceptions of neighborhood safety might influence physical activity among youth in different ways according to age group and sex.


The life cycle and larval development of Fibricola seoulensis (Trematoda: Diplostomatidae).
The life cycle of Fibricola seoulensis was studied in the laboratory and in the field, with special interests in the larval developments within the eggs and in the intermediate hosts. The first emergence of miracidia after incubation of eggs in 26C water began on the ninth day. The miracidia, elongate and cylindrical shape, had epidermal plates in the formula of 6, 9, 4 and 3, with two pairs of flame cells and lateral processes. A kind of fresh water snail, Hippeutis (H.) cantori, was found to shed furcocercous cercariae from the 13th day after experimental challenge with miracidia while Physa acuta failed to shed. The same kind of snail collected from the field also shed the same cercariae. The cercariae were equipped with 2 pairs of penetration glands and 5 pairs of flame cells. The tadpoles of Rana nigromaculata were found susceptible to experimental infection with the cercariae. The same kind of tadpoles collected from various areas were also found naturally infected. The metacercariae in the tadpoles which were infected experimentally became infective to the definitive host in 21 days. The metacercariae were located free in the body cavity of tadpoles, and attained sexual maturity in rats in 7 days. The present study successfully followed the complete life cycle of F. seoulenis and found that it is possible to maintain the life cycle in the laboratory.


Construct measurement quality improves predictive accuracy in violence risk assessment: an illustration using the personality assessment inventory.
Much of the risk assessment literature has focused on the predictive validity of risk assessment tools. However, these tools often comprise a list of risk factors that are themselves complex constructs, and focusing on the quality of measurement of individual risk factors may improve the predictive validity of the tools. The present study illustrates this concern using the Antisocial Features and Aggression scales of the Personality Assessment Inventory (Morey, 1991). In a sample of 1,545 prison inmates and offenders undergoing treatment for substance abuse (85% male), we evaluated (a) the factorial validity of the ANT and AGG scales, (b) the utility of original ANT and AGG scales and newly derived ANT and AGG scales for predicting antisocial outcomes (recidivism and institutional infractions), and (c) whether items with a stronger relationship to the underlying constructs (higher factor loadings) were in turn more strongly related to antisocial outcomes. Confirmatory factor analyses (CFAs) indicated that ANT and AGG items were not structured optimally in these data in terms of correspondence to the subscale structure identified in the PAI manual. Exploratory factor analyses were conducted on a random split-half of the sample to derive optimized alternative factor structures, and cross-validated in the second split-half using CFA. Four-factor models emerged for both the ANT and AGG scales, and, as predicted, the size of item factor loadings was associated with the strength with which items were associated with institutional infractions and community recidivism. This suggests that the quality by which a construct is measured is associated with its predictive strength. Implications for risk assessment are discussed.


NAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration.
Chronic cocaine use leads to biochemical and behavioral changes that can persist for weeks to months after drug administration is discontinued. Alterations in gene expression in the mammalian CNS may contribute to these long-term neural consequences of cocaine abuse. A combined in situ transcription-PCR amplification strategy was used to isolate a novel mRNA, NAC-1, from the nucleus accumbens of rats 3 weeks after discontinuing 3 weeks of intravenous cocaine self-administration. In rats that self-administered cocaine, levels of NAC-1 were increased approximately 50% in the nucleus accumbens but not in the dorsal striatum or hippocampus, when compared with levels from yoked-saline controls. In situ hybridization analysis demonstrated increased numbers of NAC-1-expressing cells in the nucleus accumbens of rats who had self-administered cocaine. NAC-1 mRNA exists as one form, approximately 4400 nucleotides (nt) in size, and also is present at much lower amounts in non-neural tissues. A full-length cDNA clone was isolated from a whole brain library. The predicted polypeptide sequence contains a POZ domain in the first 120 amino acids; the same POZ domain sequence mediates protein-protein interactions among some transcriptional regulators. NAC-1 mRNA levels were also increased in the nucleus accumbens 1 week after 6 d of noncontingent cocaine treatments. Regulation of NAC-1 mRNA in the nucleus accumbens demonstrates a long-term effect of cocaine use on cellular function that may be relevant in behavioral sensitization or cocaine self-administration.


Storing paediatric genomic data for sequential interrogation across the lifespan.
Genomic sequencing (GS) is increasingly used in paediatric medicine to aid in screening, research and treatment. Some health systems are trialling GS as a first-line test in newborn screening programmes. Questions about what to do with genomic data after it has been generated are becoming more pertinent. While other research has outlined the ethical reasons for storing deidentified genomic data to be used in research, the ethical case for storing data for future clinical use has not been explicated. In this paper, we examine the ethical case for storing genomic data with the intention of using it as a lifetime health resource. In this model, genomic data would be stored with the intention of reanalysis at certain points through one's life. We argue this could benefit individuals and create an important public resource. However, several ethical challenges must first be met to achieve these benefits. We explore issues related to privacy, consent, justice and equality. We conclude by arguing that health systems should be moving towards futures that allow for the sequential interrogation of genomic data throughout the lifespan.


A writer's guide to education scholarship: Qualitative education scholarship (part 2).
Education scholarship can be conducted using a variety of methods, from quantitative experiments to qualitative studies. Qualitative methods are less commonly used in emergency medicine (EM) education research but are well-suited to explore complex educational problems and generate hypotheses. We aimed to review the literature to provide resources to guide educators who wish to conduct qualitative research in EM education. We conducted a scoping review to outline: 1) a list of journals that regularly publish qualitative educational papers; 2) an aggregate set of quality markers for qualitative educational research and scholarship; and 3) a list of quality checklists for qualitative educational research and scholarship. We found nine journals that have published more than one qualitative educational research paper in EM. From the literature, we identified 39 quality markers that were grouped into 10 themes: Initial Grounding Work (preparation, background); Goals, Problem Statement, or Question; Methods (general considerations); Sampling Techniques; Data Collection Techniques; Data Interpretation and Theory Generation; Measures to Optimize Rigour and Trustworthiness; Relevance to the Field; Evidence of Reflective Practice; Dissemination and Reporting. Lastly, five quality checklists were found for guiding educators in reporting their qualitative work. Many problems that EM educators face are well-suited to exploration using qualitative methods. The results of our scoping review provide publication venues, quality indicators, and checklists that may be useful to EM educators embarking on qualitative projects.


Assessment Scores of a Mock Objective Structured Clinical Examination Administered to 99 Anesthesiology Residents at 8 Institutions.
Objective Structured Clinical Examinations (OSCEs) are used in a variety of high-stakes examinations. The primary goal of this study was to examine factors influencing the variability of assessment scores for mock OSCEs administered to senior anesthesiology residents. Using the American Board of Anesthesiology (ABA) OSCE Content Outline as a blueprint, scenarios were developed for 4 of the ABA skill types: (1) informed consent, (2) treatment options, (3) interpretation of echocardiograms, and (4) application of ultrasonography. Eight residency programs administered these 4 OSCEs to CA3 residents during a 1-day formative session. A global score and checklist items were used for scoring by faculty raters. We used a statistical framework called generalizability theory, or G-theory, to estimate the sources of variation (or facets), and to estimate the reliability (ie, reproducibility) of the OSCE performance scores. Reliability provides a metric on the consistency or reproducibility of learner performance as measured through the assessment. Of the 115 total eligible senior residents, 99 participated in the OSCE because the other residents were unavailable. Overall, residents correctly performed 84% (standard deviation [SD] 16%, range 38%-100%) of the 36 total checklist items for the 4 OSCEs. On global scoring, the pass rate for the informed consent station was 71%, for treatment options was 97%, for interpretation of echocardiograms was 66%, and for application of ultrasound was 72%. The estimate of reliability expressing the reproducibility of examinee rankings equaled 0.56 (95% confidence interval [CI], 0.49-0.63), which is reasonable for normative assessments that aim to compare a resident's performance relative to other residents because over half of the observed variation in total scores is due to variation in examinee ability. Phi coefficient reliability of 0.42 (95% CI, 0.35-0.50) indicates that criterion-based judgments (eg, pass-fail status) cannot be made. Phi expresses the absolute consistency of a score and reflects how closely the assessment is likely to reproduce an examinee's final score. Overall, the greatest (14.6%) variance was due to the person by item by station interaction (3-way interaction) indicating that specific residents did well on some items but poorly on other items. The variance (11.2%) due to residency programs across case items was high suggesting moderate variability in performance from residents during the OSCEs among residency programs. Since many residency programs aim to develop their own mock OSCEs, this study provides evidence that it is possible for programs to create a meaningful mock OSCE experience that is statistically reliable for separating resident performance.


Bright Fluorescent Nanotags from Bottlebrush Polymers with DNA-Tipped Bristles.
Bright signal outputs are needed for fluorescence detection of biomolecules at their native expression levels. Increasing the number of labels on a probe often results in crowding-induced self-quenching of chromophores, and maintaining the function of the targeting moiety (e.g., an antibody) is a concern. Here we demonstrate a simple method to accommodate thousands of fluorescent dye molecules on a single antibody probe while avoiding the negative effects of self-quenching. We use a bottlebrush polymer from which extend hundreds of duplex DNA strands that can accommodate hundreds of covalently attached and/or thousands of noncovalently intercalated fluorescent dyes. This polymer-DNA assembly sequesters the intercalated fluorophores against dissociation and can be tethered through DNA hybridization to an IgG antibody. The resulting fluorescent nanotag can detect protein targets in flow cytometry, confocal fluorescence microscopy, and dot blots with an exceptionally bright signal that compares favorably to commercially available antibodies labeled with organic dyes or quantum dots.


Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation.
Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.


Use of free circulating DNA for diagnosis, prognosis and treatment of cancer.
This application claims a new method for diagnosis, prognosis and treatment of cancer using a non-invasive technique, the analysis of free circulating DNA in body fluids as a biomarker. The claimed procedure is based on the analysis of gene promoter methylation status and DNA integrity and concentration in the body fluid. Interestingly, DNA isolation from complex milieus is not required.


Evaluating the success of conservation actions in safeguarding tropical forest biodiversity.
We reviewed the evidence on the extent and efficacy of conservation of tropical forest biodiversity for each of the classes of conservation action defined by the new International Union for Conservation of Nature (IUCN) classification. Protected areas are the most tested conservation approach, and a number of studies show they are generally effective in slowing deforestation. There is some documentation of the extent of sustainable timber management in tropical forest, but little information on other landscape-conservation tactics. The extent and effectiveness of ex situ species conservation is quite well known. Forty-one tropical-forest species now survive only in captivity. Other single-species conservation actions are not as well documented. The potential of policy mechanisms, such as international conventions and provision of funds, to slow extinctions in tropical forests is considerable, but the effects of policy are difficult to measure. Finally, interventions to promote tropical conservation by supporting education and livelihoods, providing incentives, and furthering capacity building are all thought to be important, but their extent and effectiveness remain poorly known. For birds, the best studied taxon, the sum of such conservation actions has averted one-fifth of the extinctions that would otherwise have occurred over the last century. Clearly, tropical forest conservation works, but more is needed, as is critical assessment of what works in what circumstances, if mass extinction is to be averted.


The 1.2-megabase genome sequence of Mimivirus.
We recently reported the discovery and preliminary characterization of Mimivirus, the largest known virus, with a 400-nanometer particle size comparable to mycoplasma. Mimivirus is a double-stranded DNA virus growing in amoebae. We now present its 1,181,404-base pair genome sequence, consisting of 1262 putative open reading frames, 10% of which exhibit a similarity to proteins of known functions. In addition to exceptional genome size, Mimivirus exhibits many features that distinguish it from other nucleocytoplasmic large DNA viruses. The most unexpected is the presence of numerous genes encoding central protein-translation components, including four amino-acyl transfer RNA synthetases, peptide release factor 1, translation elongation factor EF-TU, and translation initiation factor 1. The genome also exhibits six tRNAs. Other notable features include the presence of both type I and type II topoisomerases, components of all DNA repair pathways, many polysaccharide synthesis enzymes, and one intein-containing gene. The size and complexity of the Mimivirus genome challenge the established frontier between viruses and parasitic cellular organisms. This new sequence data might help shed a new light on the origin of DNA viruses and their role in the early evolution of eukaryotes.


ChAdOx1 nCoV-19 (AZD1222) or nCoV-19-Beta (AZD2816) protect Syrian hamsters against Beta Delta and Omicron variants.
ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus-vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 has been shown to have 74% vaccine efficacy against symptomatic disease in clinical trials. However, variants of concern (VoCs) have been detected, with substitutions that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial, even though current real-world data is suggesting good efficacy following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluate the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. Minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 3- or 5- days post inoculation, in contrast to lungs of control animals. In Omicron-challenged hamsters, a single dose of AZD2816 or AZD1222 reduced virus shedding. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.


Identification of a suicide victim by facial reconstruction.
Facial reconstruction is used in an attempt to identify an individual by a three dimensional representation of the facial features using the skull as the foundation after metrical and non-metrical analysis to determine age, race and gender. The skeletonized remains of a female who was reported missing six years previously were recovered from the summit of Table Mountain in Cape Town. Some personal possessions were also recovered, one of which was a shark tooth pendant which the victim's parents recognized. Although there were distinctive dental features, the antemortem dental records had been lost during the initial investigation which therefore precluded identification by this means. However, positive identification was required and facial reconstruction on the skull was undertaken which the parents duly identified. The method used for facial reconstruction is described.


Effect of 5'-deoxy-5'-isobutylthioadenosine on formation and release of adenosine from neonatal and adult rat ventricular myocytes.
1. Studies in rat polymorphonuclear leucocytes have suggested that 5'-deoxy-5'-isobutylthioadenosine (IBTA), an inhibitor of the IMP-selective cytosolic 5'-nucleotidase, may be used to test its role in adenosine formation in intact cells. We investigated adenosine formation in neonatal and adult rat cardiomyocytes. 2. 2-Deoxyglucose (30 mM) with oligomycin (2 micrograms/ml) induced a 90-100% fall in ATP concentration in 10 min in neonatal and 60 min in adult heart cells. Adenosine accumulation was substantially increased, accounting for 13% of the fall in ATP concentration in neonatal cells and 56% in adult cells. 3. Anti-(rat liver ecto-5'-nucleotidase) serum did not inhibit adenosine accumulation. Furthermore, dipyridamole (10 microM), a nucleoside-transport blocker, inhibited by 80% the appearance of the newly formed adenosine in the medium, showing that adenosine is produced intracellularly by both adult and neonatal-rat myocytes in response to inhibition of oxidative metabolism. 4. IBTA (3 mM) inhibited by 80% the appearance of adenosine in the medium, but did not inhibit total adenosine accumulation by neonatal-rat myocytes and only modestly inhibited total adenosine accumulation by adult myocytes. 5. IBTA, like dipyridamole, inhibited incorporation of extracellular adenosine (10 microM) into neonatal and adult ventricular myocyte nucleotides by 60-70%. Transport of IBTA (100 microM) into the cells did not appear to be inhibited by dipyridamole (30 microM). 6. We conclude that IBTA acted primarily to inhibit adenosine release from myocytes. The small effect on adenosine formation rates implies that the IMP-selective cytosolic 5'-nucleotidase plays a minor role in this tissue.


Exertional Rhabdomyolysis: Epidemiology, Diagnosis, Treatment, and Prevention.
Exertional rhabdomyolysis (ER) is a medical condition whereby damage to skeletal muscle is induced by excessive physical activity in otherwise healthy individuals. The individual performs so much activity that he/ she presumably depletes local muscle energy stores and muscle cells are unable to maintain cellular integrity, resulting in cell damage and the release of cellular contents, with resultant secondary complications. In the military services, the incidence of ER appeared to increase in the period 2004 to 2015. Risk factors for ER include male sex, younger age, a prior heat injury, lower educational level, lower chronic physical activity, and activity in the warmer months of the year. Acute kidney injury is the most serious potential complication of ER and is thought to be due to a disproportionate amount of free myoglobin that causes renal vasoconstriction, nephrotoxic effects, and renal tubular obstructions. Patients typically present with a history of heavy and unaccustomed exercise with muscle pain, swelling, weakness, and decreased range of motion, largely localized to the muscle groups that were involved in the activity. Diagnostic criteria include the requisite clinical presentation with a serum creatine kinase level at least level 5 times higher than the upper limit of normal and/ or a urine dipstick positive for blood (due to the presence of myoglobin) but lacking red blood cells under microscopic urinalysis. Core treatment is largely supportive with aggressive fluid hydration. Although the great majority of individuals return to activity without consequence, patients should initially be stratified into high and low risk for recurrence, and those at high risk provided additional evaluation. Risk of ER in normal healthy individuals can be reduced by emphasizing graded, individual preconditioning before beginning a more strenuous exercise regimen after recommended work/rest and hydration schedules in hot weather, and discussing supplements and medications with knowledgeable medical personnel.


Household epidemic models with varying infection response.
This paper is concerned with SIR (susceptible → infected → removed) household epidemic models in which the infection response may be either mild or severe, with the type of response also affecting the infectiousness of an individual. Two different models are analysed. In the first model, the infection status of an individual is predetermined, perhaps due to partial immunity, and in the second, the infection status of an individual depends on the infection status of its infector and on whether the individual was infected by a within- or between-household contact. The first scenario may be modelled using a multitype household epidemic model, and the second scenario by a model we denote by the infector-dependent-severity household epidemic model. Large population results of the two models are derived, with the focus being on the distribution of the total numbers of mild and severe cases in a typical household, of any given size, in the event that the epidemic becomes established. The aim of the paper is to investigate whether it is possible to determine which of the two underlying explanations is causing the varying response when given final size household outbreak data containing mild and severe cases. We conduct numerical studies which show that, given data on sufficiently many households, it is generally possible to discriminate between the two models by comparing the Kullback-Leibler divergence for the two fitted models to these data.


Being Present In Space: The Role Of Allocentric And Egocentric Reference Frames.
The general aim of the present study was to investigate the effect of an interactive aerial view of the experienced environment during the encoding and retrieving of spatial information on the feeling of presence. Our findings showed that this real-time interactive aerial view (both small and large) during the encoding and retrieval of spatial information seems to led to a greater sense of presence. It is argued that the use of this aerial view, which provides a real-time allocentric viewpoint-dependent spatial representation, would ease the translation of a stored allocentric representation into an egocentric one, and this process, consequently, would help individuals to feel present in space.


Self-management of diabetes and associated comorbidities in rural and remote communities: a scoping review.
Chronic health conditions are more prevalent in rural and remote areas than in metropolitan areas; living in rural and remote areas may present particular barriers to the self-management of chronic conditions like diabetes and comorbidities. The aims of this review were to: (1) synthesise evidence examining the self-management of diabetes and comorbidities among adults living in rural and remote communities; and (2) describe barriers and enablers underpinning self-management reported in studies that met our inclusion criteria. A systematic search of English language papers was undertaken in PsycINFO, Medline Complete, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Complete, EMBASE and the Cochrane Database of Systematic Reviews, searching for literature indexed from the beginning of the database until 6 March 2020. Essential key concepts were diabetes, comorbidities, self-management and rural or remote. Twelve studies met the inclusion criteria. Six of these reported interventions to promote self-management for adults with diabetes in rural and remote communities and described comorbidities. These interventions had mixed results; only three demonstrated improvements in clinical outcomes or health behaviours. All three of these interventions specifically targeted adults living with diabetes and comorbidities in rural and remote areas; two used the same telehealth approach. Barriers to self-management included costs, transport problems and limited health service access. Interventions should take account of the specific challenges of managing both diabetes and comorbidities; telehealth may address some of the barriers associated with living in rural and remote areas.


Bridging the Gap between Vitiligo Segmentation and Clinical Scores.
Quantitative evaluation of vitiligo is crucial for assessing treatment response. Dermatologists evaluate vitiligo regularly to adjust their treatment plans, which requires extra work. Furthermore, the evaluations may not be objective due to inter- and intra-assessor variability. Though automatic vitiligo segmentation methods provide an objective evaluation, previous methods mainly focus on patch-wise images, and their results cannot be translated into clinical scores for treatment adjustment. Thus, full-body vitiligo segmentation needs to be developed for recording vitiligo changes in different body parts of a patient and for calculating the clinical scores. To bridge this gap, the first full-body vitiligo dataset with 1740 images, following the international vitiligo photo standard, was established. Compared with patch-wise images, full-body images have more complicated ambient light conditions and larger variances in lesion size and distribution. Additionally, in some hand and foot images, skin can be fully covered by either vitiligo or healthy skin. Previous patch-wise segmentation studies completely ignore these cases, as they assume that the contrast between vitiligo and healthy skin is available in each image for segmentation. To address the aforementioned challenges, the proposed algorithm in this study exploits a tailor-made contrast enhancement scheme and long-range comparison. Furthermore, a novel confidence score refinement module is proposed to manage images fully covered by vitiligo or healthy skin. Our results can be converted to clinical scores and used by clinicians. Compared to the state-of-the-art method, the proposed algorithm reduces the average per-image vitiligo involvement percentage error from 3.69 % to 1.81 %, and the top 10 % per-image errors from 23.17 % to 8.29 %. Our algorithm achieves 1.17 % and 3.11 % for the mean and max error for the per-patient vitiligo involvement percentage, which is better than an experienced dermatologist's naked-eye evaluation.


Loss of calpastatin leads to activation of calpain in human lens epithelial cells.
Activation of calpains (calpain 2 and Lp82) in rodent lenses readily causes proteolysis and cataract formation. In contrast, primate lenses are quite resistant to activation of calpains. The hypothesis is that high levels of human endogenous calpain inhibitor, calpastatin (CS), prevent calpain activation in human lenses. The purpose of the present study was to directly test if CS is a major inhibitory factor in a human lens epithelial cell line, HLE B-3. Small interfering RNAs (siRNAs) were used to knock down expression of CS in HLE B-3. The cells then were cultured with the calcium ionophore, ionomycin, with or without a calpain inhibitor SNJ-1945. Transcripts for calpain 2 and CS were measured by quantitative PCR (qPCR). Calpain 2 activity was detected by immunoblotting for the calpain-specific, α-spectrin breakdown product and for activation-associated, fragments of calpain 2. Expression of CS in HLE B-3 was remarkably higher than in α-TN4 (mouse comparator cell line). Proteolysis of α-spectrin was observed in the soluble proteins from α-TN4 incubated with Ca(2+), but not in the human HLE B-3. When CS-reduced HLE B-3 cells (transfected with CS siRNA) were cultured with ionomycin, calpain 2 was activated, specific proteolysis of α-spectrin occurred, and cell death ensued; SNJ-1945 inhibited these changes. Our data demonstrated that the high levels of endogenous CS do, indeed, inhibit calpain activity in normal human lens epithelial cells. We speculate that age-related oxidation might cause loss of CS activity in human lens epithelial cells, allowing activation of long-dormant calpain 2, proteolysis of critical cytoskeletal proteins, and cataract formation.


Manipulation of the elastic modulus of polymers at the nanoscale: influence of UV-ozone cross-linking and plasticizer.
The mechanical stability of polymeric nanostructures is critical to the processing, assembly, and performance of numerous existing and emerging technologies. A key predictor of mechanical stability is the elastic modulus. However, a significant reduction in modulus has been reported for thin films and nanostructures when the thickness or size of the polymer material decreases below a critical length scale. Routes to mitigate or even eliminate this reduction in modulus, and thus enhancing the mechanically stability of polymeric nanostructures, would be extremely valuable. Here, two routes to modulate the mechanical properties of polymers at the nanoscale are described. Exposure to ultraviolet light and ozone (UVO) cross-links the near surface region of high molecular mass PS films, rendering the elastic modulus independent of thickness. However, UVO cannot eliminate the decrease in modulus of low molecular mass PS or PMMA due to limited reaction depth and photodegradation, respectively. Alternatively, the thickness dependence of the elastic modulus of both PS and PMMA can be eliminated by addition of dioctyl phthalate (DOP) at 5% by mass. Furthermore, an increase in modulus is observed for films with thicknesses less than 30 nm with 5% DOP by mass in comparison to neat PS. Although DOP acts as a plasticizer for both PS and PMMA in the bulk, evidence indicates that DOP acts as an antiplasticizer at the nanoscale. By maintaining or even increasing the elastic modulus of polymers at the nanoscale, these methods could lead to improved stability of polymeric nanostructures and devices.


Plasmon enhanced photoacoustic generation from volumetric electromagnetic hotspots.
This work reports plasmon enhanced photoacoustic generation by using a three dimensional plasmonic absorber. The 3D plasmonic absorber comprises a thin polymer film on glass nanopillar arrays with nanogap-rich silver nanoislands. The 3D plasmonic absorber clearly shows 24.6 times higher enhancement of photoacoustic signals at an excitation wavelength of 630 nm than a simple polymeric absorber. The photoacoustic enhancement results from the volumetric electromagnetic field enhancement on a light-absorbing polymer through 3D plasmonic nanostructures. This novel photoacoustic absorber provides a new direction for highly efficient ultrasonic generation.


Hyperthyroxinemia in patients treated with high-dose propranolol.
Six patients with hyperthyroxinemia (five men and one woman) were evaluated for possible hyperthyroidism. All were taking large daily doses of propranolol--480 +/- 155 (+/- SE) mg--for treatment of angina pectoris. The patients had no clinical evidence of hyperthyroidism, although three had small goiters. Further evaluation of the patients revealed elevated serum free thyroxine levels and/or free thyroxine index, low-normal serum triiodothyronine levels, and elevated serum reverse triiodothyronine levels in all six. The thyroid-stimulating hormone response to thyrotropin-releasing hormone was normal in two patients, subnormal in three patients, and absent in one patient. One patient was restudied while receiving low-dose propranolol (80 mg a day), with normalization of all thyroid functional parameters. The data suggest that the abnormalities seen in patients taking high doses of propranolol were due to drug-induced blockade of iodothyronine deiodination. Signs and symptoms of hyperthyroidism are lacking in patients taking large doses of propranolol. If such a patient is discovered to have an elevated serum thyroxine level, a more complete evaluation of thyroid function is necessary before the diagnosis of thyrotoxicosis can be made. The thyrotropin-releasing hormone test may be of particular value in this circumstance.


Peer assessment to improve medical student's contributions to team-based projects: randomised controlled trial and qualitative follow-up.
Medical schools increasingly incorporate teamwork in their curricula but medical students often have a negative perception of team projects, in particular when there is unequal participation. The purpose of this study is to evaluate whether a novel peer evaluation system improves teamwork contributions and reduces the risk of students "free loading". A cluster randomised controlled trial (RCT) with qualitative follow up enrolled 37 teams (n = 223 students). Participating teams were randomised to intervention group (19 teams) or control group (18 teams). The validated Comprehensive Assessment Team Member Effectiveness (CATME) tool was used as the outcome measure, and was completed at baseline (week 2) and at the end of the project (week 10). The team contribution subscale was the primary outcome, with other subscales as secondary outcomes. Six focus group discussions were held with students to capture the team's experiences and perceptions of peer assessment and its effects on team work. The results of the RCT showed that there was no difference in team contribution, and other forms of team effectiveness, between intervention and control teams. The focus group discussions highlighted students' negative attitudes, and lack of implementation of this transparent, points-based peer assessment system, out of fear of future consequences for relationships with peers. The need to assess peers in a transparent way to stimulate open discussion was perceived as threatening by participants. Teams suggested that other peer assessment systems could work such as rewarding additional or floating marks to high performing team members. Other models of peer assessment need to be developed and tested that are non-threatening and that facilitate early acceptance of this mode of assessment.


Set2 Methyltransferase Facilitates DNA Replication and Promotes Genotoxic Stress Responses through MBF-Dependent Transcription.
Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast.


Effects of external and internal cues on gait function in Williams syndrome.
Williams syndrome (WS), a rare genetically based neurodevelopmental disorder, is characterized by gait abnormalities that resemble basal ganglia-parkinsonian deficits in the internal regulation of stride length. In the current study, we explored whether visual or attentional cues would improve gait function in adults with WS, when compared to adults with Down syndrome (DS) and neurologically normal controls. The spatiotemporal characteristics of gait were measured using the GAITRite walkway while participants walked with visual cues set at 20% greater than preferred stride length (externally cued), or with an attentional strategy of maintaining the stride length without the assistance of visual cues (internally cued). Although the WS and DS groups were able to achieve the criterion and normalize stride length in both conditions, the WS group significantly reduced their gait speed and cadence in the externally cued condition when compared to controls. In the internally cued condition, the WS group also showed reduced speed and increased intra-individual variability in speed and stride time. These findings suggest that the primary deficit is not one of difficulty regulating stride length in WS, but rather indicates more widespread dysfunction within visuomotor regions.


Hypertrophic Cardiomyopathy and Implantable Defibrillators in Sweden: Inappropriate Shocks and Complications Requiring Surgery.
The expanded use of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) based on risk stratification in individuals without known previous ventricular arrhythmia is justified by an acceptable risk of device-related adverse events. Such complications, leading to surgical procedures or inappropriate electrical shocks, may impact mortality, morbidity, quality of life, and cost-effectiveness. From the Swedish ICD Registry, implants due to HCM since 1995 until November 2012 in patients aged ≥18 years were identified and medical records reviewed. Inappropriate ICD shock occurred in 14.3% (46 of 321 patients; mean follow-up 5.4 years) with a recurrent episode in 28.2% of them. In multivariable analysis, hazard ratio (HR) for atrial fibrillation was 3.5 (95% confidence interval 1.8-6.8; P < 0.001) but showed no significant association to male sex (HR = 0.77), age (HR = 0.99), secondary indication (HR = 1.02) or device, ICD-DR/CRTD vs. ICD-VR (HR 1.07). Inappropriate shocks were triggered by atrial fibrillation/flutter or ectopic tachycardia (56.5%), sinus tachycardia (14.5%), lead dysfunction (14.5%), and T-wave oversensing (13.0%). A reintervention, besides elective device replacement, occurred in 92 patients (totally 150 procedures). The majority were lead-related (70.0%) procedures, especially of the ICD lead. Reintervention was associated with female sex (HR = 1.6 P = 0.04). Inappropriate ICD shock triggered by atrial arrhythmias, lead dysfunction, or complications requiring surgical interventions, is a concern in HCM patients who will be eligible for long-term prevention of sudden death. Efforts to avoid adverse events and provide balanced risk-benefit information are important, especially in primary prevention.


Anthralin, a non-TPA type tumor promoter, synergistically enhances phorbol ester-caused prostaglandin E2 release from primary cultured mouse epidermal cells.
Primary cultures of mouse epidermal cells (i.e., target cells of skin tumor promotion) stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) release prostaglandin E2 within 30 min. Anthralin, a non-TPA type tumor promoter, also stimulated PGE2 release; however, no release was detectable at least up to 4 hr after the addition of anthralin. When the cells were incubated with TPA plus anthralin, both PGE2 and arachidonic acid release were synergistically enhanced. Other non-TPA type tumor promoters, i.e., chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, did not potentiate the TPA-caused PGE2 release. In protein kinase C-down regulated cells, the synergistic stimulation of PGE2 and arachidonic acid release by TPA plus anthralin were not detected. Anthralin plus TPA did not alter the incorporation of arachidonic acid into cellular phospholipids. Cellular cyclooxygenase activity was increased 2 hr after TPA stimulation. Anthralin-caused increase in cyclooxygenase activity was detected at 6 hr after the addition of anthralin. Cyclooxygenase activity was synergistically increased by treating the cells with TPA plus anthralin. Cycloheximide and actinomycin D inhibited the increase in cyclooxygenase activity caused by anthralin or TPA plus anthralin. These results indicate that anthralin synergistically stimulates TPA-caused PGE2 release by synergistically increasing arachidonic acid release and cellular cyclooxygenase activity.


Helicobacter pylori infection and nonmalignant diseases.
Several interesting studies have been published on nonmalignant Helicobacter pylori-related conditions over the past year, which are reviewed in this article. A revival of interest in the histologic classification of gastritis has led to grading of gastritis into stages correlating with risk of neoplastic progression, new data to improve this concept have been published. Unselected prescription of proton-pump inhibitors in patients with dyspepsia has been questioned by the finding that withdrawal of proton-pump inhibitors induces acid-related symptoms in healthy volunteers, probably by the mechanism of rebound gastric acid hypersecretion. Additional data on the rationale of tapering proton-pump inhibitor therapy are therefore awaited. Moreover, new data on peptic ulcer disease and its complications provide clear recommendations for daily clinical practice. Testing and eradication of H. pylori in patients with peptic ulcer bleeding is essential. However, in H. pylori-negative peptic ulcer disease, high overall patient mortality should be acknowledged, and this should guide considering continuation of nonsteroidal anti-inflammatory drugs. The role of H. pylori in the pathogenesis of gastroesophageal reflux disease is still unclear. An association has been described by several studies; however, it cannot be translated to individual risks for development of gastroesophageal reflux disease after H. pylori eradication. Possibly, additional data on subgroups, such as gastric ulcer, duodenal ulcer patients, and associated gastric mucosal changes, will solve this issue.


Microfluidics-based self-assembly of peptide-loaded microgels: Effect of three dimensional (3D) printed micromixer design.
In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPs), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-cross-linked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, small-angle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortex-mediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production.


Pressure-driven fluidic delivery through carbon tube bundles.
The aim of this work is to demonstrate controlled flow through macroscopically long (approximately 1 cm) carbon tubes (0.5-1.8 microm in radius). A model, high-throughput, pressure-driven fluidic setup, which features a large number of parallel carbon tubes forming a bundle, is fabricated and tested. The carbon tubes are synthesized and self-assembled via co-electrospinning and subsequent carbonization. The setup accommodates pressure-driven flows with flow discharge rates of the order of 1 nL s(-1) (73 x 10(-11) kg s(-1)) for low-viscosity liquids and 30 nL s(-1) (36.3 x 10(-12) kg s(-1)) for gases into a water pool under imposed pressure drops below 4 bar. The measurements demonstrate the ability to sustain well-controlled laminar flows through these long carbon tube bundles and elucidate the main transport features. A novel procedure is also formulated to recover the flow-carrying tube inner-diameter distribution from the measured dependence of the fluid volumetric or mass flow rate on the imposed pressure drop.


beta-Catenin-dependent Wnt signalling controls the epithelial organisation of somites through the activation of paraxis.
The regulation of cell adhesion in epithelia is a fundamental process governing morphogenesis in embryos and a key step in the progression of invasive cancers. Here, we have analysed the molecular pathways controlling the epithelial organisation of somites. Somites are mesodermal epithelial structures of vertebrate embryos that undergo several changes in cell adhesion during early embryonic life. We show that Wnt6 in the ectoderm overlaying the somites, but not Wnt1 in the neighbouring neural tube, is the most likely candidate molecule responsible for the maintenance of the epithelial structure of the dorsal compartment of the somite: the dermomyotome. We characterised the signalling pathway that mediates Wnt6 activity. Our experiments suggest that the Wnt receptor molecule Frizzled7 probably transduces the Wnt6 signal. Intracellularly, this leads to the activation of the beta-catenin/LEF1-dependent pathway. Finally, we demonstrate that the bHLH transcription factor paraxis, which was previously shown to be a major player in the epithelial organisation of somites, is a target of the beta-catenin signal. We conclude that beta-catenin activity, initiated by Wnt6 and mediated by paraxis, is required for the maintenance of the epithelial structure of somites.


European Headache Federation recommendations for placebo and nocebo terminology.
Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials. The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented. Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement). The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects).


High expression of microRNA-130b correlates with poor prognosis of patients with hepatocellular carcinoma.
Whether microRNA-130b(miR-130b) can serve as a prognostic biomarker of hepatocellular carcinoma (HCC) has not been investigated. In the present study, we investigated the feasibility of miR-130b as a novel prognostic biomarker for HCC. We retrospectively investigated 97 patients diagnosed with HCC who underwent routine curative surgery between May 2007 and July 2012. miR-130b expression in HCC tissues and paired normal adjacent liver tissues was measured by reverse transcription and real-time PCR (RT-PCR). Survival curves were plotted using the Kaplan-Meier method and differences in survival rates were analyzed using the log-rank test. miR-130b expression level was significantly higher in HCC tissues compared with normal adjacent liver tissues (P<0.0001). The 5-year overall survival (OS) of high miR-130b expression group was significantly shorter than that of low miR-130b expression group (43.6% vs. 71.5%; P=0.022). Moreover, the 5-year disease-free survival (DFS) of high miR-130b expression group was also significantly shorter than that of low miR-130b expression group (25.9% vs. 63.9%; P=0.012). In a multivariate Cox model, we found that miR-130b expression was an independent prognostic factor for both 5-year OS (hazards ratio [HR] =2.523, 95% confidence interval [CI] =1.024-7.901, P=0.011) and 5-year DFS (HR=4.003, CI=1.578-7.899, P=0.005) in HCC. The results indicated that high expression of microRNA-130b was correlated with significant characteristics of patients with HCC, and it might be useful as a novel prognostic biomarker for HCC. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_160.