Copeptin for the prediction of recurrent cerebrovascular events after transient ischemic attack: results from the CoRisk study.
Copeptin has been associated with recurrent cerebrovascular events after transient ischemic attack (TIA). In an independent cohort, we evaluated copeptin for the prediction of recurrent cerebrovascular events within 3 months after TIA and assessed the incremental value of copeptin compared with the ABCD2 (age, blood, clinical features of TIA, duration of symptoms, presence of diabetes mellitus) and ABCD3-I (ABCD2, dual TIA [the presence of ≥2 TIA symptoms within 7 days], imaging [the presence of abnormal findings on neuroimaging]) scores. This prospective, multicenter cohort study was conducted at 3 tertiary Stroke Centers in Switzerland and Germany. From March 2009 through April 2011, we included 302 patients with TIA admitted within 24 hours from symptom onset. Of 28 patients with a recurrent cerebrovascular event within 3 months (stroke or TIA), 11 patients had a stroke. Although the association of copeptin with recurrent cerebrovascular events was not significant, the association with stroke alone as end point was significant. After adjusting for the ABCD2 score, a 10-fold increase in copeptin levels was associated with an odds ratio for stroke of 3.39 (95% confidence interval, 1.28-8.96; P=0.01). After addition of copeptin to the ABCD2 score, the area under the curve of the ABCD2 score improved from 0.60 (95% confidence interval, 0.46-0.74) to 0.74 (95% confidence interval, 0.60-0.88, P=0.02). In patients with MRI (n=223), the area under the curve of the ABCD3-I score increased in similar magnitude, although not significantly. Based on copeptin, 31.2% of patients were correctly reclassified across the risk categories of the ABCD2 score (net reclassification improvement; P=0.17). Copeptin improved the prognostic value of the ABCD2 score for the prediction of stroke but not TIA, and it may help clinicians in refining risk stratification for patients with TIA. http://www.clinicaltrials.gov. Unique identifier: NCT00878813.


Mental health systems in countries: where are we now?
More than 85% of the world's population lives in 153 low-income and middle-income countries (LAMICs). Although country-level information on mental health systems has recently become available, it still has substantial gaps and inconsistencies. Most of these countries allocate very scarce financial resources and have grossly inadequate manpower and infrastructure for mental health. Many LAMICs also lack mental health policy and legislation to direct their mental health programmes and services, which is of particular concern in Africa and South East Asia. Different components of mental health systems seem to vary greatly, even in the same-income categories, with some countries having developed their mental health system despite their low-income levels. These examples need careful scrutiny to derive useful lessons. Furthermore, mental health resources in countries seem to be related as much to measures of general health as to economic and developmental indicators, arguing for improved prioritisation for mental health even in low-resource settings. Increased emphasis on mental health, improved resources, and enhanced monitoring of the situation in countries is called for to advance global mental health.


Entangled decision forests and their application for semantic segmentation of CT images.
This work addresses the challenging problem of simultaneously segmenting multiple anatomical structures in highly varied CT scans. We propose the entangled decision forest (EDF) as a new discriminative classifier which augments the state of the art decision forest, resulting in higher prediction accuracy and shortened decision time. Our main contribution is two-fold. First, we propose entangling the binary tests applied at each tree node in the forest, such that the test result can depend on the result of tests applied earlier in the same tree and at image points offset from the voxel to be classified. This is demonstrated to improve accuracy and capture long-range semantic context. Second, during training, we propose injecting randomness in a guided way, in which node feature types and parameters are randomly drawn from a learned (nonuniform) distribution. This further improves classification accuracy. We assess our probabilistic anatomy segmentation technique using a labeled database of CT image volumes of 250 different patients from various scan protocols and scanner vendors. In each volume, 12 anatomical structures have been manually segmented. The database comprises highly varied body shapes and sizes, a wide array of pathologies, scan resolutions, and diverse contrast agents. Quantitative comparisons with state of the art algorithms demonstrate both superior test accuracy and computational efficiency.


Can surgeons assess CT suitability for endovascular repair (EVAR) in ruptured abdominal aortic aneurysm? Implications for a ruptured EVAR trial.
The purpose of this study was to determine whether surgeons without formal radiological training are able to assess suitability of patients with ruptured abdominal aortic aneurysms (AAA) for EVAR. The CT scans of 20 patients with AAA were reviewed under timed conditions by six vascular surgeons. Twenty minutes was allocated per scan. They were asked to determine if each aneurysm would be treatable by EVAR in the emergency setting and, if so, to measure for device selection. The results were then compared with those of a vascular radiologist. Six surgeons agreed on the suitability of endovascular repair in 45% of cases (95% CI, 23.1-68.5%; 9/20 scans; kappa = 0.41 [p = 0.01]) and concurred with the radiologist in eight of these. Individually, agreement ranged from 13 to 16 of the 20 scans, 65-80% between surgeons. The kappa value for agreement between all the surgeons and the radiologist was 0.47 (p = 0.01, moderate agreement). For the individual surgeons, this ranged from 0.3 to 0.6 (p = 0.01). In conclusion, while overall agreement was moderate between the surgeons and the radiologist, it is clear that if surgeons are to assess patients for ruptured EVAR in the future, focused training of surgical trainees is required.


Unidirectional transmission in non-symmetric gratings made of isotropic material.
We achieve a broadband unidirectional transmission or One-way diffraction grating by cascading two parallel gratings made of isotropic material with different periods. In order to significantly reduce the reciprocal transmission of the zero order, one of them is chosen to be a subwavelength grating and designed as a wideband reflector for the incident-wave. It is demonstrated that more than 65 percent of the incident-wave energy can be transmitted unidirectionally with less than 0.22 percent transmission in the opposite direction at normal incidence for TE polarization. And, the relative bandwidth of the unidirectional transmission is greater than 10 percent.


Self-Assembly of Spider Silk-Fusion Proteins Comprising Enzymatic and Fluorescence Activity.
The recombinant spider silk protein eADF4(C16) was genetically fused either with esterase 2 (EST2) or green fluorescent protein (GFP). The fusions EST-eADF4(C16) and GFP-eADF4(C16) were spectroscopically investigated and showed native structures of EST and GFP. The structural integrity was confirmed by the enzymatic activity of EST and the fluorescence of GFP. The spider silk moiety retained its intrinsically unstructured conformation in solution and the self-assembly into either nanofibrils or nanoparticles could be controlled by the concentration of phosphate. Particles, however, showed significantly lower activity of the EST and GFP domains likely caused by a steric hindrance. However, upon self-assembly of EST-eADF4(C16) and GFP-eADF4(C16) into fibrils the protein activities were retained. In general, the fusion of globular enzymes with the spider silk domain allows the generation of fibrous biomaterials with catalytic or light emitting properties.


Moving forward in microplastic research: A Norwegian perspective.
Given the increasing attention on the occurrence of microplastics in the environment, and the potential environmental threats they pose, there is a need for researchers to move quickly from basic understanding to applied science that supports decision makers in finding feasible mitigation measures and solutions. At the same time, they must provide sufficient, accurate and clear information to the media, public and other relevant groups (e.g., NGOs). Key requirements include systematic and coordinated research efforts to enable evidence-based decision making and to develop efficient policy measures on all scales (national, regional and global). To achieve this, collaboration between key actors is essential and should include researchers from multiple disciplines, policymakers, authorities, civil and industry organizations, and the public. This further requires clear and informative communication processes, and open and continuous dialogues between all actors. Cross-discipline dialogues between researchers should focus on scientific quality and harmonization, defining and accurately communicating the state of knowledge, and prioritization of topics that are critical for both research and policy, with the common goal to establish and update action plans for holistic benefit. In Norway, cross-sectoral collaboration has been fundamental in supporting the national strategy to address plastic pollution. Researchers, stakeholders and the environmental authorities have come together to exchange knowledge, identify knowledge gaps, and set targeted and feasible measures to tackle one of the most challenging aspects of plastic pollution: microplastic. In this article, we present a Norwegian perspective on the state of knowledge on microplastic research efforts. Norway's involvement in international efforts to combat plastic pollution aims at serving as an example of how key actors can collaborate synergistically to share knowledge, address shortcomings, and outline ways forward to address environmental challenges.


Balancing financial incentives during COVID-19: A comparison of provider payment adjustments across 20 countries.
Provider payment mechanisms were adjusted in many countries in response to the COVID-19 pandemic in 2020. Our objective was to review adjustments for hospitals and healthcare professionals across 20 countries. We developed an analytical framework distinguishing between payment adjustments compensating income loss and those covering extra costs related to COVID-19. Information was extracted from the Covid-19 Health System Response Monitor (HSRM) and classified according to the framework. We found that income loss was not a problem in countries where professionals were paid by salary or capitation and hospitals received global budgets. In countries where payment was based on activity, income loss was compensated through budgets and higher fees. New FFS payments were introduced to incentivize remote services. Payments for COVID-19 related costs included new fees for out- and inpatient services but also new PD and DRG tariffs for hospitals. Budgets covered the costs of adjusting wards, creating new (ICU) beds, and hiring staff. We conclude that public payers assumed most of the COVID-19-related financial risk. In view of future pandemics policymakers should work to increase resilience of payment systems by: (1) having systems in place to rapidly adjust payment systems; (2) being aware of the economic incentives created by these adjustments such as cost-containment or increasing the number of patients or services, that can result in unintended consequences such as risk selection or overprovision of care; and (3) periodically evaluating the effects of payment adjustments on access and quality of care.


Induction of the cell cycle in baby rat kidney cells by adenovirus type 5 E1A in the absence of E1B and a possible influence of p53.
From previous studies on the induction of DNA synthesis in quiescent primary baby rat kidney cells by adenovirus type 5 (Ad5) E1A deletion mutants, we concluded that induction is prevented only when cellular proteins p300 and pRb are both uncomplexed with E1A (J.A. Howe, J.S. Mymryk, C. Egan, P.E. Branton, and S.T. Bayley, Proc. Natl. Acad. Sci. USA 87:5883-5887, 1990). We have now examined induction by these same mutants in virus lacking the E1B region, so that cellular p53 was no longer complexed to the E1B 55-kDa protein. E1A mutants that fail to bind pRb induced DNA synthesis at a significantly lower level in Ad5 lacking E1B than in Ad5 containing E1B. Apparently, therefore, uncomplexed p53 can partially replace p300 in cooperating with pRb to suppress DNA synthesis in baby rat kidney cells.


Prediction of reading skill several years later depends on age and brain region: implications for developmental models of reading.
We investigated whether brain activity was predictive of future reading skill and, if so, how this brain-behavior correlation informs developmental models of reading. A longitudinal study followed 26 normally developing human children ranging in age from 9 to 15 years who were initially assessed for reading skill and performed a rhyming judgment task during functional magnetic resonance imaging. Patterns of brain activation in this task predicted changes between initial and a follow-up assessment of nonword reading skill administered up to 6 years later. Brain activity in areas typically active during imaging studies of reading was found to predict future nonword reading ability, but the predictive ability of these areas depended on age. Increased activity relative to peers in neural circuits associated with phonological recoding (i.e., inferior frontal gyrus and basal ganglia) was predictive of greater gains in reading fluency in younger children, whereas increased activity relative to peers in orthographic processing circuits (i.e., fusiform gyrus) was predictive of smaller gains in fluency for older children. Interpreted within the context of a connectionist model of reading, these results suggest that younger children who are more sensitive to higher-order phonological word characteristics (e.g., coarticulations) may make greater reading proficiency gains, whereas older children who focus more on whole-word orthographic representations may make smaller proficiency gains.


Emergence of CD4+ and CD8+ Polyfunctional T Cell Responses Against Immunodominant Lytic and Latent EBV Antigens in Children With Primary EBV Infection.
Long term carriers were shown to generate robust polyfunctional T cell (PFC) responses against lytic and latent antigens of Epstein-Barr virus (EBV). However, the time of emergence of PFC responses against EBV antigens, pattern of immunodominance and difference between CD4+ and CD8+ T cell responses during various stages of EBV infection are not clearly understood. A longitudinal study was performed to assess the development of antigen-specific PFC responses in children diagnosed to have primary symptomatic (infectious mononucleosis [IM]) and asymptomatic (AS) EBV infection. Evaluation of IFN-γ secreting CD8+ T cell responses upon stimulation by HLA class I-specific peptides of EBV lytic and latent proteins by ELISPOT assay followed by assessment of CD4+ and CD8+ PFC responses upon stimulation by a panel of overlapping EBV peptides for co-expression of IFN-γ, TNF-α, IL-2, perforin and CD107a by flow cytometry were performed. Cytotoxicity of T cells against autologous lymphoblastoid cell lines (LCLs) as well as EBV loads in PBMC and plasma were also determined. Both IM and AS patients had elevated PBMC and plasma viral loads which declined steadily during a 12-month period from the time of diagnosis whilst decrease in the magnitude of CD8+ T cell responses toward EBV lytic peptides in contrast to increase toward latent peptides was shown with no significant difference between those of IM and AS patients. Both lytic and latent antigen-specific CD4+ and CD8+ T cells demonstrated polyfunctionality (defined as greater or equal to three functions) concurrent with enhanced cytotoxicity against autologous LCLs and steady decrease in plasma and PBMC viral loads over time. Immunodominant peptides derived from BZLF1, BRLF1, BMLF1 and EBNA3A-C proteins induced the highest proportion of CD8+ as well as CD4+ PFC responses. Diverse functional subtypes of both CD4+ and CD8+ PFCs were shown to emerge at 6-12 months. In conclusion, EBV antigen-specific CD4+ and CD8+ PFC responses emerge during the first year of primary EBV infection, with greatest responses toward immunodominant epitopes in both lytic and latent proteins, correlating to steady decline in PBMC and plasma viral loads.


A novel solid lipid nanoparticle formulation for active targeting to tumor α(v) β(3) integrin receptors reveals cyclic RGD as a double-edged sword.
The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications.


Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.
Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.


Wave-amplitude synthesis applied to Gaussian-beam scattering by an off-axis sphere.
Electromagnetic scattering of a Gaussian beam by an off-axis dielectric sphere is treated by the sum-of-waves formulation, which is inherent in Lorenz-Mie theory. Each "wave" is a spherical eigenvector, defined in the natural frame of the scatterer, and the coefficient of that wave is the "wave amplitude." Decomposition of the beam into homogeneous plane waves lays the ground for a synthesis of the wave amplitudes, which is done by an integration over the polar angle that defines the direction of propagation of the plane-wave constituents of the beam. Concise analytical results are developed for (a) the electric-field intensity in every part of space, (b) the bistatic and monostatic radar cross sections of the scatterer, and (c) the power extracted from the beam by scattering and absorption. Numerical calculations are made for a spherical glycerol droplet of radius 1.5 μm that is excited by an adjacent, infrared, Gaussian beam of wavelength 1.1424 μm and spot size 2 μm. The numerical application manifests (a) how the beam is coupled with the droplet and (b) the effect of the droplet on the power intercepted by a receiver-end fiber placed on the beam axis, beyond the focal plane. Comparisons to numerical results obtained by a finite-element method software (a) validate the sum-of-waves theory, (b) evaluate the performance of the code implementing that theory, and, succinctly,


Sleep Quality in Young Adult Informal Caregivers: Understanding Psychological and Biological Processes.
Providing informal care for a relative or friend with medical or mental needs can extol a physical burden on the caregiver, including impaired aspects of sleep quality such as suboptimal sleep duration, lengthened sleep latency, frequent awakenings, daytime sleepiness, and poor self-rated sleep quality. Diminished sleep quality can worsen the health in the caregiver, including dysregulation of hypothalamic-pituitary-adrenal axis (HPA) activity. Few studies have attempted to describe sleep in young adults who provide regular informal care. This study examines subjective and objective indicators of sleep quality and diurnal cortisol rhythms among young adult caregivers relative to non-caregiving peers. We expect that caregivers will exhibit poorer objective and subjective sleep quality and greater dysregulation in diurnal cortisol indices, than demographically similar non-caregivers, and that caregivers with poorer sleep will exhibit pronounced cortisol dysregulation. Participant self-reported sleep quality over the prior month via the Pittsburgh Sleep Quality Index and objective sleep quality was observed via wrist actigraph for three consecutive days. Diurnal salivary cortisol was also measured across the three days of actigraph monitoring. Informal caregivers exhibited more self-reported sleep disturbance and greater sleep latency than non-caregivers, as well as more objectively measured sleep fragmentation. Caregivers with a shorter sleep duration were observed to have flatter diurnal cortisol slopes than caregivers with a relatively longer sleep duration. Young adult caregivers appear to be at risk for impairment in sleep quality, which in turn might impact health through HPA axis dysregulation. Longitudinal research is needed to identify these relationships across time.


The use of visual context during the production of referring expressions.
Most theories of reference assume that a referent's saliency in the linguistic context determines the choice of referring expression. However, it is less clear whether cognitive factors relating to the nonlinguistic context also have an effect. We investigated whether visual context influences the choice of a pronoun over a repeated noun phrase when speakers refer back to a referent in a preceding sentence. In Experiment 1, linguistic mention as well as visual presence of a competitor with the same gender as the referent resulted in fewer pronouns for the referent, suggesting that both linguistic and visual context determined the choice of referring expression. Experiment 2 showed that even when the competitor had a different gender from the referent, its visual presence reduced pronoun use, indicating that visual context plays a role even if the use of a pronoun is unambiguous. Thus, both linguistic and nonlinguistic information affect the choice of referring expression.


Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors.
Human rotavirus (RV) infection is a leading cause of dehydrating diarrhea in infants and young children worldwide. Since therapeutic approaches to RV gastroenteritis are limited to alleviation of dehydration with oral rehydration solutions, more direct approaches to palliate symptoms of RV gastroenteritis are required. Treatments with probiotics have been increasingly recognized as alternative safe and low cost treatments for moderate infectious diarrhea. In this study, Bifidobacterium bifidum G9-1 (BBG9-1), which has been used as an intestinal drug for several decades, was shown to have a remarkable protective effect against RV gastroenteritis in a suckling mice model. As well as prophylactic oral administration of BBG9-1 from 2 days before RV infection, therapeutic oral administration of BBG9-1 from 1 day after RV infection significantly alleviated RV-induced diarrhea. Therapeutic administration of BBG9-1 reduced various types of damage in the small intestine, such as epithelial vacuolization and villous shortening, and significantly diminished the infectious RV titer in mixtures of cecal contents and feces. It was also shown that therapeutic administration of BBG9-1 significantly increased the number of acidic mucin-positive goblet cells and the gene expression of mucosal protective factors including MUC2, MUC3, MUC4, TGFβ1 and TFF3 in the small intestine. This led to alleviation of low gut permeability shown as decreased gene expression levels of occludin, claudin-1 and villin-1 after RV infection. Furthermore, in the small intestine, therapeutic administration of BBG9-1 significantly palliated the decreased gene expression of SGLT-1, which plays an important role in water absorption. In the large intestine, administered BBG9-1 was shown to replicate to assimilate undigested nutrients, resulting in normalization of the abnormally high osmotic pressure. These results suggested that water malabsorption caused by RV infection was alleviated in mice administered BBG9-1. Thus, the present study showed that oral administration of BBG9-1 palliated diarrhea partly through protection against RV-induced lesions by inducing mucosal protective factors. Oral administration of BBG9-1 is thought to be an efficient method for management of an RV epidemic for both prophylactic and therapeutic purposes.


Proteome analysis of Helicobacter pylori: major proteins of type strain NCTC 11637.
Proteome analysis involves the simultaneous resolution and display of proteins produced by an organism, followed by the quantitation, characterisation and identification of these proteins. As part of an ongoing study mapping and comparing the proteins expressed by various strains of the pathogenic bacterium Helicobacter pylori, we have resolved and identified 93 of the most abundant proteins expressed by type reference strain NCTC 11637. Proteins were separated by two-dimensional gel electrophoresis and stained with Coomassie G250. Intensely-stained spots were excised and digested with trypsin, and the resulting peptides were characterised by mass spectrometry. Proteins were then identified by correlating actual peptide profiles with theoretical profiles generated from published nucleotide sequences. Ninety-three of the most intensely-stained protein spots were identified as the products of 35 genes, giving a ratio of 2.7 protein gene-products per gene. The products of the tsaA, pfr, ureA and ureB genes were amongst several proteins present in multiple isoforms. Peptide mass fingerprinting data were used to identify probable post-translational protein modifications. These results suggest that H. pylori proteins are subject to a high degree of post-translational modification. Comparative proteomics of H. pylori strains should greatly assist in investigating the pathogenic properties of this bacterium.


Prediction of evolutionarily conserved interologs in Mus musculus.
Identification of protein-protein interactions is an important first step to understand living systems. High-throughput experimental approaches have accumulated large amount of information on protein-protein interactions in human and other model organisms. Such interaction information has been successfully transferred to other species, in which the experimental data are limited. However, the annotation transfer method could yield false positive interologs due to the lack of conservation of interactions when applied to phylogenetically distant organisms. To address this issue, we used phylogenetic profile method to filter false positives in interologs based on the notion that evolutionary conserved interactions show similar patterns of occurrence along the genomes. The approach was applied to Mus musculus, in which the experimentally identified interactions are limited. We first inferred the protein-protein interactions in Mus musculus by using two approaches: i) identifying mouse orthologs of interacting proteins (interologs) based on the experimental protein-protein interaction data from other organisms; and ii) analyzing frequency of mouse ortholog co-occurrence in predicted operons of bacteria. We then filtered possible false-positives in the predicted interactions using the phylogenetic profiles. We found that this filtering method significantly increased the frequency of interacting protein-pairs coexpressed in the same cells/tissues in gene expression omnibus (GEO) database as well as the frequency of interacting protein-pairs shared the similar Gene Ontology (GO) terms for biological processes and cellular localizations. The data supports the notion that phylogenetic profile helps to reduce the number of false positives in interologs. We have developed protein-protein interaction database in mouse, which contains 41109 interologs. We have also developed a web interface to facilitate the use of database http://lgsun.grc.nia.nih.gov/mppi/.


Sleep disordered breathing: effects of adenotonsillectomy on behaviour and psychological functioning.
Children on the adenotonsillectomy waiting list aged 6 years or more were screened by questionnaire and overnight sleep monitoring to identify 12 with a moderate sleep and breathing disorder (SBD) group. They were matched by age and sex with 11 children who had a similar history of snoring and sleep disturbance but without an obvious sleep and breathing problem when monitored (snorer group) and also with a group of ten children most of whom were refered for an unrelated surgical procedure (control group). All children were studied before and 3-6 months after surgery. Pre-operatively the SBD and snorer groups both had significantly more restless sleep than the control group. The SBD group also had significantly more (> 4%) dips in oxygen saturation than the other two groups. After surgery there were no longer any significant differences between the three groups. After adenotonsillectomy the SBD group showed a significant reduction in aggression, inattention and hyperactivity on the parent Conners scale, and an improvement in vigilance on the Continuous Performance Test. The snorer group also improved showing less hyperactive behaviour than pre-operatively and better vigilance. The control groups's behaviour and performance did not change significantly. There were no significant changes in the performance of the Matching Familiar Figures Test in any of the groups. Relief of mild to moderate sleep and breathing disorders in children is associated with improved behaviour and functioning. We confirm previous work which suggests that the relation between sleep disordered breathing and daytime problems in children is a causal one.


Effect of crisis plans on admissions and emergency visits: a randomized controlled trial.
To establish whether patients with a crisis plan had fewer voluntary or involuntary admissions, or fewer outpatient emergency visits, than patients without such a plan. Multicenter randomized controlled trial with two intervention conditions and one control condition. Adult outpatients diagnosed with psychotic or bipolar disorder who had experienced at least one psychiatric crisis in the previous two years. Two types of advance statement were used: (1) a crisis plan formulated by the patient with the help of a patient advocate (Patient Advocate Crisis Plan: PACP); and (2) a crisis plan developed together with the clinician (Clinician-facilitated Crisis Plan: CCP). The percentages of patients admitted voluntarily or involuntarily (on an emergency basis or by court order), and the percentage who made outpatient emergency visits over an 18-month follow-up period. A total of 212 patients were included: 69 in the PACP condition, 70 in the CCP condition, and 73 in the control condition. No effects of the two interventions were found on the numbers of voluntary admissions, involuntary admissions and emergency visits. Regarding involuntary admissions, there was no significant effect on emergency admissions, which were 17% (12/69) in the PACP condition, 10% (7/70) in the CCP condition, and 19% (14/73) in the control condition. There was a significant effect on planned court-ordered admissions, with 16% (11/69) in the PACP condition, 10% (7/70) in the CCP condition, and 26% (19/73) in the control condition. Finally, the interventions had no effect on outpatient emergency visits, with 32% (22/69) in the PACP group, 31% (22/70) in the CCP group, and 34% (25/73) in the control group. Crisis plans may be an effective intervention for reducing court-ordered admissions in patients with psychotic and bipolar disorders. Current Controlled Trails NTR1166.


Multimedia article. Laparoscopic ultralow anterior resection with colonic J-pouch-anal anastomosis.
Optimal treatment of mid to distal rectal cancers includes total mesorectal excision for oncologic clearance and, where reanastomosis is feasible, a colonic J-pouch-anal anastomosis improves bowel function. There is recent interest in performing an ultralow anterior resection laparoscopically. A technique is described that includes specimen extraction through the eventual routine defunctioning colostomy or ileostomy site. Consecutive unselected patients who underwent laparoscopic ultralow anterior resection were recruited. Patients with adenocarcinoma underwent preoperative endorectal ultrasound to individualize for neoadjuvant chemoradiotherapy, based on local extent and lymph nodes seen. The operative procedures were as shown in the video. Posterior dissection along the "total mesorectal excision plane" included incision of Waldeyer's fascia. Bowel continuity was restored by an intracoporeal double-cross stapled colonic J-pouch-anal anastomosis, but where not possible a coloplasty with pull-through handsewn coloanal anastomosis was performed. Laparoscopic ultralow anterior resection was performed on 55 patients (35 men; median age, 63 (range, 33-90) years) from March 2004 to October 2006. The median body mass index was 26.3 (19-38); 14 patients (25 percent) had a body mass index >30. Ten patients (18 percent) had an American Society of Anesthesiologists' classification of III. The indications were adenocarcinoma (n = 51), squamous-cell carcinoma of rectum (n = 1), dermoid tumor of mesorectum (n = 1), large villous adenoma (n = 1), and carcinoid with local lymph node metastases (n = 1). The adenocarcinomas were a median distance of 6 (3-12) cm from the anal verge. Neoadjuvant radiotherapy was given in 12 patients (24 percent) who had preoperative endoanal ultrasound findings of tumor extension beyond the muscularis propria and chemoradiotherapy in 7 (14 percent) of these patients where the tumor was more bulky and fixed. Laparoscopic ultralow anterior resection was completed at a median 180 (90-405) minutes, with 53.5 (2-2250) ml of blood loss, and the specimen was extracted through a 4.5 (3.5-11) cm wound. The latter included three cases (5 percent) that were converted. Significant adhesiolysis was required in 29 patients (52.7 percent) because of previous operations. The histologic grading or the adenocarcinoma patients were: Stage I, n = 14; Stage II, n = 23; Stage III, n = 11; Stage IV, n = 3. Of those who underwent curative resection (Stages I-III), the distal resection margin was 2.9 +/- 0.7 cm (mean +/- standard error) and the radial resection margins were at least 2 mm in all patients. The level of the coloanal anastomosis was a median 3.5 (0-4.5) cm from the anal verge; a coloanal pull-through anastomosis was required in one patient who had a distal cancer. The ileostomies functioned and patients tolerated free fluids at a median of two (1-9) days, and the median postoperative hospital stay was seven (3-22) days. At a median follow-up of 14 (2-33) months, none of the adenocarcinoma patients who had undergone curative resection had recurrences. Four patients (8 percent) had postoperative complications that required operative/invasive intervention (anatomotic leak n = 1, proximal bowel ischemia n = 1, port site hernia n = 1, pelvic collection n = 1). Four other patients had smaller pelvic collections that resolved with antibiotics; pelvic collections were associated with advanced stage of cancer (P = 0.047). Discharge was delayed by acute gastric distension in 11 patients; the latter was associated with poorer American Society of Anesthesiologists' risk classification (P = 0.035). Erectile dysfunction occurred in ten men, and this was associated with adjuvant chemoradiotherapy (P = 0.042). One patient (2 percent) had persistent urinary retention that required catheterization at latest follow-up. The ileostomy had been closed in 50 patients, and at last follow-up, the median stool frequency was two (1-8) bowel movements per day. Laparoscopic ultralow anterior resection could be offered routinely and completed safely in Western populations, where obesity and adhesions from previous abdominal surgery is common. A laparoscopic technique readily allowed visual identification of the autonomic nerves in the abdomen over the aorta, which could then be followed down into the pelvis. If the pelvis was deep, inversion of the 30 degrees laparoscope in the "upside down" position fascilited incision of Waldeyer's fascia. This brought the rectum proximally and anteriorly, aiding with the laparoscopic stapler transection of the distal rectum, especially if the cancer was distal, the patient was obese, and the pelvis was narrow. Extraction of the specimen at the eventual defunctioning stoma site reduced the incisions required. Preoperative chemoradiotherapy may have a role in postoperative male sexual dysfunction. Further randomized, controlled studies that include assessing five-year cancer survival/recurrence, pelvic nerve dysfunction, and bowel function are needed before laparoscopic ultralow anterior resection becomes widely accepted.


Overall Survival Endpoint in Oncology Clinical Trials: Addressing the Effect of Crossover--The Case of Pazopanib in Advanced Renal Cell Carcinoma.
To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials. An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial. Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib. This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit.


Comparative transcriptomic analysis of antimony resistant and susceptible Leishmania infantum lines.
One of the major challenges to leishmaniasis treatment is the emergence of parasites resistant to antimony. To study differentially expressed genes associated with drug resistance, we performed a comparative transcriptomic analysis between wild-type and potassium antimonyl tartrate (SbIII)-resistant Leishmania infantum lines using high-throughput RNA sequencing. All the cDNA libraries were constructed from promastigote forms of each line, sequenced and analyzed using STAR for mapping the reads against the reference genome (L. infantum JPCM5) and DESeq2 for differential expression statistical analyses. All the genes were functionally annotated using sequence similarity search. The analytical pipeline considering an adjusted p-value < 0.05 and fold change > 2.0 identified 933 transcripts differentially expressed (DE) between wild-type and SbIII-resistant L. infantum lines. Out of 933 DE transcripts, 504 presented functional annotation and 429 were assigned as hypothetical proteins. A total of 837 transcripts were upregulated and 96 were downregulated in the SbIII-resistant L. infantum line. Using this DE dataset, the proteins were further grouped in functional classes according to the gene ontology database. The functional enrichment analysis for biological processes showed that the upregulated transcripts in the SbIII-resistant line are associated with protein phosphorylation, microtubule-based movement, ubiquitination, host-parasite interaction, cellular process and other categories. The downregulated transcripts in the SbIII-resistant line are assigned in the GO categories: ribonucleoprotein complex, ribosome biogenesis, rRNA processing, nucleosome assembly and translation. The transcriptomic profile of L. infantum showed a robust set of genes from different metabolic pathways associated with the antimony resistance phenotype in this parasite. Our results address the complex and multifactorial antimony resistance mechanisms in Leishmania, identifying several candidate genes that may be further evaluated as molecular targets for chemotherapy of leishmaniasis.


The discovery of chemical neurotransmitters.
Neurotransmitters have become such an intrinsic part of our theories about brain function that many today are unaware of how difficult it was to prove their existence or the protracted dispute over the nature of synaptic transmission. The story is important not only because it is fascinating science history, but also because it exemplifies much of what is best in science and deserving to be emulated. The friendships formed among such major figures in this history as Henry Dale, Otto Loewi, Wilhelm Feldberg, Walter Cannon, and others extended over two world wars, enriching their lives and facilitating their research. Even the dispute-the "war of the sparks and the soups"--between neurophysiologists and pharmacologists over whether synaptic transmission is electrical or chemical played a positive role in stimulating the research needed to provide convincing proof.


The impact of nursing leadership on patient safety in a developing country.
This article is a report of a study to identify the ways nursing leaders and managers in a developing country have an impact on patient safety. The attempt to address the problem of patient safety in health care is a global issue. Literature addressing the significant impact that nursing leadership has on patient safety is extensive and focuses almost exclusively on the developed world. A critical ethnography was conducted with senior registered nursing leaders and managers throughout the Fiji Islands, specifically those in the Head Office of the Fiji Ministry of Health and the most senior nurse in a hospital or community health service. Semi-structured interviews were conducted with senior nursing leaders and managers in Fiji. Thematic analysis of the interviews was undertaken from a critical theory perspective, with reference to the macro socio-political system of the Fiji Ministry of Health. Four interrelated issues regarding the nursing leaders and managers' impact on patient safety emerged from the study. Empowerment of nursing leaders and managers, an increased focus on the patient, the necessity to explore conditions for front-line nurses and the direct relationship between improved nursing conditions and increased patient safety mirrored literature from developed countries. The findings have significant implications for developing countries and it is crucial that support for patient safety in developing countries become a focus for the international nursing community. Nursing leaders and managers' increased focus on their own place in the hierarchy of the health care system and on nursing conditions as these affect patient safety could decrease adverse patient outcomes. The findings could assist the global nursing community to better support developing countries in pursuing a patient safety agenda.


A putative 6-transmembrane nitrate transporter OsNRT1.1b plays a key role in rice under low nitrogen.
OsNRT1.1a is a low-affinity nitrate (NO3 (-) ) transporter gene. In this study, another mRNA splicing product, OsNRT1.1b, putatively encoding a protein with six transmembrane domains, was identified based on the rice genomic database and bioinformatics analysis. OsNRT1.1a/OsNRT1.1b expression in Xenopus oocytes showed OsNRT1.1a-expressing oocytes accumulated (15) N levels to about half as compared to OsNRT1.1b-expressing oocytes. The electrophysiological recording of OsNRT1.1b-expressing oocytes treated with 0.25 mM NO3 (-) confirmed (15) N accumulation data. More functional assays were performed to examine the function of OsNRT1.1b in rice. The expression of both OsNRT1.1a and OsNRT1.1b was abundant in roots and downregulated by nitrogen (N) deficiency. The shoot biomass of transgenic rice plants with OsNRT1.1a or OsNRT1.1b overexpression increased under various N supplies under hydroponic conditions compared to wild-type (WT). The OsNRT1.1a overexpression lines showed increased plant N accumulation compared to the WT in 1.25 mM NH4 NO3 and 2.5 mM NO3 (-) or NH4 (+) treatments, but not in 0.125 mM NH4 NO3 . However, OsNRT1.1b overexpression lines increased total N accumulation in all N treatments, including 0.125 mM NH4 NO3 , suggesting that under low N condition, OsNRT1.1b would accumulate more N in plants and improve rice growth, but also that OsNRT1.1a had no such function in rice plants.


The leaf-area shrinkage effect can bias paleoclimate and ecology research.
Leaf area is a key trait that links plant form, function, and environment. Measures of leaf area can be biased because leaf area is often estimated from dried or fossilized specimens that have shrunk by an unknown amount. We tested the common assumption that this shrinkage is negligible. We measured shrinkage by comparing dry and fresh leaf area in 3401 leaves of 380 temperate and tropical species and used phylogenetic and trait-based approaches to determine predictors of this shrinkage. We also tested the effects of rehydration and simulated fossilization on shrinkage in four species. We found that dried leaves shrink in area by an average of 22% and a maximum of 82%. Shrinkage in dried leaves can be predicted by multiple morphological traits with a standard deviation of 7.8%. We also found that mud burial, a proxy for compression fossilization, caused negligible shrinkage, and that rehydration, a potential treatment of dried herbarium specimens, eliminated shrinkage. Our findings indicate that the amount of shrinkage is driven by variation in leaf area, leaf thickness, evergreenness, and woodiness and can be reversed by rehydration. The amount of shrinkage may also be a useful trait related to ecologically and physiological differences in drought tolerance and plant life history.


The cost of preventing undernutrition: cost, cost-efficiency and cost-effectiveness of three cash-based interventions on nutrition outcomes in Dadu, Pakistan.
Cash-based interventions (CBIs) increasingly are being used to deliver humanitarian assistance and there is growing interest in the cost-effectiveness of cash transfers for preventing undernutrition in emergency contexts. The objectives of this study were to assess the costs, cost-efficiency and cost-effectiveness in achieving nutrition outcomes of three CBIs in southern Pakistan: a 'double cash' (DC) transfer, a 'standard cash' (SC) transfer and a 'fresh food voucher' (FFV) transfer. Cash and FFVs were provided to poor households with children aged 6-48 months for 6 months in 2015. The SC and FFV interventions provided $14 monthly and the DC provided $28 monthly. Cost data were collected via institutional accounting records, interviews, programme observation, document review and household survey. Cost-effectiveness was assessed as cost per case of wasting, stunting and disability-adjusted life year (DALY) averted. Beneficiary costs were higher for the cash groups than the voucher group. Net total cost transfer ratios (TCTRs) were estimated as 1.82 for DC, 2.82 for SC and 2.73 for FFV. Yet, despite the higher operational costs, the FFV TCTR was lower than the SC TCTR when incorporating the participation cost to households, demonstrating the relevance of including beneficiary costs in cost-efficiency estimations. The DC intervention achieved a reduction in wasting, at $4865 per case averted; neither the SC nor the FFV interventions reduced wasting. The cost per case of stunting averted was $1290 for DC, $882 for SC and $883 for FFV. The cost per DALY averted was $641 for DC, $434 for SC and $563 for FFV without discounting or age weighting. These interventions are highly cost-effective by international thresholds. While it is debatable whether these resource requirements represent a feasible or sustainable investment given low health expenditures in Pakistan, these findings may provide justification for continuing Pakistan's investment in national social safety nets.


Identification and functional analysis of an ammonium transporter in Streptococcus mutans.
Streptococcus mutans, a Gram-positive bacterium, is considered to be a major etiologic agent of human dental caries and reported to form biofilms known as dental plaque on tooth surfaces. This organism is also known to possess a large number of transport proteins in the cell membrane for export and import of molecules. Nitrogen is an essential nutrient for Gram-positive bacteria, though alternative sources such as ammonium can also be utilized. In order to obtain nitrogen for macromolecular synthesis, nitrogen-containing compounds must be transported into the cell. However, the ammonium transporter in S. mutans remains to be characterized. The present study focused on characterizing the ammonium transporter gene of S. mutans and its operon, while related regulatory genes were also analyzed. The SMU.1658 gene corresponding to nrgA in S. mutans is homologous to the ammonium transporter gene in Bacillus subtilis and SMU.1657, located upstream of the nrgA gene and predicted to be glnB, is a member of the PII protein family. Using a nrgA-deficient mutant strain (NRGD), we examined bacterial growth in the presence of ammonium, calcium chloride, and manganese sulfate. Fluorescent efflux assays were also performed to reveal export molecules associated with the ammonium transporter. The growth rate of NRGD was lower, while its fluorescent intensity was much higher as compared to the parental strain. In addition, confocal laser scanning microscopy revealed that the structure of biofilms formed by NRGD was drastically different than that of the parental strain. Furthermore, transcriptional analysis showed that the nrgA gene was co-transcribed with the glnB gene. These results suggest that the nrgA gene in S. mutans is essential for export of molecules and biofilm formation.


Tissue-specific prediction of directly regulated genes.
Direct binding by a transcription factor (TF) to the proximal promoter of a gene is a strong evidence that the TF regulates the gene. Assaying the genome-wide binding of every TF in every cell type and condition is currently impractical. Histone modifications correlate with tissue/cell/condition-specific ('tissue specific') TF binding, so histone ChIP-seq data can be combined with traditional position weight matrix (PWM) methods to make tissue-specific predictions of TF-promoter interactions. We use supervised learning to train a naïve Bayes predictor of TF-promoter binding. The predictor's features are the histone modification levels and a PWM-based score for the promoter. Training and testing uses sets of promoters labeled using TF ChIP-seq data, and we use cross-validation on 23 such datasets to measure the accuracy. A PWM+histone naïve Bayes predictor using a single histone modification (H3K4me3) is substantially more accurate than a PWM score or a conservation-based score (phylogenetic motif model). The naïve Bayes predictor is more accurate (on average) at all sensitivity levels, and makes only half as many false positive predictions at sensitivity levels from 10% to 80%. On average, it correctly predicts 80% of bound promoters at a false positive rate of 20%. Accuracy does not diminish when we test the predictor in a different cell type (and species) from training. Accuracy is barely diminished even when we train the predictor without using TF ChIP-seq data. Our tissue-specific predictor of promoters bound by a TF is called Dr Gene and is available at http://bioinformatics.org.au/drgene. email@example.com Supplementary data are available at Bioinformatics online.


Effects of exercise intensity on lymphocyte H2O2 production and antioxidant defences in soccer players.
Physical exercise is capable of enhancing or suppressing the immune response depending on the intensity and duration of exercise. This study investigated how exercise intensity influences the lymphocyte antioxidant response and the induction of cellular oxidative damage. Eighteen voluntary male pre-professional soccer players participated in this study. Sportsmen played a 60 min training match, and were divided into three groups depending on the intensity degree during the match: low, medium and high intensities. Malondialdehyde (MDA), vitamins C and E and haem oxygenase-1 (HO-1) gene expression were measured in lymphocytes. Reactive oxygen species (ROS) production was determined in lymphocytes and neutrophils. Lymphocyte MDA levels and H(2)O(2) production were significantly increased in the group which performed the most intense exercise. Neutrophil counts and ROS production increased progressively with the exercise intensity. Vitamin C significantly decreased after exercise in the highest-intensity group in comparison with initial values, whereas vitamin E levels significantly increased in the medium and high-intensity groups. HO-1 gene expression significantly increased in the medium and high-intensity groups. Exercise intensity affects the lymphocyte and neutrophil oxidant/antioxidant balance, but only exercise of high intensity induces lymphocyte oxidative damage.


The brain-adipocyte-gut network: Linking obesity and depression subtypes.
Major depressive disorder (MDD) and obesity are dominant and inter-related health burdens. Obesity is a risk factor for MDD, and there is evidence MDD increases risk of obesity. However, description of a bidirectional relationship between obesity and MDD is misleading, as closer examination reveals distinct unidirectional relationships in MDD subtypes. MDD is frequently associated with weight loss, although obesity promotes MDD. In contrast, MDD with atypical features (MDD-AF) is characterised by subsequent weight gain and obesity. The bases of these distinct associations remain to be detailed, with conflicting findings clouding interpretation. These associations can be viewed within a systems biology framework-the psycho-immune neuroendocrine (PINE) network shared between MDD and metabolic disorders. Shared PINE subsystem perturbations may underlie increased MDD in overweight and obese people (obesity-associated depression), while obesity in MDD-AF (depression-associated obesity) involves more complex interactions between behavioural and biomolecular changes. In the former, the chronic PINE dysfunction triggering MDD is augmented by obesity-dependent dysregulation in shared networks, including inflammatory, leptin-ghrelin, neuroendocrine, and gut microbiome systems, influenced by chronic image-associated psychological stress (particularly in younger or female patients). In MDD-AF, behavioural dysregulation, including hypersensitivity to interpersonal rejection, fundamentally underpins energy imbalance (involving hyperphagia, lethargy, hypersomnia), with evolving obesity exaggerating these drivers via positive feedback (and potentially augmenting PINE disruption). In both settings, sex and age are important determinants of outcome, associated with differences in emotional versus cognitive dysregulation. A systems biology approach is recommended for further research into the pathophysiological networks underlying MDD and linking depression and obesity.


Increased exposure to pesticides and colon cancer: Early evidence in Brazil.
Environmental factors may increase colon cancer (CC) risk. It has been suggested that pesticides could play a significant role in the etiology of this malignancy. As agriculture is one of the mainstays of the Brazilian economy, this country has become the largest pesticides consumer worldwide. The CC burden is also increasing in Brazil. Herein, we examined data from the Brazilian Federal Government to determine whether CC mortality and pesticide consumption may be associated. Database of the Ministry of Health provided CC mortality data in Brazil, while pesticide usage was accessed at the website of Brazilian Institute of Environment and Renewable Natural Resources. The CC mortality in the Brazilian states was calculated as standard mortality rates (SMR). All Bayesian analysis was performed using a Markov chain Monte Carlo method in WinBUGS software. We observed that CC mortality has exhibited a steady increase for more than a decade, which correlated with the amount of sold pesticides in the country. Both observations are concentrated in the Southern and the Southeast regions of Brazil. Although ecological studies like ours have methodological limitations, the current dataset suggests the possibility that pesticide exposure may be a risk factor for CC. It warrants further investigation.


Identifying structural signatures of shear banding in model polymer nanopillars.
Amorphous solids are critical in the design and production of nanoscale devices, but under strong confinement these materials exhibit changes in their mechanical properties which are not well understood. Phenomenological models explain these properties by postulating an underlying defect structure in these materials but do not detail the microscopic properties of these defects. Using machine learning methods, we identify mesoscale defects that lead to shear banding in model polymer nanopillars well below the glass transition temperature as a function of pillar diameter. Our results show that the primary structural features responsible for shear banding on this scale are fluctuations in the diameter of the pillar. Surprisingly, these fluctuations are quite small compared to the diameter of the pillar, less than half of a particle diameter in size. At intermediate pillar diameters, we find that these fluctuations tend to concentrate along the minor axis of shear band planes. We also see the importance of mean "softness" as a classifier of shear banding grow as a function of pillar diameter. Softness is a new field that characterizes local structure and is highly correlated with particle-level dynamics such that softer particles are more likely to rearrange. This demonstrates that softness, a quantity that relates particle-level structure to dynamics on short time and length scales, can predict large time and length scale phenomena related to material failure.


Bacterial genes mutL, mutS, and dcm participate in repair of mismatches at 5-methylcytosine sites.
Certain amber mutations in the cI gene of bacteriophage lambda appear to recombine very frequently with nearby mutations. The aberrant mutations included C-to-T transitions at the second cytosine in 5'CC(A/T)GG sequences (which are subject to methylation by bacterial cytosine methylase) and in 5'CCAG and 5'CAGG sequences. Excess cI+ recombinants arising in crosses that utilize these mutations are attributable to the correction of mismatches by a bacterial very-short-patch (VSP) mismatch repair system. In the present study I found that two genes required for methyladenine-directed (long-patch) mismatch repair, mutL and mutS, also functioned in VSP mismatch repair; mutH and mutU (uvrD) were dispensable. VSP mismatch repair was greatly reduced in a dcm Escherichia coli mutant, in which 5-methylcytosine was not methylated. However, mismatches in heteroduplexes prepared from lambda DNA lacking 5-methylcytosine were repaired in dcm+ bacteria. These results indicate that the product of gene dcm has a repair function in addition to its methylase activity.


The causes of parental vaccine refusal: results of a survey from Giresun, Turkey.
While efforts have raised immunization levels in developing countries, high rates of vaccine refusal in both developing and developed countries are causing concern worldwide. We aimed to determine the causes of vaccine refusal among parents refusing or postponing the vaccination of their children. This descriptive, cross-sectional study was performed in the Giresun province of Turkey. The study population included families who were unwilling or refused to vaccinate at least one of their children under the scope of the Turkey Enhanced Program of Immunization. Data were obtained during the year 2018 by face-toface interviews with each vaccine hesitant parent (VHP). Vaccine refusal incidence was 1.2% in the year 2018. In 8 (14.8%) of the children, the vaccination was recorded to be postponed due to health problems, while 46 (85.2%) children were not vaccinated due to parental vaccine refusal. Two-thirds of unvaccinated children were living outside the province center of Giresun. The parents consisted of young adults whose average age was 30.6±6.6 years. VHPs were mostly university graduates (61.1% of mothers-70.3% of fathers). While at least one of the VHPs was a religious official in 24.1%, at least one of the either VHP was a teacher in 20.3%. The most common reasons for vaccine refusal were `fear of vaccine side-effects` (55.6%), and `problems in previous vaccinations` (33.3%). In 44.4 % of refusal cases, no specific reason was stated. Primary healthcare providers, who are in close contact with parents, have an important role to provide the right health information. Various in-service training can be provided to improve the communication skills of healthcare providers. In these training sessions, besides comprehensive information about vaccines, it should be aimed to provide parents with the ability to understand their concerns, to approach them sensitively and to present the information they need effectively.


Analysis of object motion in the ventral part of the medial superior temporal area of the macaque visual cortex.
1. The medial superior temporal area (MST) is an extrastriate area of the macaque visual cortex. Cells in MST have large receptive fields and respond to moving stimuli with directional selectivity. We previously suggested that the dorsal part of MST is mainly involved in analysis of field motion caused by movements of the animal itself, because most cells in the dorsal part preferentially responded to movements of a wide textured field rather than to movements of a small stimulus. To determine whether the remaining ventral part of MST differs in function from the dorsal part, we examined properties of cells in the ventral part in comparison with those of cells in the dorsal part, using anesthetized and paralyzed preparation. 2. Most cells in the ventral part preferably responded to movements of a small stimulus rather than to movements of a wide textured field. 3. Although the cells in the ventral part did not respond to movements of a textured field over a large window, many of them began to respond when a small stationary object was introduced in front of the moving field. The direction to which the cells responded in this stimulus configuration was opposite to the direction in which they responded to movements of an object on a stationary background. Activities of these cells thus represented the direction of relative movement of an object on a background, irrespective of whether the image of the object or the background moved on the retina. 4. We conclude that the ventral part of MST is distinctive from the dorsal part of MST and is mainly involved in the analysis of object movements in external space.


Demographic characteristics of doctors who intend to follow clinical academic careers: UK national questionnaire surveys.
It is well recognised that women are underrepresented in clinical academic posts. Our aim was to determine which of a number of characteristics-notably gender, but also ethnicity, possession of an intercalated degree, medical school attended, choice of specialty-were predictive of doctors' intentions to follow clinical academic careers. Questionnaires to all UK-trained medical graduates of 2005 sent in 2006 and again in 2010, graduates of 2009 in 2010 and graduates of 2012 in 2013. At the end of their first year of medical work, 13.5% (368/2732) of men and 7.3% (358/4891) of women specified that they intended to apply for a clinical academic training post; and 6.0% (172/2873) of men and 2.2% (111/5044) of women specified that they intended to pursue clinical academic medicine as their eventual career. A higher percentage of Asian (4.8%) than White doctors (3.3%) wanted a long-term career as a clinical academic, as did a higher percentage of doctors who did an intercalated degree (5.6%) than others (2.2%) and a higher percentage of Oxbridge graduates (8.1%) than others (2.8%). Of the graduates of 2005, only 30% of those who in 2006 intended a clinical medicine career also did so when re-surveyed in 2010 (men 44%, women 12%). There are noteworthy differences by gender and other demographic factors in doctors' intentions to pursue academic training and careers. The gap between men and women in aspirations for a clinical academic career is present as early as the first year after qualification.


Multiple Chronic Conditions and Functional Outcome after Ischemic Stroke: A Systematic Review and Meta-Analysis.
Multiple chronic conditions (MCC) contribute to functional disability in the general population although its role in predicting functional outcome (FO) among patients with stroke is not well understood. There is no universal agreement on the approach to measuring MCC in stroke, and findings have been mixed regarding MCC being an independent predictor for poststroke FO. This review aims to summarize the findings of studies that have investigated the relationship between MCC and FO after ischemic stroke using a MCC index. PubMed and Embase were systematically searched for studies conducted among ischemic stroke patients that have examined the adjusted association between prestroke MCC and FO. The quality of the included studies was appraised using a risk of bias (RoB) assessment checklist. A meta-analysis was performed for the association between MCC and FO using a random effects model to estimate the overall pooled ORs. Twelve of the 18 studies included were hospital-based cohort studies, with a median RoB score of 4.75 points (range 1-9, higher scores for higher RoB). Studies predominantly used the Charlson Comorbidity Index (CCI), or the Modified CCI to measure MCC burden, and the modified Rankin scale to measure FO. Half of the studies reported a significant negative association between MCC and FO, which was also found by the meta-analysis with a pooled OR of 1.11 (95% CI 1.05-1.18). The current review supports that increased MCC is associated with worse poststroke FO although population-based studies of this association are lacking. Future research should aim to develop more refined measures of MCC that consider the severity and interactions of comorbid conditions reflective of the broader stroke population and to understand the relationship between MCC and poststroke FO with thorough adjustment for confounding factors.


Revisiting the influenza vaccine.
The Centers for Disease Control and Prevention (CDC) has declared the decline in preventable diseases through vaccination to be 1 of the 10 great public health achievements in the past decade in the United States. Still, influenza epidemics occur every year in the United States and are associated with high rates of morbidity and mortality. A substantial portion of the US population chooses not to get vaccinated against influenza despite the illness and death associated with the disease. Low rates of vaccination are of particular concern in high-risk patients. The CDC's Advisory Committee on Immunization Practices has broadened its influenza vaccine recommendations to include all individuals older than 6 months. Education of patients about the value of influenza vaccination will help to increase vaccination rates.


Repression of the hindbrain developmental program by Cdx factors is required for the specification of the vertebrate spinal cord.
The spinal cord is a unique vertebrate feature that originates, together with the hindbrain, from the caudal neural plate. Whereas the hindbrain subdivides into rhombomeres, the spinal cord remains unsegmented. We have identified Cdx transcription factors as key determinants of the spinal cord region in zebrafish. Loss of Cdx1a and Cdx4 functions causes posterior expansion of the hindbrain at the expense of the unsegmented spinal cord. By contrast, cdx4 overexpression in the hindbrain impairs rhombomere segmentation and patterning and induces the expression of spinal cord-specific genes. Using cell transplantation, we demonstrate that Cdx factors function directly within the neural ectoderm to specify spinal cord. Overexpression of 5' Hox genes fails to rescue hindbrain and spinal cord defects associated with cdx1a/cdx4 loss-of-function, suggesting a Hox-independent mechanism of spinal cord specification. In the absence of Cdx function, the caudal neural plate retains hindbrain characteristics and remains responsive to surrounding signals, particularly retinoic acid, in a manner similar to the native hindbrain. We propose that by preventing the posterior-most region of the neural plate from following a hindbrain developmental program, Cdx factors help determine the size of the prospective hindbrain and spinal cord territories.


How to schedule night shift work in order to reduce health and safety risks.
Objectives This discussion paper aims to provide scientifically based recommendations on night shift schedules, including consecutive shifts, shift intervals and duration of shifts, which may reduce health and safety risks. Short-term physiological effects in terms of circadian disruption, inadequate sleep duration and quality, and fatigue were considered as possible links between night shift work and selected health and safety risks, namely, cancer, cardio-metabolic disease, injuries, and pregnancy-related outcomes. Method In early 2020, 15 experienced shift work researchers participated in a workshop where they identified relevant scientific literature within their main research area. Results Knowledge gaps and possible recommendations were discussed based on the current evidence. The consensus was that schedules which reduce circadian disruption may reduce cancer risk, particularly for breast cancer, and schedules that optimize sleep and reduce fatigue may reduce the occurrence of injuries. This is generally achieved with fewer consecutive night shifts, sufficient shift intervals, and shorter night shift duration. Conclusions Based on the limited, existing literature, we recommend that in order to reduce the risk of injuries and possibly breast cancer, night shift schedules have: (i) ≤3 consecutive night shifts; (ii) shift intervals of ≥11 hours; and (iii) ≤9 hours shift duration. In special cases - eg, oil rigs and other isolated workplaces with better possibilities to adapt to daytime sleep - additional or other recommendations may apply. Finally, to reduce risk of miscarriage, pregnant women should not work more than one night shift in a week.


Feasibility of conducting an early pregnancy diet and lifestyle e-health intervention: the Pregnancy Lifestyle Activity Nutrition (PLAN) project.
Childhood obesity is a global issue. Excessive weight gain in early pregnancy is independently associated with obesity in the next generation. Given the uptake of e-health, our primary aim was to pilot the feasibility of an e-health intervention, starting in the first trimester, to promote healthy lifestyle and prevent excess weight gain in early pregnancy. Methods: Women were recruited between 8 and 11 weeks gestation and randomised to the intervention or routine antenatal care. The intervention involved an e-health program providing diet, physical activity and well-being advice over 12 weeks. Women (n = 57, 43.9% overweight/obese) were recruited at 9.38 ± 1.12 (control) and 9.06 ± 1.29 (intervention) weeks' gestation, mainly from obstetric private practices (81.2%). Retention was 73.7% for the 12-week intervention, 64.9% at birth and 55.8% at 3 months after birth.No difference in gestational weight gain or birth size was detected. Overall treatment effect showed a mean increase in score ranking the perceived confidence of dietary change (1.2 ± 0.46, p = 0.009) and score ranking readiness to exercise (1.21 ± 0.51, p = 0.016) over the intervention. At 3 months, infants weighed less in the intervention group (5405 versus 6193 g, p = 0.008) and had a lower ponderal index (25.5 ± 3.0 versus 28.8 ± 4.0 kg/m3) compared with the control group. A lifestyle intervention starting in the first-trimester pregnancy utilising e-health mode of delivery is feasible. Future studies need strategies to target recruitment of participants of lower socio-economic status and ensure maximal blinding. Larger trials (using technology and focused on early pregnancy) are needed to confirm if decreased infant adiposity is maintained.


Benefits from living together? Clades whose species use similar habitats may persist as a result of eco-evolutionary feedbacks.
Contents 66 I. 67 II. 68 III. 69 IV. 70 V. 73 VI. 75 VII. 77 78 References 78 SUMMARY: Recent decades have seen declines of entire plant clades while other clades persist despite changing environments. We suggest that one reason why some clades persist is that species within these clades use similar habitats, because such similarity may increase the degree of co-occurrence of species within clades. Traditionally, co-occurrence among clade members has been suggested to be disadvantageous because of increased competition and enemy pressure. Here, we hypothesize that increased co-occurrence among clade members promotes mutualist exchange, niche expansion or hybridization, thereby helping species avoid population decline from environmental change. We review the literature and analyse published data for hundreds of plant clades (genera) within a well-studied region and find major differences in the degree to which species within clades occupy similar habitats. We tentatively show that, in clades for which species occupy similar habitats, species tend to exhibit increased co-occurrence, mutualism, niche expansion, and hybridization - and rarely decline. Consistently, throughout the geological past, clades whose species occupied similar habitats often persisted through long time-spans. Overall, for many plant species, the occupation of similar habitats among fellow clade members apparently reduced their vulnerability to environmental change. Future research should identify when and how this previously unrecognized eco-evolutionary feedback operates.


The use of automated bioacoustic recorders to replace human wildlife surveys: an example using nightjars.
To be able to monitor and protect endangered species, we need accurate information on their numbers and where they live. Survey methods using automated bioacoustic recorders offer significant promise, especially for species whose behaviour or ecology reduces their detectability during traditional surveys, such as the European nightjar. In this study we examined the utility of automated bioacoustic recorders and the associated classification software as a way to survey for wildlife, using the nightjar as an example. We compared traditional human surveys with results obtained from bioacoustic recorders. When we compared these two methods using the recordings made at the same time as the human surveys, we found that recorders were better at detecting nightjars. However, in practice fieldworkers are likely to deploy recorders for extended periods to make best use of them. Our comparison of this practical approach with human surveys revealed that recorders were significantly better at detecting nightjars than human surveyors: recorders detected nightjars during 19 of 22 survey periods, while surveyors detected nightjars on only six of these occasions. In addition, there was no correlation between the amount of vocalisation captured by the acoustic recorders and the abundance of nightjars as recorded by human surveyors. The data obtained from the recorders revealed that nightjars were most active just before dawn and just after dusk, and least active during the middle of the night. As a result, we found that recording at both dusk and dawn or only at dawn would give reasonably high levels of detection while significantly reducing recording time, preserving battery life. Our analyses suggest that automated bioacoustic recorders could increase the detection of other species, particularly those that are known to be difficult to detect using traditional survey methods. The accuracy of detection is especially important when the data are used to inform conservation.


Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract.
Populations of interstitial cells of Cajal (ICC) are altered in several gastrointestinal neuromuscular disorders. ICC are identified typically by ultrastructure and expression of Kit (CD117), a protein that is also expressed on mast cells. No other molecular marker currently exists to independently identify ICC. The expression of ANO1 (DOG1, TMEM16A), a Ca(2+)-activated Cl(-) channel, in gastrointestinal stromal tumors suggests it may be useful as an ICC marker. The aims of this study were therefore to determine the distribution of Ano1 immunoreactivity compared with Kit and to establish whether Ano1 is a reliable marker for human and mouse ICC. Expression of Ano1 in human and mouse stomach, small intestine, and colon was investigated by immunofluorescence labeling using antibodies to Ano1 alone and in combination with antibodies to Kit. Colocalization of immunoreactivity was demonstrated by epifluorescence and confocal microscopy. In the muscularis propria, Ano1 immunoreactivity was restricted to cells with the morphology and distribution of ICC. All Ano1-positive cells in the muscularis propria were also Kit positive. Kit-expressing mast cells were not Ano1 positive. Some non-ICC in the mucosa and submucosa of human tissues were Ano1 positive but Kit negative. A few (3.2%) Ano1-positive cells in the human gastric muscularis propria were labeled weakly for Kit. Ano1 labels all classes of ICC and represents a highly specific marker for studying the distribution of ICC in mouse and human tissues with an advantage over Kit since it does not label mast cells.


Synthetic soil crusts against green-desert transitions: a spatial model.
Semiarid ecosystems are threatened by global warming due to longer dehydration times and increasing soil degradation. Mounting evidence indicates that, given the current trends, drylands are likely to expand and possibly experience catastrophic shifts from vegetated to desert states. Here, we explore a recent suggestion based on the concept of ecosystem terraformation, where a synthetic organism is used to counterbalance some of the nonlinear effects causing the presence of such tipping points. Using an explicit spatial model incorporating facilitation and considering a simplification of states found in semiarid ecosystems including vegetation, fertile and desert soil, we investigate how engineered microorganisms can shape the fate of these ecosystems. Specifically, two different, but complementary, terraformation strategies are proposed: Cooperation-based: C-terraformation; and Dispersion-based: D-terraformation. The first strategy involves the use of soil synthetic microorganisms to introduce cooperative loops (facilitation) with the vegetation. The second one involves the introduction of engineered microorganisms improving their dispersal capacity, thus facilitating the transition from desert to fertile soil. We show that small modifications enhancing cooperative loops can effectively modify the aridity level of the critical transition found at increasing soil degradation rates, also identifying a stronger protection against soil degradation by using the D-terraformation strategy. The same results are found in a mean-field model providing insights into the transitions and dynamics tied to these terraformation strategies. The potential consequences and extensions of these models are discussed.


PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma.
Synovial sarcomas (SS) consistently show a characteristic chromosomal translocation, t(X;18)(p11;q11), which usually leads to the formation of 2 chimeric fusion transcripts, SYT-SSX1 and -SSX2. A recent multi-institutional retrospective study revealed that the SYT-SSX fusion type emerged as the only independent significant factor for overall survival in cases of SS. The aims of this study were; i). to investigate the frequency of PTEN gene alteration, ii). to evaluate whether the mutation status in various tumor suppressor genes (TSG) is responsible for the clinical and histologic heterogeneity in SS. Forty-nine cases of SS were examined for the presence of PTEN gene mutation by polymerase chain reaction - single-strand conformation polymorphism followed by DNA direct sequencing. The obtained data was combined with those of previously reported TSG mutations such as p53, adenomatous polyposis coli, and E-cadherin genes. Follow-up was available for 44 patients, and survival analysis was performed according to the mutation status of these TSG. PTEN mutations were detected in 7 cases (14.3%), and all of these were monophasic tumors. More than half of the mutations detected were located in exon 9, which has been shown to play a less important role in PTEN functioning, and the PTEN mutation was not associated with patients' prognosis. Mutations in these TSG other than silent mutations were detected in 20 out of 49 cases (40.8%), although the mutation status in TSG was not associated with overall survival rate in patients with SS. Secondary genetic alterations in these TSG seem to have a less important prognostic impact on patients with SS.


Attachment style predicts affect, cognitive appraisals, and social functioning in daily life.
The way in which attachment styles are expressed in the moment as individuals navigate their real-life settings has remained an area largely untapped by attachment research. The present study examined how adult attachment styles are expressed in daily life using experience sampling methodology (ESM) in a sample of 206 Spanish young adults. Participants were administered the Attachment Style Interview (ASI) and received personal digital assistants that signaled them randomly eight times per day for 1 week to complete questionnaires about their current experiences and social context. As hypothesized, participants' momentary affective states, cognitive appraisals, and social functioning varied in meaningful ways as a function of their attachment style. Individuals with an anxious attachment, as compared with securely attached individuals, endorsed experiences that were congruent with hyperactivating tendencies, such as higher negative affect, stress, and perceived social rejection. By contrast, individuals with an avoidant attachment, relative to individuals with a secure attachment, endorsed experiences that were consistent with deactivating tendencies, such as decreased positive states and a decreased desire to be with others when alone. Furthermore, the expression of attachment styles in social contexts was shown to be dependent upon the subjective appraisal of the closeness of social contacts, and not merely upon the presence of social interactions. The findings support the ecological validity of the ASI and the person-by-situation character of attachment theory. Moreover, they highlight the utility of ESM for investigating how the predictions derived from attachment theory play out in the natural flow of real life.


Microlenses fabricated by ultraviolet excimer laser irradiation of poly(methyl methacrylate) followed by styrene diffusion.
A new technique of microlens array fabrication based on the use of excimer laser radiation is described. Poly(methyl methacrylate) (PMMA) substrates are treated with many low-energy KrF laser pulses and exposed to styrene vapor. The irradiated material swells, producing spherical microlenses that are stabilized by UV polymerization. The chemistry of this process and the optical quality of the lenses are discussed.


Should criteria for drug dependence differ across drugs?
To examine the pros and cons of using the same diagnostic criteria for dependence across all drugs versus using dependence criteria specific to the drug of interest. A qualitative review of the similarities and differences in nicotine versus alcohol and opiate dependence is used as an example of the utility of using generic versus drug-specific criteria. Many scientists implicitly recognize that nicotine dependence is different when they do not include nicotine dependence when studying 'drug dependence'. Nicotine and alcohol/opiate dependence have many similarities (e.g. both can cause withdrawal). Among the several differences, the most important is that nicotine dependence does not cause acute behavioral impairment. Some of the generic dependence criteria do not apply to nicotine dependence (e.g. giving up activities to use the drug) and some well-validated measures of nicotine dependence (e.g. time to first cigarette) are not included in the generic criteria. Empirical tests of the relative utility of generic versus drug-specific criteria are needed.


Diagnostic Capability of Capsule Endoscopy in Small Bowel Diseases.
Capsule Endoscopy (CE) is a recently developed noninvasive technique for imaging of small bowel pathologies. It is a swallowable wireless mini-camera for getting images of the gastrointestinal (GI) mucosa. General indications of CE are obscure bleeding, iron deficiency anemia, Crohn disease, abdominal pain, polyposis coli, celiac disease and small bowel tumors. Obstruction must be excluded with small bowel radiography before using CE. Bowel preparation can be recommended for good visualization. The main indication is obscure GI bleeding. Even though useful for the other indications in selected cases, large polypoid lesions may be missed. Diagnostic capability of CE and double balloon enteroscopy (DBE) are similar and CE is a good complemantary method for DBE.


Gravid Anopheles gambiae sensu stricto avoid ovipositing in Bermuda grass hay infusion and it's volatiles in two choice egg-count bioassays.
A number of mosquito species in the Culex and Aedes genera prefer to lay eggs in Bermuda grass (Cynodon dactylon) hay infusions compared to water alone. These mosquitoes are attracted to volatile compounds from the hay infusions making the infusions effective baits in gravid traps used for monitoring vectors of arboviral and filarial pathogens. Since Bermuda grass is abundant and widespread, it is plausible to explore infusions made from it as a potential low cost bait for outdoor monitoring of the elusive malaria vector Anopheles gambiae s.s. This study investigated preferential egg laying of individual An. gambiae s.s. in hay infusion or in tap water treated with volatiles detected in hay infusion headspace compared to tap water alone, using two-choice egg-count bioassays. Infusions were prepared by mixing 90 g of dried Bermuda grass (hay) with 24 L of unchlorinated tap water in a bucket, and leaving it for 3 days at ambient temperature and humidity. The volatiles in the headspace of the hay infusion were sampled with Tenax TA traps for 20 h and analysed using gas chromatography coupled to mass spectrometry. In total, 18 volatiles were detected in the infusion headspace. Nine of the detected compounds and nonanal were selected for bioassays. Eight of the selected compounds have previously been suggested to attract/stimulate egg laying in An. gambiae s.s. Gravid females were significantly (p < 0.05) less likely to lay eggs in hay infusion dilutions of 25, 50 and 100 % and in tap water containing any of six compounds (3-methylbutanol, phenol, 4-methylphenol, nonanal, indole, and 3-methylindole) compared to tap water alone. The oviposition response to 10 % hay infusion or any one of the remaining four volatiles (4-hepten-1-ol, phenylmethanol, 2-phenylethanol, or 4-ethylphenol) did not differ from that in tap water. Anopheles gambiae s.s. prefers to lay eggs in tap water rather than Bermuda grass hay infusion. This avoidance of the hay infusion appears to be mediated by volatile organic compounds from the infusion. It is, therefore, unlikely that Bermuda grass hay infusion as formulated and used in gravid traps for Culex and Aedes mosquitoes will be suitable baits for monitoring gravid An. gambiae s.s.


Distinct functional roles of primate grasping hands and feet during arboreal quadrupedal locomotion.
It has long been thought that quadrupedal primates successfully occupy arboreal environments, in part, by relying on their grasping feet to control balance and propulsion, which frees their hands to test unstable branches and forage. If this interlimb decoupling of function is real, there should be discernible differences in forelimb versus hind limb musculoskeletal control, specifically in how manual and pedal digital flexor muscles are recruited to grasp during arboreal locomotion. New electromyography data from extrinsic flexor muscles in red ruffed lemurs (Varecia rubra) walking on a simulated arboreal substrate reveal that toe flexors are activated at relatively higher levels and for longer durations than finger flexors during stance phase. This demonstrates that the extremities of primates indeed have different functional roles during arboreal locomotion, with the feet emphasizing maintenance of secure grips. When this dichotomous muscle activity pattern between the forelimbs and hind limbs is coupled with other features of primate quadrupedal locomotion, including greater hind limb weight support and the use of diagonal-sequence footfall patterns, a complex suite of biomechanical characters emerges in primates that allow for the co-option of hands toward non-locomotor roles. Early selection for limb functional differentiation in primates probably aided the evolution of fine manipulation capabilities in the hands of bipedal humans.


Spreading of aqueous solutions of trisiloxanes and conventional surfactants over PTFE AF coated silicone wafers.
Kinetics of spreading of aqueous trisiloxane surfactant T(n) (with n = 4, 6, and 8 ethoxy groups) solutions and conventional aqueous surfactant solutions (Tween 20, C12E4, SDS) over silicon wafers coated with PTFE AF is experimentally investigated. It has been found that trisiloxane solutions spread on highly hydrophobic PTFE AF coated silicone wafers; however, they do not show superspreading behavior on these highly hydrophobic substrates. Solutions of conventional nonionic surfactants investigated show kinetics of spreading similar to trisiloxanes. Three regimes of spreading have been identified (i) complete non-wetting during the spreading process at low concentrations, (ii) a transition from initial nonwetting to partial wetting at the end of the spreading process at intermediate concentrations, and (iii) partial wetting both at the beginning and the end of the spreading process at higher concentrations. Transition from the first regime (i) to the second regime (ii) takes place at the critical aggregation concentration (CAC) or critical micelle concentration (CMC), transition from regime (ii) to regime (iii) happens at the critical wetting concentration (CWC). In the case of regime (i) the spreading of nonionic surfactants solutions investigated on PTFE AF coated silicone wafers is slow and follows a theoretically predicted law (Starov; et al. J. Colloid Interface Sci. 2000, 227 (1), 185). In the case of regimes (ii) and (iii), the spreading of the nonionic surfactant solutions investigated proceeds in two stages: the fast short first stage, which is followed by a much slower second stage. It is shown that the slow stage develops according to a previously described theoretical model. According to this theory the surfactant molecules adsorb in front of the moving three-phase contact line (autophilic phenomenon), which results in a partial hydrophilisation of an initially hydrophobic substrate and a spreading as a consequence. We assume that the first stage of the spreading is related to the disintegration of surfactant aggregates in the vicinity of the moving three-phase contact line.


Genic constraint against nonsynonymous variation across the mouse genome.
Selective constraint, the depletion of variation due to negative selection, provides insights into the functional impact of variants and disease mechanisms. However, its characterization in mice, the most commonly used mammalian model, remains limited. This study aims to quantify mouse gene constraint using a new metric called the nonsynonymous observed expected ratio (NOER) and investigate its relationship with gene function. NOER was calculated using whole-genome sequencing data from wild mouse populations (Mus musculus sp and Mus spretus). Positive correlations were observed between mouse gene constraint and the number of associated knockout phenotypes, indicating stronger constraint on pleiotropic genes. Furthermore, mouse gene constraint showed a positive correlation with the number of pathogenic variant sites in their human orthologues, supporting the relevance of mouse models in studying human disease variants. NOER provides a resource for assessing the fitness consequences of genetic variants in mouse genes and understanding the relationship between gene constraint and function. The study's findings highlight the importance of pleiotropy in selective constraint and support the utility of mouse models in investigating human disease variants. Further research with larger sample sizes can refine constraint estimates in mice and enable more comprehensive comparisons of constraint between mouse and human orthologues.


MHC-peptide tetramers for the analysis of antigen-specific T cells.
The development of the fluorescently labeled tetrameric MHC-peptide complex has enabled the direct visualization, quantification and phenotypic characterization of antigen-specific T cells using flow cytometry and has transformed our understanding of cellular immune responses. The combination of this technology with functional assays provides many new insights into these cells, allowing investigation into their lifecycle, manner of death and effector function. In this article, we hope to provide an overview of the techniques used in the construction of these tetramers, the problems and solutions associated with them, and the methods used in the study of antigen-specific T cells. Understanding how the antigen-specific cells develop and function in different circumstances and with different pathogens will be key to understanding natural host defense, as well as vaccine design and assessment.