Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials

Background Oseltamivir has been used to treat children with influenza for nearly 2 decades, with treatment currently approved for infants aged ≥2 weeks. However, efficacy and safety remain controversial. Newer randomized, placebo-controlled trials (RCTs), not included in previous meta-analyses, can add to the evidence base. Methods We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a 2-stage, random-effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RMST) by treatment group. We also examined complications and safety. Results We identified 5 trials that included 2561 patients in the intention-to-treat (ITT) and 1598 in the intention-to-treat infected (ITTI) populations. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference, -17.6 hours; 95% confidence interval [CI], -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours; 95% CI, -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group. Conclusions Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.
Brr6 and Brl1 locate to nuclear pore complex assembly sites to promote their biogenesis

The paralogous Brr6 and Brl1 are conserved integral membrane proteins of the nuclear envelope (NE) with an unclear role in nuclear pore complex (NPC) biogenesis. Here, we analyzed double-degron mutants of Brr6/Brl1 to understand this function. Depletion of Brr6 and Brl1 caused defects in NPC biogenesis, whereas the already assembled NPCs remained unaffected. This NPC biogenesis defect was not accompanied by a change in lipid composition. However, Brl1 interacted with Ndc1 and Nup188 by immunoprecipitation, and with transmembrane and outer and inner ring NPC components by split yellow fluorescent protein analysis, indicating a direct role in NPC biogenesis. Consistently, we found that Brr6 and Brl1 associated with a subpopulation of NPCs and emerging NPC assembly sites. Moreover, BRL1 overexpression affected NE morphology without a change in lipid composition and completely suppressed the nuclear pore biogenesis defect of nup116&Dgr; and gle2&Dgr; cells. We propose that Brr6 and Brl1 transiently associate with NPC assembly sites where they promote NPC biogenesis.
The interfacial character of antibody paratopes: analysis of antibody‐antigen structures

Summary: In this study, computational methods are applied to investigate the general properties of antigen engaging residues of a paratope from a non‐redundant dataset of 403 antibody‐antigen complexes to dissect the contribution of hydrogen bonds, hydrophobic, van der Waals contacts and ionic interactions, as well as role of water molecules in the antigen‐antibody interface. Consistent with previous reports using smaller datasets, we found that Tyr, Trp, Ser, Asn, Asp, Thr, Arg, Gly, His contribute substantially to the interactions between antibody and antigen. Furthermore, antibody‐antigen interactions can be mediated by interfacial waters. However, there is no reported comprehensive analysis for a large number of structured waters that engage in higher ordered structures at the antibody‐antigen interface. From our dataset, we have found the presence of interfacial waters in 242 complexes. We present evidence that suggests a compelling role of these interfacial waters in interactions of antibodies with a range of antigens differing in shape complementarity. Finally, we carry out 296 835 pairwise 3D structure comparisons of 771 structures of contact residues of antibodies with their interfacial water molecules from our dataset using CLICK method. A heuristic clustering algorithm is used to obtain unique structural similarities, and found to separate into 368 different clusters. These clusters are used to identify structural motifs of contact residues of antibodies for epitope binding. Availability and implementation: This clustering database of contact residues is freely accessible at http://mspc.bii.a‐star.edu. sg/minhn/pclick.html. Contact: minhn@bii.a‐star.edu. sg, chandra@bii.a‐star.edu. sg or zhong_pingyu@immunol.a‐star.edu. sg Supplementary information: Supplementary data are available at Bioinformatics online.
MVA.85A Boosting of BCG and an Attenuated, phoP Deficient M. tuberculosis Vaccine Both Show Protective Efficacy Against Tuberculosis in Rhesus Macaques

Background Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. Methods and Findings Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNγ responses. Antigen 85A-specific IFNγ secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNγ levels post-infection as the strongest immunocorrelate for protection (spearman's rho: −0.60). Conclusions Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.
Traits and trade-offs in whole-tree hydraulic architecture along the vertical axis of Eucalyptus grandis

Background and Aims Sapwood traits like vessel diameter and intervessel pit characteristics play key roles in maintaining hydraulic integrity of trees. Surprisingly little is known about how sapwood traits covary with tree height and how such trait-based variation could affect the efficiency of water transport in tall trees. This study presents a detailed analysis of structural and functional traits along the vertical axes of tall Eucalyptus grandis trees. Methods To assess a wide range of anatomical and physiological traits, light and electron microscopy was used, as well as field measurements of tree architecture, water use, stem water potential and leaf area distribution. Key Results Strong apical dominance of water transport resulted in increased volumetric water supply per unit leaf area with tree height. This was realized by continued narrowing (from 250 to 20 µm) and an exponential increase in frequency (from 600 to 13 000 cm-2) of vessels towards the apex. The widest vessels were detected at least 4 m above the stem base, where they were associated with the thickest intervessel pit membranes. In addition, this study established the lower limit of pit membrane thickness in tall E. grandis at ~375 nm. This minimum thickness was maintained over a large distance in the upper stem, where vessel diameters continued to narrow. Conclusions The analyses of xylem ultrastructure revealed complex, synchronized trait covariation and trade-offs with increasing height in E. grandis. Anatomical traits related to xylem vessels and those related to architecture of pit membranes were found to increase efficiency and apical dominance of water transport. This study underlines the importance of studying tree hydraulic functioning at organismal scale. Results presented here will improve understanding height-dependent structure-function patterns in tall trees.
Clinicopathological analysis of metaplastic meningioma: report of 15 cases in Huashan Hospital.

OBJECTIVE Metaplastic meningioma is a rare subtype of benign meningiomas, classified as WHO grade I with well prognosis. Here we presented our experiences on 15 cases of metaplastic meningioma, to investigate the clinicopathological features, therapies and prognosis of these cases. METHODS 15 patients underwent surgical treatment for intracranial metaplastic meningioma between 2001 and 2010 at Neurosurgery Department of Huashan Hospital, Shanghai, China. The clinical data, radiological manifestation, treatment strategy, pathological findings and prognosis of all patients were analyzed retrospectively. RESULTS Among the 15 cases (10 males and 5 females), the age ranged from 22 to 74 years old (the mean age was 50.67-year old). The clinical manifestations include headache, dizziness, seizure attack, vision decrease, and weakness of bilateral lower limbs. All the patients received surgical treatment, combined with radiotherapy in some cases. In the follow-up period, recurrence occurred in 2 cases, of which 1 patient died of other system complications. CONCLUSIONS Metaplastic meningiomas are characterized by focal or widespread mesenchymal differentiation with formation of bone, cartilage, fat, and xanthomatous tissue elements. Surgical removal is the optimal therapy, and the overall prognosis is well. But recurrence may occur in some cases, thus radiotherapy is necessary for such kind of patients.
Thickness and thermal processing contribution on piezoelectric characteristics of Pb(Zr-Ti)O3 thick films deposited on curved IN738 using sol–gel technique

Lead zirconate-titanate (PZT) thick films of perovskite structure Pb(ZrxTi1-x)O3 were fabricated on the curved surface of IN738 nickel-based supper alloy substrate up to 15 µm thickness using sol–gel deposition technique without polyvinylpyrrolidone. The films were heated at 200℃ with 10 wt% excess PbO, pyrolyzed at 400℃, and subsequently annealed at 650℃, 700℃, and 800℃. Au and Pt thin films were deposited as bottom and top electrodes, respectively. PZT films of different thicknesses and thermal treatment conditions were characterized to investigate the effect of process on crystalline phase development, orientation, and microstructure morphology. Thereby, formation of fairly smooth, semi-dense, and crack-free random orientated thick films as well as an increase in the average grain size and stress relaxation was observed as the film thickness increased. Having optimized the coating process, intrinsic and extrinsic dielectric, ferroelectric and piezoelectric properties were measured as a function of the film thickness, orientation, grain size, and domain wall motions to evaluate the remnant polarization (Pr = 7.6–17.5 µC/cm2), coercive field (Ec = 2.5–4 kV/cm), permittivity (ɛr = 276–326), dielectric loss (tanδ(%) = 2.7–3), and piezoelectric charge coefficient (d33 = 71–145 pm/V) of the PZT thick films prepared potentially to be used as high bandwidth 1–5 MHz structural health monitoring transducers.
Contribution to Malaria Transmission of Symptomatic and Asymptomatic Parasite Carriers in Cambodia

Background Eliminating falciparum malaria in Cambodia is a top priority, requiring the implementation of novel tools and strategies to interrupt its transmission. To date, few data are available regarding the contributions to malaria transmission of symptomatic and asymptomatic carriers. Methods Direct-membrane and skin feeding assays (DMFAs, SFAs) were performed, using Anopheles minimus and Anopheles dirus, to determine infectivity of symptomatic falciparum-infected patients and malaria asymptomatic carriers; a subset of the latter were followed up for 2 months to assess their transmission potential. Results By microscopy and real-time polymerase chain reaction, Plasmodium falciparum gametocyte prevalence rates were, respectively, 19.3% (n = 21/109) and 44% (n = 47/109) on day (D) 0 and 17.9% (n = 5/28) and 89.3% (n = 25/28) in recrudescent patients (Drec) (RT-PCR Drec vs D0 P = .002). Falciparum malaria patient infectivity was low on D0 (6.2%; n = 3/48) and in Drec (8.3%; n = 1/12). Direct-membrane feeding assays and SFAs gave similar results. None of the falciparum (n = 0/19) and 3 of 28 Plasmodium vivax asymptomatic carriers were infectious to mosquitoes, including those that were followed up for 2 months. Overall, P. falciparum gametocytemias were low except in a few symptomatic carriers. Conclusions Only symptomatic falciparum malaria patients were infectious to mosquito vectors at baseline and recrudescence, highlighting the need to detect promptly and treat effectively P. falciparum patients.
The Slow Dynamics of Intracellular Sodium Concentration Increase the Time Window of Neuronal Integration: A Simulation Study

Changes in intracellular Na+ concentration ([Na+]i) are rarely taken into account when neuronal activity is examined. As opposed to Ca2+, [Na+]i dynamics are strongly affected by longitudinal diffusion, and therefore they are governed by the morphological structure of the neurons, in addition to the localization of influx and efflux mechanisms. Here, we examined [Na+]i dynamics and their effects on neuronal computation in three multi-compartmental neuronal models, representing three distinct cell types: accessory olfactory bulb (AOB) mitral cells, cortical layer V pyramidal cells, and cerebellar Purkinje cells. We added [Na+]i as a state variable to these models, and allowed it to modulate the Na+ Nernst potential, the Na+-K+ pump current, and the Na+-Ca2+ exchanger rate. Our results indicate that in most cases [Na+]i dynamics are significantly slower than [Ca2+]i dynamics, and thus may exert a prolonged influence on neuronal computation in a neuronal type specific manner. We show that [Na+]i dynamics affect neuronal activity via three main processes: reduction of EPSP amplitude in repeatedly active synapses due to reduction of the Na+ Nernst potential; activity-dependent hyperpolarization due to increased activity of the Na+-K+ pump; specific tagging of active synapses by extended Ca2+ elevation, intensified by concurrent back-propagating action potentials or complex spikes. Thus, we conclude that [Na+]i dynamics should be considered whenever synaptic plasticity, extensive synaptic input, or bursting activity are examined.
Differential Roles of Lung Dendritic Cell Subsets Against Respiratory Virus Infection

Respiratory viruses can induce acute respiratory disease. Clinical symptoms and manifestations are dependent on interactions between the virus and host immune system. Dendritic cells (DCs), along with alveolar macrophages, constitute the first line of sentinel cells in the innate immune response against respiratory viral infection. DCs play an essential role in regulating the immune response by bridging innate and adaptive immunity. In the steady state, lung DCs can be subdivided into CD103+ conventional DCs (cDCs), CD11b+ cDCs, and plasmacytoid DCs (pDCs). In the inflammatory state, like a respiratory viral infection, monocyte-derived DCs (moDCs) are recruited to the lung. In inflammatory lung, discrimination between moDCs and CD11b+ DCs in the inflamed lung has been a critical challenge in understanding their role in the antiviral response. In particular, CD103+ cDCs migrate from the intraepithelial base to the draining mediastinal lymph nodes to primarily induce the CD8+ T cell response against the invading virus. Lymphoid CD8α+ cDCs, which have a developmental relationship with CD103+ cDCs, also play an important role in viral antigen presentation. Moreover, pDCs have been reported to promote an antiviral response by inducing type I interferon production rather than adaptive immunity. However, the role of these cells in respiratory infections remains unclear. These different DC subsets have functional specialization against respiratory viral infection. Under certain viral infection, contextually controlling the balance of these specialized DC subsets is important for an effective immune response and maintenance of homeostasis.
Probabilistic hindcasts and projections of the coupled climate , carbon cycle , and Atlantic meridional overturning circulation system : A Bayesian fusion of century-scale observations with a simple model

How has the Atlantic Meridional Overturning Circulation (AMOC) varied over the past centuries and what is the risk of an anthropogenic AMOC collapse? We report probabilistic projections of the future climate which improve on previous AMOC projection studies by (i) greatly expanding the considered observational constraints and (ii) carefully sampling the tail areas of the parameter probability distribution function (pdf). We use a Bayesian inversion to constrain a simple model of the coupled climate, carbon cycle, and AMOC systems using observations to derive multi-century hindcasts and projections. Our hindcasts show considerable skill in representing the observational constraints. We show that robust AMOC risk estimates can require carefully sampling the parameter pdfs. We find a low probability of experiencing an AMOC collapse within the 21st century for a business-as-usual emissions scenario. The probability of experiencing an AMOC collapse within two centuries is 1/10. The probability of crossing a forcing threshold and triggering a future AMOC collapse (by 2300) is approximately 1/30 in the 21st century and over 1/3 in the 22nd. Given the simplicity of the model structure and uncertainty in the forcing assumptions, our analysis should be considered a proof of concept and the quantitative conclusions subject to severe caveats.
A low-latency adaptive asynchronous interconnection network using bi-modal router nodes

A new bi-modal asynchronous arbitration node is introduced for use as a building block in an adaptive asynchronous interconnection network. The target network topology is a variant Mesh-of-Trees (MoT), combining a binary fan-out network (i.e. routing) and a binary fan-in network (i.e. arbitration) for each source-sink pair. The key feature of the new arbitration node is that it dynamically reconfigures based on the traffic it receives, entering a special “single-channel-bias” mode when the other channel has no recent activity. Arbitration is totally bypassed on the critical path, resulting in significantly lower node latency and, in high-traffic scenarios, improved throughput. The router nodes were implemented in IBM 90nm technology using ARM standard cells. SPICE simulations indicate that the bi-modal arbitration node provided significant reductions in latency (41.6%), and increased throughput (19.8%, in high-traffic single-channel scenarios), when in biased mode. Node reconfiguration required at most 338 ps. Simulations were then performed on two distinct MoT indirect networks, “baseline” and “adaptive” (the latter incorporating the new bi-modal node), on eight diverse synthetic benchmarks, using mixes of random and deterministic traffic. Improvements in system latency up to 19.8% and throughput up to 27.8% were obtained using the adaptive network. Overall end-to-end latencies, through 6 router nodes and 5 hops, of 1.8-2.8 ns (at 25% load) and throughputs of 0.27-1.8 Gigaflits/s (at saturation rate) were also observed.
Cognitive changes in prevalent and incident cardiovascular disease: a 12-year follow-up in the Maastricht Aging Study (MAAS).

Aims Cardiovascular disease (CVD) has been suggested to accelerate cognitive decline and to be a risk factor for dementia, but still little is known about the cognitive course after a first cardiovascular event. Therefore, the present study aims to investigate the cognitive trajectories in both prevalent and incident CVD over a 12-year time period in the general population. Methods and results Cognitively healthy participants (age 24-82 years, n = 1823) of a prospective cohort study were serially assessed at baseline, 6 and 12 years. Verbal memory, executive function, and information processing speed were analysed in adults with prevalent, incident, and no CVD. Random effects models were used to test the association between CVD and change in cognitive function over time. At baseline, participants with prevalent CVD showed more decline in memory and information processing speed than healthy controls. Participants with incident CVD also showed more decline in these cognitive domains, but this was only significant in the follow-up period from 6 to 12 years. Associations were more pronounced in participants aged younger than 65 years at baseline, and in sub-analyses with angina pectoris or myocardial infarction as the most prevalent CVD conditions. Conclusion Prevalent and incident CVD predict cognitive decline in middle-aged individuals. Findings for incident CVD suggest that the onset of decline is linked in time with the vascular event itself. Timely CVD management may delay the onset of decline.
Why Are There Social Gradients in Preventative Health Behavior? A Perspective from Behavioral Ecology

Background Within affluent populations, there are marked socioeconomic gradients in health behavior, with people of lower socioeconomic position smoking more, exercising less, having poorer diets, complying less well with therapy, using medical services less, ignoring health and safety advice more, and being less health-conscious overall, than their more affluent peers. Whilst the proximate mechanisms underlying these behavioral differences have been investigated, the ultimate causes have not. Methodology/Principal Findings This paper presents a theoretical model of why socioeconomic gradients in health behavior might be found. I conjecture that lower socioeconomic position is associated with greater exposure to extrinsic mortality risks (that is, risks that cannot be mitigated through behavior), and that health behavior competes for people's time and energy against other activities which contribute to their fitness. Under these two assumptions, the model shows that the optimal amount of health behavior to perform is indeed less for people of lower socioeconomic position. Conclusions/Significance The model predicts an exacerbatory dynamic of poverty, whereby the greater exposure of poor people to unavoidable harms engenders a disinvestment in health behavior, resulting in a final inequality in health outcomes which is greater than the initial inequality in material conditions. I discuss the assumptions of the model, and its implications for strategies for the reduction of health inequalities.