Miracle-dz/UniFAR-FTUs huggingface dataset:
Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1

Transplantation of gene-corrected autologous hepatocytes can cure metabolic disease in a preclinical pig model of hereditary tyrosinemia type 1. Skipping the waiting list The only cure for hereditary tyrosinemia type 1 (HT1)—an inherited metabolic disease—is a liver transplant. However, owing to the shortage of liver donors, Hickey et al. turned to gene therapy as a way to cure HT1. The authors took liver cells from pigs that have HT (through a defect in the gene Fah), transduced them with the correct Fah, and then put the cells back into the same animals. The ex vivo gene therapy approach prevented liver failure and fibrosis and also restored metabolic function, which is deteriorated in HT1 disease. Having demonstrated in large animals the use of materials that are safe for use in people, the technology is now poised to move into patients, to regenerate their own livers and spare them the long wait times on the liver transplant list. We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase–deficient (Fah−/−) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah−/− pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter. Pigs received autologous transplants of hepatocytes by portal vein infusion. After transplantation, the protective drug 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione (NTBC) was withheld from recipient pigs to provide a selective advantage for expansion of corrected FAH+ cells. Proliferation of transplanted cells, assessed by both immunohistochemistry and noninvasive positron emission tomography imaging of NIS-labeled cells, demonstrated near-complete liver repopulation by gene-corrected cells. Tyrosine and succinylacetone levels improved to within normal range, demonstrating complete correction of tyrosine metabolism. In addition, repopulation of the Fah−/− liver with transplanted cells inhibited the onset of severe fibrosis, a characteristic of nontransplanted Fah−/− pigs. This study demonstrates correction of disease in a pig model of metabolic liver disease by ex vivo gene therapy. To date, ex vivo gene therapy has only been successful in small animal models. We conclude that further exploration of ex vivo hepatocyte genetic correction is warranted for clinical use.
A reconfigurable fabric for accelerating large-scale datacenter services

Datacenter workloads demand high computational capabilities, flexibility, power efficiency, and low cost. It is challenging to improve all of these factors simultaneously. To advance datacenter capabilities beyond what commodity server designs can provide, we have designed and built a composable, reconfigurable fabric to accelerate portions of large-scale software services. Each instantiation of the fabric consists of a 6×8 2-D torus of high-end Stratix V FPGAs embedded into a half-rack of 48 machines. One FPGA is placed into each server, accessible through PCIe, and wired directly to other FPGAs with pairs of 10 Gb SAS cables. In this paper, we describe a medium-scale deployment of this fabric on a bed of 1,632 servers, and measure its efficacy in accelerating the Bing web search engine. We describe the requirements and architecture of the system, detail the critical engineering challenges and solutions needed to make the system robust in the presence of failures, and measure the performance, power, and resilience of the system when ranking candidate documents. Under high load, the largescale reconfigurable fabric improves the ranking throughput of each server by a factor of 95% for a fixed latency distribution-or, while maintaining equivalent throughput, reduces the tail latency by 29%.
T-Cell Responses to the DBLα-Tag, a Short Semi-Conserved Region of the Plasmodium falciparum Membrane Erythrocyte Protein 1

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant surface antigen expressed on mature forms of infected erythrocytes. It is considered an important target of naturally acquired immunity. Despite its extreme sequence heterogeneity, variants of PfEMP1 can be stratified into distinct groups. Group A PfEMP1 have been independently associated with low host immunity and severe disease in several studies and are now of potential interest as vaccine candidates. Although antigen-specific antibodies are considered the main effector mechanism in immunity to malaria, the induction of efficient and long-lasting antibody responses requires CD4+ T-cell help. To date, very little is known about CD4+ T-cell responses to PfEMP1 expressed on clinical isolates. The DBLα-tag is a small region from the DBLα-domain of PfEMP1 that can be amplified with universal primers and is accessible in clinical parasite isolates. We identified the dominant expressed PfEMP1 in 41 individual clinical parasite isolates and expressed the corresponding DBLα-tag as recombinant antigen. Individual DBLα-tags were then used to activate CD4+ T-cells from acute and convalescent blood samples in children who were infected with the respective clinical parasite isolate. Here we show that CD4+ T-cell responses to the homologous DBLα-tag were induced in almost all children during acute malaria and maintained in some for 4 months. Children infected with parasites that dominantly expressed group A-like PfEMP1 were more likely to maintain antigen-specific IFNγ-producing CD4+ T-cells than children infected with parasites dominantly expressing other PfEMP1. These results suggest that group A-like PfEMP1 may induce long-lasting effector memory T-cells that might be able to provide rapid help to variant-specific B cells. Furthermore, a number of children induced CD4+ T-cell responses to heterologous DBLα-tags, suggesting that CD4+ T-cells may recognise shared epitopes between several DBLα-tags.
Lamellipodium is a myosin-independent mechanosensor

Significance Cell physiology can be regulated by the mechanics of the extracellular environment. Here, we demonstrate that cell spreading is a mechanosensitive process regulated by weak forces generated at the cell periphery and independent of motor activity. We show that stiffness sensing depends on the kinetics of the initial adhesion bonds that are subjected to forces driven by protein polymerization. This work demonstrates how the binding kinetics of adhesion molecules are sensitively tuned to a range of forces that enable mechanosensation. The ability of adherent cells to sense changes in the mechanical properties of their extracellular environments is critical to numerous aspects of their physiology. It has been well documented that cell attachment and spreading are sensitive to substrate stiffness. Here, we demonstrate that this behavior is actually biphasic, with a transition that occurs around a Young’s modulus of ∼7 kPa. Furthermore, we demonstrate that, contrary to established assumptions, this property is independent of myosin II activity. Rather, we find that cell spreading on soft substrates is inhibited due to reduced myosin-II independent nascent adhesion formation within the lamellipodium. Cells on soft substrates display normal leading-edge protrusion activity, but these protrusions are not stabilized due to impaired adhesion assembly. Enhancing integrin–ECM affinity through addition of Mn2+ recovers nascent adhesion assembly and cell spreading on soft substrates. Using a computational model to simulate nascent adhesion assembly, we find that biophysical properties of the integrin–ECM bond are optimized to stabilize interactions above a threshold matrix stiffness that is consistent with the experimental observations. Together, these results suggest that myosin II-independent forces in the lamellipodium are responsible for mechanosensation by regulating new adhesion assembly, which, in turn, directly controls cell spreading. This myosin II-independent mechanism of substrate stiffness sensing could potentially regulate a number of other stiffness-sensitive processes.
Recruitment and establishment of the gut microbiome in arctic shorebirds

ABSTRACT Gut microbiota play a key role in host health. Mammals acquire gut microbiota during birth, but timing of gut microbial recruitment in birds is unknown. We evaluated whether precocial chicks from three species of arctic‐breeding shorebirds acquire gut microbiota before or after hatching, and then documented the rate and compositional dynamics of accumulation of gut microbiota. Contrary to earlier reports of microbial recruitment before hatching in chickens, quantitative PCR and Illumina sequence data indicated negligible microbiota in the guts of shorebird embryos before hatching. Analyses of chick feces indicated an exponential increase in bacterial abundance of guts 0‐2 days post‐hatch, followed by stabilization. Gut communities were characterized by stochastic recruitment and convergence towards a community dominated by Clostridia and Gammaproteobacteria. We conclude that guts of shorebird chicks are likely void of microbiota prior to hatch, but that stable gut microbiome establishes as early as 3 days of age, probably from environmental inocula. &NA; Graphical Abstract Figure. Shorebird embryos hatch with negligible gut microbiota, and chicks acquire a stable bacterial community within three days of hatching
Microphysiologic systems in female reproductive biology

Microphysiologic systems (MPS), including new organ-on-a-chip technologies, recapitulate tissue microenvironments by employing specially designed tissue or cell culturing techniques and microfluidic flow. Such systems are designed to incorporate physiologic factors that conventional 2D or even 3D systems cannot, such as the multicellular dynamics of a tissue–tissue interface or physical forces like fluid sheer stress. The female reproductive system is a series of interconnected organs that are necessary to produce eggs, support embryo development and female health, and impact the functioning of non-reproductive tissues throughout the body. Despite its importance, the human reproductive tract has received less attention than other organ systems, such as the liver and kidney, in terms of modeling with MPS. In this review, we discuss current gaps in the field and areas for technological advancement through the application of MPS. We explore current MPS research in female reproductive biology, including fertilization, pregnancy, and female reproductive tract diseases, with a focus on their clinical applications. Impact statement This review discusses existing microphysiologic systems technology that may be applied to study of the female reproductive tract, and those currently in development to specifically investigate gametes, fertilization, embryo development, pregnancy, and diseases of the female reproductive tract. We focus on the clinical applicability of these new technologies in fields such as assisted reproductive technologies, drug testing, disease diagnostics, and personalized medicine.
Male Mating Rate Is Constrained by Seminal Fluid Availability in Bedbugs, Cimex lectularius

Sexual selection, differences in reproductive success between individuals, continues beyond acquiring a mating partner and affects ejaculate size and composition (sperm competition). Sperm and seminal fluid have very different roles in sperm competition but both components encompass production costs for the male. Theoretical models predict that males should spend ejaculate components prudently and differently for sperm and seminal fluid but empirical evidence for independent variation of sperm number and seminal fluid volume is scarce. It is also largely unknown how sperm and seminal fluid variation affect future mating rate. In bedbugs we developed a protocol to examine the role of seminal fluids in ejaculate allocation and its effect on future male mating rate. Using age-related changes in sperm and seminal fluid volume we estimated the lowest capacity at which mating activity started. We then showed that sexually active males allocate 12% of their sperm and 19% of their seminal fluid volume per mating and predicted that males would be depleted of seminal fluid but not of sperm. We tested (and confirmed) this prediction empirically. Finally, the slightly faster replenishment of seminal fluid compared to sperm did not outweigh the faster decrease during mating. Our results suggest that male mating rate can be constrained by the availability of seminal fluids. Our protocol might be applicable to a range of other organisms. We discuss the idea that economic considerations in sexual conflict research might benefit from distinguishing between costs and benefits that are ejaculate dose-dependent and those that are frequency-dependent on the mating rate per se.
An efficient Bayesian meta-analysis approach for studying cross-phenotype genetic associations

Simultaneous analysis of genetic associations with multiple phenotypes may reveal shared genetic susceptibility across traits (pleiotropy). For a locus exhibiting overall pleiotropy, it is important to identify which specific traits underlie this association. We propose a Bayesian meta-analysis approach (termed CPBayes) that uses summary-level data across multiple phenotypes to simultaneously measure the evidence of aggregate-level pleiotropic association and estimate an optimal subset of traits associated with the risk locus. This method uses a unified Bayesian statistical framework based on a spike and slab prior. CPBayes performs a fully Bayesian analysis by employing the Markov chain Monte Carlo (MCMC) technique Gibbs sampling. It takes into account heterogeneity in the size and direction of the genetic effects across traits. It can be applied to both cohort data and separate studies of multiple traits having overlapping or non-overlapping subjects. Simulations show that CPBayes produces a substantially better accuracy in the selection of associated traits underlying a pleiotropic signal than the subset-based meta-analysis ASSET. We used CPBayes to undertake a genome-wide pleiotropic association study of 22 traits in the large Kaiser GERA cohort and detected nine independent pleiotropic loci associated with at least two phenotypes. This includes a locus at chromosomal region 1q24.2 which exhibits an association simultaneously with the risk of ve di erent diseases: Dermatophytosis, Hemorrhoids, Iron De ciency, Osteoporosis, and Peripheral Vascular Disease. The GERA cohort analysis suggests that CPBayes is more powerful than ASSET with respect to detecting independent pleiotropic variants. We provide an R-package ‘CPBayes’ implementing the proposed method.
Thermal and Thermoelastic Properties of Isotropic Composites

The results of theoretical estimates are given for several thermal and thermoelastic constants of macroscopically isotropic composite materials. The composites considered consist of random mixtures of N isotropic constituents, at least ( N — 1) of which are presumed to be distributed in a particulate fashion, with the particles roughly spherical in shape. The results are based on "self-consistent" calcula tions, details of which are given in appendices. Equations (some of which are old, but are repeated for con venience) are given for the following quantities: elastic constants, thermal expansion coefficients, heat capacities (at constant volume and constant pressure), thermal conductivity, and, finally, Gruneisen and related constants.
Hierarchical Reinforcement Learning: Approximating Optimal Discounted TSP Using Local Policies

In this work, we provide theoretical guarantees for reward decomposition in deterministic MDPs. Reward decomposition is a special case of Hierarchical Reinforcement Learning, that allows one to learn many policies in parallel and combine them into a composite solution. Our approach builds on mapping this problem into a Reward Discounted Traveling Salesman Problem, and then deriving approximate solutions for it. In particular, we focus on approximate solutions that are local, i.e., solutions that only observe information about the current state. Local policies are easy to implement and do not require substantial computational resources as they do not perform planning. While local deterministic policies, like Nearest Neighbor, are being used in practice for hierarchical reinforcement learning, we propose three stochastic policies that guarantee better performance than any deterministic policy.
Dynamics of mono‐ and dual‐species biofilm formation and interactions between Staphylococcus aureus and Gram‐negative bacteria

Microorganisms are not commonly found in the planktonic state but predominantly form dual‐ and multispecies biofilms in almost all natural environments. Bacteria in multispecies biofilms cooperate, compete or have neutral interactions according to the involved species. Here, the development of mono‐ and dual‐species biofilms formed by Staphylococcus aureus and other foodborne pathogens such as Salmonella enterica subsp. enterica serovar Enteritidis, potentially pathogenic Raoultella planticola and non‐pathogenic Escherichia coli over the course of 24, 48 and 72 h was studied. Biofilm formation was evaluated by the crystal violet assay (CV), enumeration of colony‐forming units (CFU cm−2) and visualization using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). In general, Gram‐negative bacterial species and S. aureus interacted in a competitive manner. The tested Gram‐negative bacteria grew better in mixed dual‐species biofilms than in their mono‐species biofilms as determined using the CV assay, CFU ml−2 enumeration, and CLSM and SEM visualization. In contrast, the growth of S. aureus biofilms was reduced when cultured in dual‐species biofilms. CLSM images revealed grape‐like clusters of S. aureus and monolayers of Gram‐negative bacteria in both mono‐ and dual‐species biofilms. S. aureus clusters in dual‐species biofilms were significantly smaller than clusters in S. aureus mono‐species biofilms.
Moderators and predictors of response to behavior therapy for tics in Tourette syndrome

Objective: To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders. Methods: Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9–69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression–Improvement score assessed by masked evaluators. Results: The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction. Conclusions: Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication. ClinicalTrials.gov identifiers: The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively). Classification of evidence: This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup.
Tribological behaviour of TiAlN coated carbides in dry sliding tests

Purpose: The tribological behaviour of the PVD-TiAlN-coated carbide inserts was studied in dry sliding against carbon and stainless steel and cast iron counterparts. The friction and wear effects were examined at variable sliding speeds and normal loads. Design/methodology/approach: A pin-on-disc device with round tool inserts was applied to conduct friction and wear tests in which both the friction coefficient and the linear wear of the tribo-pairs were continuously recorded versus sliding distance. The volumetric wear rate was used to compare the wear resistance of the tribo-pairs tested. Light microscopy (LOM), scanning electron microscopy (SEM) and X-ray microanalyses by EDAX were applied for observations of wear scars and wear products. Findings: Severe adhesive wear of the mating surfaces was found to be predominant mechanism in dry friction between the TiAlN coating and the AISI 304 austenitic steel. In this case the protective TiAlN layer was removed even under the lowest load and sliding speed applied. On the contrary, both TiAlN/C45 and TiAlN/ EN-GJL-300 pairs showed the mild abrasive wear mechanism with the occurrence of tribo-oxidation. For these cases the protective function of the PVD-arc TiAlN layer appeared to be sufficient. Research limitations/implications: The above findings to be transmitted to machining need confirmation in real machining conditions. However, they suggest serious limitations in use of the coatings tested. Practical implications: The results can be helpful in the tool choice for the three materials machined. Originality/value: Some specific frictional behaviours and relevant wear mechanisms observed are highlighted and quantified.