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Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines to reveal that the vast majority (79%) of sex-biased genes are targets of transcription factors that display sex-biased expression. Further, we developed a two-step regression method that identified sex-biased expression quantitative trait loci (sb-eQTL) across the genome. In contrast to previous work, these sb-eQTL are abundant (n=10,754; FDR 5%) and reproducible (replication up to π 1 =0.56). These sb-eQTL are enriched in over 600 GWAS phenotypes, including 120 sb-eQTL associated with the female-biased autoimmune disease multiple sclerosis. Our results demonstrate widespread genetic impacts on sexual dimorphism and identify possible mechanisms and clinical targets for sex differences in diverse diseases., Competing Interests: Competing interests: Authors declare that they have no competing interests.

Carbon fiber-reinforced plastic (CFRP) is a lightweight material. The automotive industry has focused on producing a steel/CFRP hybrid part to reduce overall weight. After manufacturing, delamination can occur at the interface between the CFRP and steel owing to the hybrid part constituting dissimilar materials. However, most studies have focused only on designing the manufacturing processes for the hybrid part or evaluating the adhesive used at the interface. Therefore, it is necessary to predict the behavior of the interface after demolding the hybrid part. This study aimed to predict the interface behavior of a steel/CFRP hybrid part by considering its forming and cohesive properties. First, double cantilever beam (DCB) and end-notched flexure (ENF) tests were performed to obtain cohesive parameters, such as energy release rate of modes I and II (G I , G II ). The experimentally obtained properties were applied to the bonding area of the hybrid part. Subsequently, a forming simulation was performed to obtain the stress of the steel blank in the hybrid part. The stress distribution after forming was utilized as the initial condition for spring-back simulation. Finally, the interface behavior of the hybrid part was predicted by a spring-back simulation. The simulation was conducted using the residual stress of steel outer and the cohesive properties on the interface, without the application of any external forces. The cases of spring-back simulation were divided as delamination occurrence and attached state. The simulation results for prediction of delamination occurrence and bonding showed good agreement in both cases with experimental ones. The proposed method would contribute to expanding the manufacturing of the hybrid part by stamping and reducing the manufacturing cost by prediction of delamination occurrence.

This paper presents an optimized design approach using nonlinear dynamic analysis and finite element methods to ensure the structural integrity of square-shaped containers made from ductile cast iron for intermediate- and low-level radioactive waste packaging. Ductile cast iron, with its spherical graphite structure, effectively distributes stress throughout the material, leading to a storage capacity increase of approximately 18%. Considering the critical need for containers that maintain integrity under extreme conditions like earthquakes, the design focuses on mitigating stress concentrations at the corners of square structures. Nonlinear dynamic analyses were conducted in five drop directions: three specified by ASTM-D5276 standards and two additional directions to account for different load patterns. Fractures were observed in four out of the five scenarios. For each direction where fractures occurred, equivalent loads causing similar displacement fields were applied to linear static models, which were then used for multi-load topology optimization. Three optimized models were derived, each increasing the volume by 1.4% to 1.6% compared to the original model, and the design that best met the structural integrity requirements during drop scenarios was selected. To further enhance the optimization process, weights were assigned to different load conditions based on numerical analysis results, balancing the impact of maximum stress, average stress, and plastic deformation energy. The final model, with its increased storage capacity and enhanced structural integrity, offers a practical solution for radioactive waste management, overcoming limitations in previous designs by effectively addressing complex load conditions.

Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell-type and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of IPF and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWAS, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.

Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever Salmonella infections have remained elusive. Here, we show that S . Typhi and S . Paratyphi A can persist within human macrophages, whereas S . Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on Salmonella pathogenicity island 2 (SPI2). S . Typhi and S . Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of S . Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired T H 1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow S . Typhi and S . Paratyphi A to cause chronic infections., Importance: Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Salmonella Typhi and Salmonella Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever Salmonella serovars lack 12 specific virulence factors possessed by nontyphoidal Salmonella serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of Salmonella with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections., Competing Interests: The authors declare no conflict of interest.

This study presents a methodology to prevent the overdesign of electric dispensers for dental impression materials by analyzing the necessary load and determining the appropriate pressurization speed and drive motor capacity. We derived an equation to calculate the required torque and rotational speed of the motor based on the extrusion load and the speed of the impression material. A specialized load measurement system was developed to measure the load necessary to extrude the impression material. Through experiments and image processing, we measured the radius of curvature of the trajectory of the impression material and correlated it with the pressurization speed. Techniques such as position coordinate plotting, curve fitting, and circle fitting were employed to determine the pressurization speed that aligns with the manufacturer's recommended curvature radius. These findings led to a substantial decrease in the necessary motor torque and rotational speed compared with the current standards. This research provides a systematic approach to sizing drive motors using extrusion load and pressurization speed, aiming to reduce overdesign, power consumption, and the weight and size of the motor and battery, thereby contributing to the development of more efficient and compact dental impression material dispensers., Competing Interests: The authors declare no conflicts of interest.

The spring-in phenomenon of the composite parts can affect the assembly process. This study aims to predict the spring-in phenomenon of a carbon fiber reinforced plastic (CFRP) part. Here, we predict the spring-in of the CFRP part using a coupled analysis of the forming and cooling processes during the stamping process. First, a simulation of the entire forming process, such as the transfer of the composite laminate, gravity analysis, and forming was performed to obtain the temperature distribution of the CFRP part. Subsequently, a finite-element (FE) simulation of the cooling process was conducted to predict the spring-in phenomenon of the shaped CFRP part using the temperature data obtained in the forming simulation. Finally, a CFRP part was manufactured and compared with the results of the FE simulation.

Background and Aims: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH., Approach and Results: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress., Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair., (Copyright © 2023 American Association for the Study of Liver Diseases.)

This study examines the impacts of copper and boron in parts per million (ppm) on the microstructure and mechanical properties of spheroidal graphite cast iron (SCI). Boron's inclusion increases the ferrite content whereas copper augments the stability of pearlite. The interaction between the two significantly influences the ferrite content. Differential scanning calorimetry (DSC) analysis indicates that boron alters the enthalpy change of the α + Fe3C → γ conversion and the α → γ conversion. Scanning electron microscope (SEM) analysis confirms the locations of copper and boron. Mechanical property assessments using a universal testing machine show that the inclusion of boron and copper decreases the tensile strength and yield strength of SCI, but simultaneously enhances elongation. Additionally, in SCI production, the utilization of copper-bearing scrap and trace amounts of boron-containing scrap metal, especially in the casting of ferritic nodular cast iron, offers potential for resource recycling. This highlights the importance of resource conservation and recycling in advancing sustainable manufacturing practices. These findings provide critical insights into the effects of boron and copper on SCI's behavior, contributing to the design and development of high-performance SCI materials.

Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with interleukin-7 receptor-α gene ( IL7R ) in MS-risk. Based on evolutionary and functional arguments, we postulated that DDX39B enhances immune tolerance thereby decreasing MS risk. Consistent with such a role we show that DDX39B controls the expression of many MS susceptibility genes and important immune-related genes. Among these we identified Forkhead Box P3 ( FOXP3 ), which codes for the master transcriptional factor in CD4 + /CD25 + T regulatory cells. DDX39B knockdown led to loss of immune-regulatory and gain of immune-effector expression signatures. Splicing of FOXP3 introns, which belong to a previously unrecognized type of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance., Competing Interests: MH, CN, GS, LW, AA, VJ, XY, SW, FB, SG, DK, WF, SB No competing interests declared, GG, MG I acknowledge that I have significant ownership in Autoimmunity Biologic Solutions, Inc (Galveston, TX), which is commercializing therapies that target the IL7R pathway in autoimmune diseases. While I do not believe this represents a conflict of interest it can lead to the perception of said conflict, (© 2023, Hirano, Galarza-Muñoz et al.)

In this study, the characteristics of the SKD61 material used for the stem of an extruder were analyzed through structural analysis, tensile testing, and fatigue testing. The extruder works by pushing a cylindrical billet into a die with a stem to reduce its cross-sectional area and increase its length, and it is currently used to extrude complex and diverse shapes of products in the field of plastic deformation processes. Finite element analysis was used to determine the maximum stress on the stem, which was found to be 1152 MPa, lower than the yield strength of 1325 MPa obtained from tensile testing. Fatigue testing was conducted using the stress-life (S-N) method, considering the characteristics of the stem, and statistical fatigue testing was employed to create an S-N curve. The predicted minimum fatigue life of the stem at room temperature was 424,998 cycles at the location with the highest stress, and the fatigue life decreased with increasing temperature. Overall, this study provides useful information for predicting the fatigue life of extruder stems and improving their durability.

Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi ( S. Typhi), the cause of typhoid fever. One key defense during bacterial infection is nutritional immunity: host cells attempt to restrict bacterial replication by denying bacteria access to key nutrients or supplying toxic metabolites. Here, a cellular genome-wide association study of intracellular replication by S . Typhi in nearly a thousand cell lines from around the world-and extensive follow-up using intracellular S. Typhi transcriptomics and manipulation of magnesium availability-demonstrates that the divalent cation channel mucolipin-2 (MCOLN2 or TRPML2) restricts S. Typhi intracellular replication through magnesium deprivation. Mg 2+ currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg 2+ limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Recent advances in additive manufacturing have provided more freedom in the design of metal parts; hence, the prototyping of fluid machines featuring extremely complex geometries has been investigated extensively. The fabrication of fluid machines via additive manufacturing requires significant attention to part stability; however, studies that predict regions with a high risk of collapse are few. Therefore, a novel algorithm that can detect collapse regions precisely is proposed herein. The algorithm reflects the support span over the faceted surface via propagation and invalidates overestimated collapse regions based on the overhang angle. A heat exchanger model with an extremely complex internal space is adopted to validate the algorithm. Three samples from the model are extracted and their prototypes are fabricated via laser powder bed fusion. The results yielded by the fabricated samples and algorithm with respect to the sample domain are compared. Regions of visible collapse identified on the surface of the fabricated samples are predicted precisely by the algorithm. Thus, the supporting span reflected by the algorithm provides an extremely precise prediction of collapse.

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and a major threat to women's reproductive health in particular. This obligate intracellular pathogen resides and replicates within a cellular compartment termed an inclusion, where it is sheltered by unknown mechanisms from gamma-interferon (IFNγ)-induced cell-autonomous host immunity. Through a genetic screen, we uncovered the Chlamydia inclusion membrane protein gamma resistance determinant (GarD) as a bacterial factor protecting inclusions from cell-autonomous immunity. In IFNγ-primed human cells, inclusions formed by garD loss-of-function mutants become decorated with linear ubiquitin and are eliminated. Leveraging cellular genome-wide association data, we identified the ubiquitin E3 ligase RNF213 as a candidate anti-Chlamydia protein. We demonstrate that IFNγ-inducible RNF213 facilitates the ubiquitylation and destruction of GarD-deficient inclusions. Furthermore, we show that GarD operates as a cis-acting stealth factor barring RNF213 from targeting inclusions, thus functionally defining GarD as an RNF213 antagonist essential for chlamydial growth during IFNγ-stimulated immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The purpose of this study is to evaluate the fatigue life of an automotive engine valve spring when the micro defect is applied to a 2300 MPa-class oil-tempered wire (OT wire) with 2.5 mm of diameter as the critical flaw depth. First, the deformation of the surface flaws in the OT wire during the valve spring manufacturing processes was derived via FE analysis using the sub-modeling technique, and the residual stress of the final spring was measured and applied to the spring stress analysis model. Second, the strength of the valve spring was analyzed to examine the presence of residual stress and compare the applied stress levels by the surface flaw. Third, the influence of micro defects on the fatigue life of the spring was evaluated by applying the stress on the surface flaw derived through the spring strength analysis to the S-N curve derived through a rotary bending fatigue test with the OT wire. The flaw depth of 40 µm, which is the existing criterion for surface flaw management, does not reduce the fatigue life., (© 2022. The Author(s).)

Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology. Despite these successes, most of the heritability of infectious diseases remains to be explained. As the field advances, current limitations may be overcome by applying methodological innovations such as cellular GWA studies and phenome-wide association (PheWA) studies as well as by improving methodological rigor with more precise case definitions, deeper phenotyping, increased cohort diversity, and functional validation of candidate loci in the laboratory or human challenge studies.

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20 th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 ( ERAP1 ; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

To evaluate the dynamic characteristics at all positions of the main spindle of a machine tool, an experimental point was selected using a full factorial design, and a vibration test was conducted. Based on the measurement position, the resonant frequency was distributed from approximately 236 to 242 Hz. The approximation model was evaluated based on its resonant frequencies and dynamic stiffness using regression and interpolation methods. The accuracy of the resonant frequency demonstrated by the kriging method was approximately 89%, whereas the highest accuracy of the dynamic stiffness demonstrated by the polynomial regression method was 81%. To further verify the approximation model, its dynamic characteristics were measured and verified at additional experimental points. The maximum errors yielded by the model, in terms of the resonant frequency and dynamic stiffness, were 1.6% and 7.1%, respectively.

The multi-pass shape drawing process is mainly used in metal forming processes to manufacture long components with constant arbitrary cross-sectional shapes along their lengths. The cross-roller guide is a typical component that is manufactured by a multi-pass shape drawing process. The cross-roller guide is mostly used in optical measurement equipment where high-precision movement is required. Therefore, the dimensional accuracy of the cross-roller guide is very important since it can influence precision linear motion. However, the unfilled defects can occur in a case where the product has a complex cross-sectional shape. In this study, a new design method for an intermediate die is suggested by using an equal-radial-velocity variation method in order to reduce the unfilled defects. The proposed design method can reduce the unfilled defects by minimizing the radial velocity variation in the deformation zone of the drawing die. The intermediate die was designed by geometrical information of the final product without prior finite element (FE) analysis. The suggested method was applied to design the multi-pass shape drawing process for manufacturing the cross-roller guide. FE analysis was performed to validate the effectiveness of the proposed method in comparison to the conventional design method that uses equipotential lines in the multi-pass shape drawing process. Finally, a shape drawing experiment was performed to compare the target shape and the FE analysis with the experimental data.

The use of carbon fiber-reinforced plastics (CFRP) is markedly increasing, particularly for the manufacturing of automotive parts, to achieve better mechanical properties and a light weight. However, it is difficult to manufacture multi-material products because of the problems due to the adhesive between CFRP and steel. The prepreg compression molding (PCM) of laminated CFRP can reduce the production time and increase the flexibility of the manufacturing process. In this study, a new manufacturing process is proposed for CFRP reinforcement on a hot stamped B-pillar using PCM. A finite element (FE) simulation of the hot stamping process is conducted to predict the dimensions of the B-pillar. The feasibility of PCM manufacturing is explored by the simulation of the thermoforming of a CFRP set on a shaped B-pillar. The temperature conditions of the CFRP and B-pillar for the PCM are determined by considering the heat transfer between the CFRP and steel. Finally, the PCM of the B-pillar consisting of steel and CFRP was performed to compare with the analytical results for verification. The evaluation of the B-pillar was conducted by the observation of the cross-section for the B-pillar and interlayer by scanning electron microscopy (SEM). As a result, a steel/CFRP B-pillar assembly could be efficiently manufactured using the PCM process without an additional adhesive process.

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged single-molecule, real-time sequencing (SMRT-seq) to examine the m 6 A DNA methylome of two Salmonella enterica serovar Typhimurium strains: 14028s and a Δ metJ mutant with derepressed methionine metabolism, grown in Luria broth or medium that simulates the intracellular environment. We found that the methylome is remarkably static: >95% of adenosine bases retain their methylation status across conditions. Integration of methylation with transcriptomic data revealed limited correlation between changes in methylation and gene expression. Further, examination of the transcriptome in Δ yhdJ bacteria lacking the m 6 A methylase with the most dynamic methylation pattern in our data set revealed little evidence of YhdJ-mediated gene regulation. Curiously, despite G(m 6 A)TC motifs being particularly resistant to change across conditions, incorporating dam mutants into our analyses revealed two examples where changes in methylation and transcription may be linked across conditions. This includes the novel finding that the Δ metJ motility defect may be partially driven by hypermethylation of the chemotaxis gene tsr . Together, these data redefine the S. Typhimurium epigenome as a highly stable system that has rare but important roles in transcriptional regulation. Incorporating these lessons into future studies will be critical as we progress through the epigenomic era. IMPORTANCE While recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. We found that most DNA methylation is static in Salmonella enterica serovar Typhimurium, even when the bacteria are grown under dramatically different conditions that cause broad changes in the transcriptome. Further, even when the methylation of individual bases change, these changes generally do not correlate with changes in gene expression. Finally, we demonstrate methods by which data can be stratified in order to identify coupled changes in methylation and gene expression.

In metal product manufacturing, additive manufacturing (AM) is a method that has the advantage of fabricating complex shapes and customized production, unlike existing machining methods. However, owing to the characteristics of the AM process, anisotropy of macrostructure occurs because of various causes such as the scan direction, melting, fusion, and cooling of the powdered material. The macrostructure anisotropy is realized from the scan direction, and when a single layer is stacked in one direction, it is expressed as orthogonal anisotropy. Here, the classical lamination theory is applied to simply calculate the individual orthotropic layers by superimposing them. Through this, the authors analyzed whether the mechanical properties of the product are isotropically expressed with a periodic layer rotation strategy. To determine if the mechanical properties can be reasonably considered to be isotropic, a shock absorber mount for a vehicle was manufactured by AM. The tensile and vibration test performed on the product was compared with the finite element analysis and experimental results. As a result of the comparison, it was confirmed that the macroscopically of the product was considered isotropic as the load-displacement diagram and the fracture location coincided, as well as the natural frequency and mode shape.

Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with Chlamydia trachomatis ( C. trachomatis ), the wide range of genital and ocular disease manifestations are likely influenced by human genetic differences that regulate interactions between C. trachomatis and host cells. We leveraged this diversity in cellular responses to demonstrate the importance of variation at the Toll-like receptor 1 ( TLR1 ), TLR6 , and TLR10 locus to cytokine production in response to C. trachomatis . We determined that a single-nucleotide polymorphism (SNP) (rs1057807), located in a region that forms a loop with the TLR6 promoter, is associated with increased expression of TLR1, TLR6 , and TLR10 and secreted levels of ten C. trachomatis- induced cytokines. Production of these C. trachomatis- induced cytokines is primarily dependent on MyD88 and TLR6 based on experiments using inhibitors, blocking antibodies, RNAi, and protein overexpression. Population genetic analyses further demonstrated that the mean IL-6 response of cells from two European populations were higher than the mean response of cells from three African populations and that this difference was partially attributable to variation in rs1057807 allele frequency. In contrast, a SNP associated with a different pro-inflammatory cytokine (rs2869462 associated with the chemokine CXCL10) exhibited an opposite response, underscoring the complexity of how different genetic variants contribute to an individual's immune response. This multidisciplinary study has identified a long-range chromatin interaction and genetic variation that regulates TLR6 to broaden our understanding of how human genetic variation affects the C. trachomatis- induced immune response., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Leishmaniasis is a neglected tropical disease with diverse outcomes ranging from self-healing lesions, to progressive non-healing lesions, to metastatic spread and destruction of mucous membranes. Although resolution of cutaneous leishmaniasis is a classic example of type-1 immunity leading to self-healing lesions, an excess of type-1 related inflammation can contribute to immunopathology and metastatic spread. Leishmania genetic diversity can contribute to variation in polarization and robustness of the immune response through differences in both pathogen sensing by the host and immune evasion by the parasite. In this study, we observed a difference in parasite chemokine suppression between the Leishmania (L.) subgenus and the Viannia (V.) subgenus, which is associated with severe immune-mediated pathology such as mucocutaneous leishmaniasis. While Leishmania (L.) subgenus parasites utilize the virulence factor and metalloprotease glycoprotein-63 (gp63) to suppress the type-1 associated host chemokine CXCL10, L. (V.) panamensis did not suppress CXCL10. To understand the molecular basis for the inter-species variation in chemokine suppression, we used in silico modeling to identify a putative CXCL10-binding site on GP63. The putative CXCL10 binding site is in a region of gp63 under significant positive selection, and it varies from the L. major wild-type sequence in all gp63 alleles identified in the L. (V.) panamensis reference genome. Mutating wild-type L. (L.) major gp63 to the L. (V.) panamensis sequence at the putative binding site impaired cleavage of CXCL10 but not a non-specific protease substrate. Notably, Viannia clinical isolates confirmed that L. (V.) panamensis primarily encodes non-CXCL10-cleaving gp63 alleles. In contrast, L. (V.) braziliensis has an intermediate level of activity, consistent with this species having more equal proportions of both alleles. Our results demonstrate how parasite genetic diversity can contribute to variation in immune responses to Leishmania spp. infection that may play critical roles in the outcome of infection., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this study was to predict the adhesive behavior of steel and carbon-fiber-reinforced plastic (CFRP) hybrid parts based on the cohesive zone model (CZM). In this study, the steel sheet and CFRP were joined by epoxy resin in the CFRP prepreg during the curing process, which could generate delamination at their interface because of the springback of steel or the thermal contraction of the CFRP. First, double cantilever beam (DCB) and end-notched flexure (ENF) tests were performed to obtain various adhesion properties such as the critical energy release rate of mode I, mode II ( G I , G II ), and critical stress ( σ max ). A finite element (FE) simulation was performed to predict delamination using CZM, which was also used to describe the interfacial behavior between the steel sheet and the CFRP. Finally, a U-shape drawing test was performed for the steel/CFRP hybrid parts, and these results were compared with analytical results.

Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion. Experimental follow-up redefined ARHGEF26's role in Salmonella epithelial cell infection. Specifically, we identified complex serovar-by-host interactions whereby ARHGEF26 stimulation of S. Typhi and S. Typhimurium invasion into host cells varied in magnitude and effector-dependence based on host cell type. While ARHGEF26 regulated SopB- and SopE-mediated S. Typhi (but not S. Typhimurium) infection of HeLa cells, the largest effect of ARHGEF26 was observed with S. Typhimurium in polarized MDCK cells through a SopB- and SopE2-independent mechanism. In both cell types, knockdown of the ARHGEF26-associated protein DLG1 resulted in a similar phenotype and serovar specificity. Importantly, we show that ARHGEF26 plays a critical role in S. Typhimurium pathogenesis by contributing to bacterial burden in the enteric fever murine model, as well as inflammation in the colitis infection model. In the enteric fever model, SopB and SopE2 are required for the effects of Arhgef26 deletion on bacterial burden, and the impact of sopB and sopE2 deletion in turn required ARHGEF26. In contrast, SopB and SopE2 were not required for the impacts of Arhgef26 deletion on colitis. A role for ARHGEF26 on inflammation was also seen in cells, as knockdown reduced IL-8 production in HeLa cells. Together, these data reveal pleiotropic roles for ARHGEF26 during infection and highlight that many of the interactions that occur during infection that are thought to be well understood likely have underappreciated complexity., Competing Interests: The authors have declared that no competing interests exist.

Background: While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility., Results: Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity., Conclusions: Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14 + CD24 + macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14 + CD24 + mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Jewell, Youssef, Huang, Hauser, Fee, Rudemiller, Privratsky, Zhang, Reyes, Wang, Taylor, Gunn, Ko, Cook, Chandramohan, Crowley and Hammer.)

Recently, with the increase in awareness about a clean environment worldwide, fuel efficiency standards are being strengthened in accordance with exhaust gas regulations. In the automotive industry, various studies are ongoing on vehicle body weight reduction to improve fuel efficiency. This study aims to reduce vehicle weight by replacing the existing steel reinforcements in an automobile center pillar with a composite reinforcement. Composite materials are suitable for weight reduction because of their higher specific strength and stiffness compared to existing steel materials; however, one of the disadvantages is their high material cost. Therefore, a hybrid molding method that simultaneously performs compression and injection was proposed to reduce both process time and production cost. To replace existing steel reinforcements with composite materials, various reinforcement shapes were designed using a carbon fiber-reinforced plastic patch and glass fiber-reinforced plastic ribs. Structural analyses confirmed that, using these composite reinforcements, the same or a higher specific stiffness was achieved compared to the that of an existing center pillar using steel reinforcements. The composite reinforcements resulted in a 67.37% weight reduction compared to the steel reinforcements. In addition, a hybrid mold was designed and manufactured to implement the hybrid process.

Multi-materials of metal-polymer and metal-composite hybrid structures (MMHSs) are highly demanded in several fields including land, air and sea transportation, infrastructure construction, and healthcare. The adoption of MMHSs in transportation industries represents a pivotal opportunity to reduce the product's weight without compromising structural performance. This enables a dramatic reduction in fuel consumption for vehicles driven by internal combustion engines as well as an increase in fuel efficiency for electric vehicles. The main challenge for manufacturing MMHSs lies in the lack of robust joining solutions. Conventional joining processes, e.g., mechanical fastening and adhesive bonding involve several issues. Several emerging technologies have been developed for MMHSs' manufacturing. Different from recently published review articles where the focus is only on specific categories of joining processes, this review is aimed at providing a broader and systematic view of the emerging opportunities for hybrid thin-walled structure manufacturing. The present review paper discusses the main limitations of conventional joining processes and describes the joining mechanisms, the main differences, advantages, and limitations of new joining processes. Three reference clusters were identified: fast mechanical joining processes, thermomechanical interlocking processes, and thermomechanical joining processes. This new classification is aimed at providing a compass to better orient within the broad horizon of new joining processes for MMHSs with an outlook for future trends.

Humanity's ongoing struggle with new, re-emerging and endemic infectious diseases serves as a frequent reminder of the need to understand host-pathogen interactions. Recent advances in genomics have dramatically advanced our understanding of how genetics contributes to host resistance or susceptibility to bacterial infection. Here we discuss current trends in defining host-bacterial interactions at the genome-wide level, including screens that harness CRISPR/Cas9 genome editing, natural genetic variation, proteomics, and transcriptomics. We report on the merits, limitations, and findings of these innovative screens and discuss their complementary nature. Finally, we speculate on future innovation as we continue to progress through the postgenomic era and towards deeper mechanistic insight and clinical applications., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Residual stress may influence the mechanical behavior and durability of drawn materials. Thus, this study develops a multiple reduction die (MRD) that can reduce residual stress during the drawing process. The MRD set consists of several die tips, die cases, and lubricating equipment. All the die tips of the MRD were disposed of simultaneously. Finite element analysis of the drawing process was performed according to the reduction ratio of each die tip, and the variables in drawing process with the MRD were optimized using a deep neural network to minimize the residual stress. Experiments on the drawing process with the conventional die and MRD were performed to evaluate the residual stress and verify the effectiveness of the MRD. The results of X-ray diffraction measurements indicated that the axial and hoop residual stresses on the surface were dramatically reduced.

The multi-stage roll die forming (RDF) process is a plastic forming process that can manufacture a transmission part with a complex shape, such as a drum clutch, by using a die set with rotational rolls. However, it is difficult to satisfy dimensional accuracy because of spring-back and unfilling. The purpose of this study is to design a multi-stage RDF process for the manufacturing of a drum clutch to improve dimensional accuracy using an artificial neural network (ANN). Finite element (FE) simulation of the multi-stage RDF process is performed to predict the dimensional accuracy according to various clearances for each stage. Moreover, the ANN is used to determine the relationship between the clearance and dimensional accuracy of the drum clutch to reduce the number of FE simulation. The results of the FE simulation and ANN are used to determine the optimal clearance for each stage of the RDF process. Finally, the drum clutch is fabricated using the determined conditions. The experimental results are in good agreement with the results of FE simulation from the aspect of outer diameter, inner diameter, thickness of outer tooth, thickness of inner tooth, and face thickness of tooth.

Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by both host genetic diversity and pathogen immune evasion. Previously, we discovered a single nucleotide polymorphism (rs2869462) associated with absolute abundance of CXCL10, a pro-inflammatory T-cell chemokine. Here, we report that levels of CXCL10 change during C. trachomatis infection of cultured cells in a manner dependent on both host and pathogen. Linear modeling of cellular traits associated with CXCL10 levels identified a strong, negative correlation with bacterial burden, suggesting that C. trachomatis actively suppresses CXCL10. We identified the pathogen-encoded factor responsible for this suppression as the chlamydial protease- or proteasome-like activity factor, CPAF. Further, we applied our modeling approach to other host cytokines in response to C. trachomatis and found evidence that RANTES, another T-cell chemoattractant, is actively suppressed by Chlamydia. However, this observed suppression of RANTES is not mediated by CPAF. Overall, our results demonstrate that CPAF suppresses CXCL10 to evade the host cytokine response and that modeling of cellular infection parameters can reveal previously unrecognized facets of host-pathogen interactions.

Feasibility studies have been performed on ingots with reduced hot-top heights for the cost-effective hot forging of heavy ingots. The quality of the heavy ingots is generally affected by internal voids, which have been known to be accompanied by inclusions and segregation. To guarantee the expected mechanical performance of the forged products, these voids should be closed and eliminated during the hot open die forging process. Hence, to effectively control the internal voids, the optimum hot-top height and forging schedules need to be determined. In order to improve the utilization ratio of ingots, the ingot hot-top height needs to be minimized. To investigate the effect of the reduced hot-top height on the forged products, shaft and bar products have been manufactured via hot forging of ingots having various hot-top heights. From the operational results, the present work suggests effective forging processes to produce acceptable shaft and bar products using ingots having reduced hot tops. The mechanical properties of shop-floor products manufactured from ingots with reduced hot tops have also been measured and compared with those of conventional ingot products.

Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Clearance of intracellular pathogens, such as Leishmania ( L .) major , depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 ( gp63) . Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologs, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro , indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens., Importance: Leishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host's attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) spp. employ to suppress host chemokines: a Leishmania- encoded protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica , reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.

Mechanical properties, such as strength and stiffness, of laminated carbon fiber reinforced plastic (CFRP) are generally affected by the lay-up method. However, no precise design rules to replace steel products with CFRP have been established that satisfy these properties. Therefore, this study proposes a set of rules to design automotive parts with equivalent bending stiffness through structural analysis and genetic algorithms (GAs). First, the thickness of the CFRP product was determined by comparing the bending deformation of steel products by structural analysis. To minimize the orthotropic characteristics of CFRP, the quasi-isotropic lay-up method was implemented to determine the thickness. Next, the lay-up angle was determined using GAs. The optimized lay-up angle of the CFRP product with minimum bending deformation was determined by population generation, cross-over, mutation, and fitness evaluation. CFRP B-pillar reinforcement was fabricated using the determined conditions and the bending deformation of the single component was evaluated. Finally, the B-pillar assembled with CFRP reinforcement was investigated by the drop tower test.

Eukaryotic parasites in the genus Leishmania place approximately 350 million people per year at risk of disease. In addition to their global health significance, Leishmania spp. have served as an important model for delineating basic concepts in immunology such as T-helper cell polarization. There have been many qPCR-based assays reported for measuring parasite burden in humans and animals. However, these are largely optimized for use in clinical diagnosis and not specifically for animal models. This has led several of these assays to have suboptimal characteristics for use in animal models. For example, multi-copy number genes have been frequently used to increase sensitivity but are subject to greater plasticity within the genome and thus may confound effects of experimental manipulations in animal models. In this study, we developed a sybr-green based quantitative touchdown PCR assay for a highly conserved and single-copy putative RNA-binding protein, DRBD3. With primers that share greater than 90% sequence identity across all sequenced Leishmania spp., we demonstrate that this assay has a lower limit of detection of 100 fg of parasite DNA for Leishmania major , L. donovani , L. venezuelensis , and L. panamensis . Using C57BL6/J mice, we used this assay to monitor parasite burden over 1 month of infection with two strains of L. major (Seidman and Friedlin), and L. venezeuelensis. These characteristics rival the sensitivity of previously reported qPCR based methods of parasite quantitation while amplifying a stable, single copy gene. Use of this protocol in the future will lead to improved accuracy in animal based models and help to tease apart differences in biology of host-parasite interactions., Competing Interests: The authors declare that they have no competing interests.

Background: Sevoflurane and desflurane are widely used in balanced anaesthesia in combination with opioid analgesics. The opioid remifentanil is frequently chosen because of its extremely rapid pharmacokinetics. However, intraoperative high-dose remifentanil is associated with increased postoperative pain and rescue analgesic use owing to acute tolerance and opioid-induced hyperalgesia. This study aimed to compare intraoperative remifentanil requirements during equi-minimum alveolar concentration (MAC) sevoflurane and desflurane anaesthesia via surgical pleth index-guided remifentanil administration., Methods: Eighty-two subjects undergoing laparoscopic cholecystectomy were randomly allocated to two groups receiving either sevoflurane (n=40) or desflurane (n=42). Anaesthesia was maintained with the assigned inhaled anaesthetics and remifentanil. End-tidal anaesthetic concentration was maintained at age-corrected 1.0 MAC, and remifentanil infusion was continuously adjusted to achieve a surgical pleth index of 20-50. Mean remifentanil infusion rate, which was the primary outcome of the study, was calculated as the total infused remifentanil dose per kg body weight per minute of total operative time., Results: Mean remifentanil infusion rate [mean (standard deviation)] was significantly higher in the sevoflurane group than in the desflurane group [0.192 (0.064) vs. 0.099 (0.033) μg kg -1  min -1 ; difference, 0.093 (95% confidence interval, 0.071-0.115); P<0.001]., Conclusions: During equi-MAC anaesthesia of 1.0 MAC, sevoflurane and desflurane did not show similar intraoperative remifentanil consumption under surgical pleth index-guided opioid administration. Further studies using other monitors with different measuring mechanisms are warranted to determine the cause of this difference., Clinical Trial Registration: NCT02830243 (ClinicalTrials.gov)., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

In order to deploy virulence factors at appropriate times and locations, microbes must rapidly sense and respond to various metabolite signals. Previously, we showed a transient elevation of the methionine-derived metabolite methylthioadenosine (MTA) concentration in serum during systemic Salmonella enterica serovar Typhimurium infection. Here we explored the functional consequences of increased MTA concentrations on S Typhimurium virulence. We found that MTA, but not other related metabolites involved in polyamine synthesis and methionine salvage, reduced motility, host cell pyroptosis, and cellular invasion. Further, we developed a genetic model of increased bacterial endogenous MTA production by knocking out the master repressor of the methionine regulon, metJ Like MTA-treated S Typhimurium, the Δ metJ mutant displayed reduced motility, host cell pyroptosis, and invasion. These phenotypic effects of MTA correlated with suppression of flagellar and Salmonella pathogenicity island 1 (SPI-1) networks. S Typhimurium Δ metJ had reduced virulence in oral and intraperitoneal infection of C57BL/6J mice independently of the effects of MTA on SPI-1. Finally, Δ metJ bacteria induced a less severe inflammatory cytokine response in a mouse sepsis model. Together, these data indicate that exposure of S Typhimurium to MTA or disruption of the bacterial methionine metabolism pathway suppresses S Typhimurium virulence., (Copyright © 2018 Bourgeois et al.)

Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production. We combined H2P2 with clinical association data from patients to identify a SNP near CXCL10 as a risk factor for inflammatory bowel disease. A SNP in the transcriptional repressor ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. These data are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community., (Copyright © 2018 Elsevier Inc. All rights reserved.)