Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-ß). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS439-466 region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVSK461/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.

Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis.

Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need.

Stable Supercapacity of Binder-Free TiO2(B) Epitaxial Electrodes for All-Solid-State Nanobatteries.

Owing to its pseudocapacitive, unidimensional, rapid ion channels, TiO2(B) is a promising material for application to battery electrodes. In this study, we align these channels by epitaxially growing TiO2(B) films with the assistance of an isostructural VO2(B) template layer. In a liquid electrolyte, binder-free TiO2(B) epitaxial electrodes exhibit a supercapacity near the theoretical value of 335 mA h g-1 and an excellent charge-discharge reproducibility for ≥200 cycles, which outperform those of other TiO2(B) nanostructures. For the all-solid-state configuration employing the LiPON solid electrolyte, excellent stability persists. Our findings suggest excellent potential for miniaturizing all-solid-state nanobatteries in self-powered integrated circuits.

Multiple Functional Bonds Integrated Interphases for Long Cycle Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have garnered significant interest as one of the most promising energy suppliers for power grid energy storage. However, the poor electrode/electrolyte interfacial stability leads to continual electrolyte decomposition and transition metal dissolution, resulting in rapid performance degradation of SIBs. In this work, we propose a strategy integrating multiple functional bonds to regulate electrode/electrolyte interphase by triple-coupling of succinonitrile (SN), sodium hexafluorophosphate (NaPF6) and fluorinated ethylene carbonate (FEC). Theoretical calculation and experiment results show that the solvation structure of Na+ and ClO4- is effectively reconfigured by the solvated FEC, SN and PF6- in PC-based carbonate electrolyte. The newly developed electrolyte demonstrates increased Na+-FEC coordination, weakened interaction of Na+-PC and participation of SN and PF6- anions in solvation, resulting in the formation of a conformal interfacial layer comprising of sodium oxynitrides (NaNxOy), sodium fluoride (NaF) and phosphorus oxide compounds (NaPxOy). Consequently, a 3 Ah pouch full cell of hard carbon//NaNi1/3Fe1/3Mn1/3O2 exhibits an excellent capacity retention of 90.4% after 1000 cycles. Detailed postmortem analysis of interface chemistry is further illustrated by multiple characterization methods. This study provides a new avenue for developing electrolyte formulations with multiple functional bonds integrated interphases to significantly improve the long-term cycling stability of SIBs.

Multi-parameter distributed fiber optic sensing using double-Brillouin peak fiber in Brillouin optical time domain analysis.

In this paper, we demonstrate a multi-parameter fiber sensing system based on stimulated Brillouin scattering in a double-Brillouin peak specialty fiber with enhanced Brillouin gain response. The amplitude level of the second Brillouin gain peak, which originated from the higher-order acoustic modes, has been improved with an approximately similar amplitude level to the first Brillouin gain peak from the fundamental acoustic mode. Compared to other multi-Brillouin peak fibers presented in the literature, the proposed fiber significantly reduces the measured Brillouin frequency shift error, thus improving strain and temperature accuracies. By utilizing the sensitivity values of the strain and temperature associated with each Brillouin gain spectrum (BGS) peak, a successful discriminative measurement of strain and temperature is performed with an accuracy of ±13 µÉ›, and ±0.5 °C, respectively. The proposed double-Brillouin peak fiber appears to be a possible alternative to other multi-BGS peak fibers, for instance, large effective area fiber and dispersion compensating fibers, which are inherently accompanied by large measurement errors due to the weak Brillouin gain values originating from the higher-order acoustic modes. The demonstrated results show different strain and temperature coefficients of 47 kHz/µÉ›, 1.15 MHz/°C for peak 1 and 51 kHz/µÉ›, 1.37 MHz/°C for peak 2. Moreover, the enhanced BGS peak gains having nearly the same amplitude levels enable the discriminative measurement of strain and temperature. Such fibers in Brillouin interrogation eliminate the need for complex monitoring setups and reduce measurement errors. We recommend that for long-distance natural gas pipeline monitoring, where discriminative strain and temperature measurement is crucial, the proposed double-Brillouin peak fiber can be highly beneficial.

eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-induced Lung Fibrosis.

The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radiation exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and Nampt+/- heterozygous C57BL6 mice and nonhuman primates (NHPs, Macaca mulatta) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG1 (control) or an eNAMPT-neutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8-12 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. Nampt+/- mice and eNAMPT polyclonal antibody/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: 1) NAMPT and trichrome blue staining; 2) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGF-ß, TSP1 (thrombospondin-1), NOX4, IL-1ß, and NRF2; 3) plasma eNAMPT and IL-1ß concentrations; and 4) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.

Simultaneous interrogation of multiple cores in a shape sensor fiber with a graded index fiber micro-turnaround.

A critical limitation for optical fiber sensor technology is the complexity of the interrogators used in such measurements, which has driven continued interest in enhanced optical fibers and fiber assemblies that will simplify interrogator design. In this work, we report on a novel multicore fiber shape sensor utilizing a distal graded index (GRIN) fiber micro-turnaround. We show that four offset cores of this fiber can be interrogated simultaneously with a single high performance optical frequency domain reflectometry measurement. The GRIN turnaround is 498 µm in length and reflects signal from one offset core to an opposite core with a 2 dB roundtrip attenuation. We show that the bend sensing accuracy of our single measurement system is similar to the accuracy of sequential measurements of four individual cores. We also demonstrate fiber shape reconstruction with a single measurement over 0.55 m with 80 µm spatial resolution when the fiber is wrapped around two posts.

Fatigue Driving Detection Method Based on Combination of BP Neural Network and Time Cumulative Effect.

Fatigue driving has always received a lot of attention, but few studies have focused on the fact that human fatigue is a cumulative process over time, and there are no models available to reflect this phenomenon. Furthermore, the problem of incorrect detection due to facial expression is still not well addressed. In this article, a model based on BP neural network and time cumulative effect was proposed to solve these problems. Experimental data were used to carry out this work and validate the proposed method. Firstly, the Adaboost algorithm was applied to detect faces, and the Kalman filter algorithm was used to trace the face movement. Then, a cascade regression tree-based method was used to detect the 68 facial landmarks and an improved method combining key points and image processing was adopted to calculate the eye aspect ratio (EAR). After that, a BP neural network model was developed and trained by selecting three characteristics: the longest period of continuous eye closure, number of yawns, and percentage of eye closure time (PERCLOS), and then the detection results without and with facial expressions were discussed and analyzed. Finally, by introducing the Sigmoid function, a fatigue detection model considering the time accumulation effect was established, and the drivers' fatigue state was identified segment by segment through the recorded video. Compared with the traditional BP neural network model, the detection accuracies of the proposed model without and with facial expressions increased by 3.3% and 8.4%, respectively. The number of incorrect detections in the awake state also decreased obviously. The experimental results show that the proposed model can effectively filter out incorrect detections caused by facial expressions and truly reflect that driver fatigue is a time accumulating process.

Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.

RATIONALE: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. METHODS: Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. RESULTS: Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. CONCLUSIONS: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.

Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress.

RATIONALE: The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation. METHODS: Full-length or serially deleted MYLK luciferase reporter promoter activities were measured in human lung endothelial cells (ECs). SNP-containing non-muscle MYLK (nmMYLK) DNA fragments were generated and nmMYLK promoter binding by transcription factors (TFs) detected by protein-DNA electrophoretic mobility shift assay (EMSA). Promoter demethylation was evaluated by 5-aza-2'-deoxycytidine (5-Aza). A preclinical mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) was utilized for nmMLCK validation. RESULTS: Lung EC levels of nmMLCK were significantly increased in LPS-challenged mice and LPS, tumor necrosis factor-α (TNF-α), 18% cyclic stretch (CS) and 5-Aza each significantly up-regulated EC nmMYLK promoter activities. EC exposure to FG-4592, a prolyl hydroxylase inhibitor that increases hypoxia-inducible factor (HIF) expression, increased nmMYLK promoter activity, confirmed by HIF1α/HIF2α silencing. nmMYLK promoter deletion studies identified distal inhibitory and proximal enhancing promoter regions as well as mechanical stretch-, LPS- and TNFα-inducible regions. Insertion of ARDS-associated SNPs (rs2700408, rs11714297) significantly increased nmMYLK promoter activity via increased transcription binding (glial cells missing homolog 1 (GCM1) and intestine-specific homeobox (ISX), respectively). Finally, the MYLK rs78755744 SNP (-261G/A), residing within a nmMYLK CpG island, significantly attenuated 5-Aza-induced promoter activity. CONCLUSION: These findings indicate nmMYLK transcriptional regulation by clinically relevant inflammatory factors and ARDS-associated nmMYLK promoter variants are consistent with nmMLCK as a therapeutic target in severe inflammatory disorders.

RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression.

NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.

Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α.

We previously demonstrated involvement of NAMPT (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine NAMPT regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. NAMPT transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-ß1 [transforming growth factor-ß1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell NAMPT promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated NAMPT promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased NAMPT promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.

Ionic Liquid-Directed Nanoporous TiNb2 O7 Anodes with Superior Performance for Fast-Rechargeable Lithium-Ion Batteries.

Nanoporous TiNb2 O7 (NPTNO) material is synthesized by a sol-gel method with an ionic liquid (IL) as the nanoporous structure directing template. NPTNO exhibits a high reversible capacity of 210 mAh g-1 even at the charging rate of 50 C and an excellent cyclability of half-cell capacity retention of 74% for 1000 cycles at 5 C and LiNi0.5 Mn1.5 O4 -coupled full-cell capacity retentions of 81% and 87% for 1000 cycles at 1 C and 2 C, respectively. The studies of the 1000 cycled NPTNO electrode illustrate that the IL-directed mesoporous structure can enhance the cyclability of NPTNO cells due to the alleviation of repetitive mechanical stress and volume fluctuation induced by the repetitive Li+ insertion-extraction processes. The measured Li+ diffusion coefficients from the galvanostatic intermittent titration technique suggest that the IL-templating strategy indeed ensures the fast rechargeability of NPTNO cells based on the fast Li+ diffusion kinetics. Benefitting from the nanoporous structure, NPTNO with unhindered Li+ diffusion pathways achieves a superior rate capability in the titanium-based oxide materials and the best full-cell cyclability in the TNO materials. Therefore, the templating potential of IL is demonstrated, and the superb electrochemical performance establishes the IL-directed NPTNO as a promising anode candidate for fast-rechargeable LIBs.

Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas.

RATIONALE: Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. OBJECTIVE: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). METHODS: Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. RESULTS: Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. CONCLUSION: These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

Signatures of directional selection in a hybrid yeast population.

Meiotic recombination is a fundamental biological process that leads to crossover and gene conversion. High resolution maps of meiotic recombination have been reported in several model organisms. However, few studies have studied how rapidly selection affects the products of meiotic recombination. Here we constructed and sequenced a yeast population of 38 haploid strains derived from hybridizations of two common used strains S288c and YJM789. We identified 20 regions with strong biased allele frequency across the genome, revealing signatures of selection in a rather short period. These regions harbor ample crossovers and gene conversions, which enable us to trace how selection works on the genomic fragments after meiosis. The total length of such regions under selection accounts for 5% of the entire genome, and those regions contain many functional-related genes. In addition, recombination breaks down linkage disequilibrium to half of its maximum within 42 kb and reduces nucleotide diversity significantly in selected regions. Our study thus provides details of directional selection on the outcomes of meiotic recombination using experimental approaches, and will shed light on our understanding of the fast reshaping of population structure by selection, as well as the important roles of recombination.

Compact, high-sensitivity atomic magnetometer utilizing the light-narrowing effect and in-phase excitation.

A high-sensitivity optically pumped atomic magnetometer working in the geomagnetic range utilizing the light-narrowing effect and in-phase excitation is described. The setup is based on a simple pump-probe arrangement built around a Cs vapor cell whose active volume is 64 mm3. The transverse oscillating field is applied parallel to the probe beam to drive Zeeman resonance, and the in-phase component of the resonance signal is measured to determine the field. The sensitivity of the magnetometer is improved by pumping most atoms into the stretched state. Consequently, spin-exchange relaxation is suppressed, and a sensitivity of 0.1 pT/Hz1/2 in the range of 10 µT is achieved. This magnetometer has the advantages of large dynamic range, high performance of low-frequency stabilization, high response speed, and compact size. It can be used for many cutting-edge applications such as detection of magnetic anomalies.

Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor.

RATIONALE: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches. OBJECTIVES: To identify genetic susceptibility targets for ARDS. METHODS: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort. MEASUREMENTS AND MAIN RESULTS: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg-/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation. CONCLUSIONS: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

Ionic liquids and derived materials for lithium and sodium batteries.

The ever-growing demand for advanced energy storage devices in portable electronics, electric vehicles and large scale power grids has triggered intensive research efforts over the past decade on lithium and sodium batteries. The key to improve their electrochemical performance and enhance the service safety lies in the development of advanced electrode, electrolyte, and auxiliary materials. Ionic liquids (ILs) are liquids consisting entirely of ions near room temperature, and are characterized by many unique properties such as ultralow volatility, high ionic conductivity, good thermal stability, low flammability, a wide electrochemical window, and tunable polarity and basicity/acidity. These properties create the possibilities of designing batteries with excellent safety, high energy/power density and long-term stability, and also provide better ways to synthesize known materials. IL-derived materials, such as poly(ionic liquids), ionogels and IL-tethered nanoparticles, retain most of the characteristics of ILs while being endowed with other favourable features, and thus they have received a great deal of attention as well. This review provides a comprehensive review of the various applications of ILs and derived materials in lithium and sodium batteries including Li/Na-ion, dual-ion, Li/Na-S and Li/Na-air (O2) batteries, with a particular emphasis on recent advances in the literature. Their unique characteristics enable them to serve as advanced resources, medium, or ingredient for almost all the components of batteries, including electrodes, liquid electrolytes, solid electrolytes, artificial solid-electrolyte interphases, and current collectors. Some thoughts on the emerging challenges and opportunities are also presented in this review for further development.

Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-α-mediated Apoptosis in Human Lung Endothelial Cells.

Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular NAMPT and extracellular NAMPT (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NF-κB signaling via ligation of Toll-like receptor 4 (TLR4), further serving as a biomarker for inflammatory lung disorders such as acute respiratory distress syndrome. In contrast, intracellular NAMPT is involved in nicotinamide mononucleotide synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood. We examined the role of NAMPT in TNF-α-induced human lung endothelial cell (EC) apoptosis and demonstrated that reduced NAMPT expression (siRNA) increases EC susceptibility to TNF-α-induced apoptosis as reflected by PARP-1 cleavage and caspase-3 activation. In contrast, overexpression of NAMPT served to reduce degrees of TNF-α-induced EC apoptosis. Inhibition of nicotinamide mononucleotide synthesis by FK866 (a selective NAMPT enzymatic inhibitor) failed to alter TNF-α-induced human lung EC apoptosis, suggesting that NAMPT-dependent NAD+ generation is unlikely to be involved in regulation of TNF-α-induced EC apoptosis. We next confirmed that TNF-α-induced EC apoptosis is attributable to NAMPT secretion into the EC culture media and subsequent eNAMPT ligation of TLR4 on the EC membrane surface. Silencing of NAMPT expression, direct neutralization of secreted eNAMPT by an NAMPT-specific polyclonal antibody (preventing TLR4 ligation), or direct TLR4 antagonism all served to significantly increase EC susceptibility to TNF-α-induced EC apoptosis. Together, these studies provide novel insights into NAMPT contributions to lung inflammatory events and to novel mechanisms of EC apoptosis regulation.

Direct Determination of the Mutation Rate in the Bumblebee Reveals Evidence for Weak Recombination-Associated Mutation and an Approximate Rate Constancy in Insects.

Accurate knowledge of the mutation rate provides a base line for inferring expected rates of evolution, for testing evolutionary hypotheses and for estimation of key parameters. Advances in sequencing technology now permit direct estimates of the mutation rate from sequencing of close relatives. Within insects there have been three prior such estimates, two in nonsocial insects (Drosophila: 2.8 × 10-9 per bp per haploid genome per generation; Heliconius: 2.9 × 10-9) and one in a social species, the honeybee (3.4 × 10-9). Might the honeybee's rate be ∼20% higher because it has an exceptionally high recombination rate and recombination may be directly or indirectly mutagenic? To address this possibility, we provide a direct estimate of the mutation rate in the bumblebee (Bombus terrestris), this being a close relative of the honeybee but with a much lower recombination rate. We confirm that the crossover rate of the bumblebee is indeed much lower than honeybees (8.7 cM/Mb vs. 37 cM/Mb). Importantly, we find no significant difference in the mutation rates: we estimate for bumblebees a rate of 3.6 × 10-9 per haploid genome per generation (95% confidence intervals 2.38 × 10-9 and 5.37 × 10-9) which is just 5% higher than the estimate that of honeybees. Both genomes have approximately one new mutation per haploid genome per generation. While we find evidence for a direct coupling between recombination and mutation (also seen in honeybees), the effect is so weak as to leave almost no footprint on any between-species differences. The similarity in mutation rates suggests an approximate constancy of the mutation rate in insects.