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Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

As multi-year (MY) ENSO events become increasingly frequent in the 21st century, our traditional understanding of ENSO climate impacts is no longer sufficient. This dissertation investigates global climate impacts and associated mechanisms induced by MY and single-year (SY) ENSOs using a 2,200-year CESM1 pre-industrial simulation, forced Atmospheric General Circulation Model (AGCM) experiments, and observational datasets. The study finds that the most distinct impacts produced by MY ENSO compared to SY ENSO occurred on Antarctic sea ice concentration (SIC) during austral winter and on surface air temperature (SAT) over middle-to-high latitude continents during boreal winter. Therefore, the first three chapters of the dissertation focus on these two particular regions to provide a comprehensive understanding of the distinct impacts and the teleconnection mechanisms that enable these effects. Furthermore, this dissertation study observes that the distinct climate impacts of MY ENSO extend beyond the surface to affect soil moisture variations over four specific land areas of the world. The differential soil moisture responses between MY and SY ENSO events are documented, and the associated impact mechanisms are identified in the fourth chapter of the dissertation.In the Southern Hemisphere during austral winter, MY La Niñas induce a zonal shift in the tri-polar SIC anomaly pattern typically induced by the SY La Niñas (Chapter 2). This shift arises from the unique pre-onset conditions associated with MY La Niñas that interact with the Indian Ocean and subsequently trigger atmospheric circulation modes that affect the Antarctic SIC anomaly pattern. The dissertation further explores the Antarctic SIC response to MY El Niños and finds that MY El Niño's impacts on Antarctic SIC are not symmetric to MY La Niña's impacts on Antarctic SIC (Chapter 3). The asymmetry arises from the different pre-onset conditions between the El Niño and La Niña phases of MY ENSO events, which en

Wen Jing Sun,1,2 Yu Jin Liu1 1Department of Nursing Welfare, Changchun Humanities and Sciences College, Changchun, Jilin, 130117, People’s Republic of China; 2Department of Counseling Psychology, Dongshin University, Naju-si, Jeollanam, Republic of KoreaCorrespondence: Wen Jing Sun, Department of Nursing Welfare, Changchun Humanities and Sciences College, No. 1488, Boshuo Road, Jingyue National High-Tech Industrial Development Zone, Changchun City, Jilin, 130117, People’s Republic of China, Tel +8615904405614, Email 179403066@qq.comPurpose: The aim of this study was to investigate the sleep quality as well as the influence of social support on the sleep quality of elderly people in nursing homes in northeast China, and analyze the chain-mediating role of psychological adjustment and coping styles in social support and sleep quality, thereby to provide a scientific basis for the development of effective intervention measures in this direction.Patients and Methods: This study was conducted during January–March 2023 and adopted a cluster sampling method to select 5 elderly care institutions from across the Jilin, Liaoning, and Heilongjiang provinces in Northeast China. A questionnaire survey was conducted using the Self-mate General Situation Questionnaire, Pittsburgh Sleep Quality Index, Nursing Home Adjustment Scale for the Elderly, Social Support Rating Scale, and Medical Coping Modes Questionnaire. Statistical analysis methods, including ANOVA, logistic multi-factor regression, and Pearson’s correlation were employed in SPSS 26.0, while Amos 26.0 was used to build a structural equation model to analyze the interaction path and the mediating role between the variables.Results: The sleep quality of elderly individuals in elderly care institutions was relatively low 8.43(3.456). Social support of elderly individuals in elderly care institutions affected their sleep quality through i) both psychological adjustment and face-to-face coping style (B = 0.493, P &lt

The high-resolution DEM-IMB-LBM model can accurately describe pore-scale fluid-solid interactions, but its potential for use in geotechnical engineering analysis has not been fully unleashed due to its prohibitive computational costs. To overcome this limitation, a message passing interface (MPI) parallel DEM-IMB-LBM framework is proposed aimed at enhancing computation efficiency. This framework utilises a static domain decomposition scheme, with the entire computation domain being decomposed into multiple subdomains according to predefined processors. A detailed parallel strategy is employed for both contact detection and hydrodynamic force calculation. In particular, a particle ID re-numbering scheme is proposed to handle particle transitions across sub-domain interfaces. Two benchmarks are conducted to validate the accuracy and overall performance of the proposed framework. Subsequently, the framework is applied to simulate scenarios involving multi-particle sedimentation and submarine landslides. The numerical examples effectively demonstrate the robustness and applicability of the MPI parallel DEM-IMB-LBM framework. © 2024 Institute of Rock and Soil Mechanics, Chinese Academy of Sciences

In the development of new organic crystals for nonlinear optical and terahertz (THz) applications, it is very challenging to achieve the essentially required non-centrosymmetric molecular arrangement. Moreover, the resulting crystal structure is mostly unpredictable due to highly dipolar molecular components with complex functional substituents. In this work, new organic salt crystals with top-level macroscopic optical nonlinearity by controlling the van der Waals volume (VvdW ), rather than by trial and error, are logically designed. When the VvdW of molecular ionic components varies, the corresponding crystal symmetry shows an observable trend: change from centrosymmetric to non-centrosymmetric and back to centrosymmetric. All non-centrosymmetric crystals exhibit an isomorphic P1 crystal structure with an excellent macroscopic second-order nonlinear optical response. Apart from the top-level macroscopic optical nonlinearity, new organic crystals introducing highly electronegative fluorinated substituents with strong secondary bonding ability show excellent performance in efficient and broadband THz wave generation, high crystal density, high thermal stability, and good bulk crystal growth ability.

Nucleus instance segmentation from histopathology images suffers from the extremely laborious and expert-dependent annotation of nucleus instances. As a promising solution to this task, annotation-efficient deep learning paradigms have recently attracted much research interest, such as weakly-/semi-supervised learning, generative adversarial learning, etc. In this paper, we propose to formulate annotation-efficient nucleus instance segmentation from the perspective of few-shot learning (FSL). Our work was motivated by that, with the prosperity of computational pathology, an increasing number of fully-annotated datasets are publicly accessible, and we hope to leverage these external datasets to assist nucleus instance segmentation on the target dataset which only has very limited annotation. To achieve this goal, we adopt the meta-learning based FSL paradigm, which however has to be tailored in two substantial aspects before adapting to our task. First, since the novel classes may be inconsistent with those of the external dataset, we extend the basic definition of few-shot instance segmentation (FSIS) to generalized few-shot instance segmentation (GFSIS). Second, to cope with the intrinsic challenges of nucleus segmentation, including touching between adjacent cells, cellular heterogeneity, etc., we further introduce a structural guidance mechanism into the GFSIS network, finally leading to a unified Structurally-Guided Generalized Few-Shot Instance Segmentation (SGFSIS) framework. Extensive experiments on a couple of publicly accessible datasets demonstrate that, SGFSIS can outperform other annotation-efficient learning baselines, including semi-supervised learning, simple transfer learning, etc., with comparable performance to fully supervised learning with less than 5% annotations.

Weakly supervised instance segmentation (WSIS) using only image-level labels is a challenging task due to the difficulty of aligning coarse annotations with the finer task. However, with the advancement of deep neural networks (DNNs), WSIS has garnered significant attention. Following a proposal-based paradigm, we encounter a redundant segmentation problem resulting from a single instance being represented by multiple proposals. For example, we feed a picture of a dog and proposals into the network and expect to output only one proposal containing a dog, but the network outputs multiple proposals. To address this problem, we propose a novel approach for WSIS that focuses on the online refinement of complete instances through the use of MaskIoU heads to predict the integrity scores of proposals and a Complete Instances Mining (CIM) strategy to explicitly model the redundant segmentation problem and generate refined pseudo labels. Our approach allows the network to become aware of multiple instances and complete instances, and we further improve its robustness through the incorporation of an Anti-noise strategy. Empirical evaluations on the PASCAL VOC 2012 and MS COCO datasets demonstrate that our method achieves state-of-the-art performance with a notable margin. Our implementation will be made available at https://github.com/ZechengLi19/CIM., Comment: 7 pages

Glyphosate is a non-selective herbicide. Although glyphosate is not acutely toxic, the intake of glyphosate-based herbicides has caused many accidents. Some studies have suggested that surfactants might be the cause. The purpose of this study was to compare the toxicokinetic (TK) properties of glyphosate according to different vehicles in rats. Glyphosate (1%) was dissolved in distilled water (DW), polyoxyethylene tallow amine (POEA), and Tween 20. After a single oral treatment of glyphosate (50 mg/kg), blood was collected at time intervals, and glyphosate concentrations in the target organ (liver and kidney) were determined 24 h after final blood collection. All samples were analyzed using LC-MS/MS. The TK parameters of glyphosate were similar in the DW and Tween 20 groups. However, there were significant differences in Tmax and volume of distribution (Vd) between the DW and POEA group (p < 0.05). Glyphosate was absorbed about 10 times faster in POEA group rather than DW, and exhibited a higher distribution. However, other important TK parameters of T1/2, AUC, and Cmax were not statistically different among the different vehicle groups. Although glyphosate concentration in the liver was significantly higher in the POEA group than in the DW group, there was no significant difference in the kidney. These results indicate that the toxicokinetics of glyphosate are not significantly affected by POEA. It can be concluded that POEA toxicity itself can be attributed to the acute toxicity of glyphosate-containing products.

QC 20240206

Contains fulltext : 292692.pdf (Publisher’s version ) (Open Access)

Improving the mechanical strength of ceramic solid electrolytes such as lithium phosphorus sulfide families for pressure-driven dendrite blocking as well as reducing the electronic conductivity to prevent a dendrite formation inside the electrolytes are very important to extend the lifespan of all-solid-state lithium-metal batteries. Here, we propose a low-temperature solution-precipitation process to prepare polymer-solid electrolyte composites for a highly uniform polymer distribution in the electrolyte to enhance their mechanical strength and reduce their electronic conduction. The composites with up to 12 wt % of polymer are prepared, and the composites exhibit high ionic conductivities of up to 0.3 mS/cm. Furthermore, the electrochemical stability of the electrolyte composites on Li striping/plating cycles is investigated. We confirm that the proposed solution-precipitation process makes the composite much more stable than the bare solid electrolyte and causes them to outperform similar composites from the other existing preparation methods, such as mechanical mixing and solution dispersion.

By exciting subtropical teleconnections, sea surface temperature (SST) anomalies in the North Tropical Atlantic (NTA) during boreal spring can trigger El Niño-Southern Oscillation (ENSO) events in the following boreal winter, thereby providing a precursor for ENSO predictability. However, this NTA−ENSO connection is not stationary, and it varies considerably over multidecadal timescales, which cannot be directly explained by the Atlantic multidecadal oscillation or the global warming trend. Here we show that multidecadal changes in the NTA−ENSO connection are principally controlled by multidecadal variability associated with the North Atlantic Oscillation (NAO). During the positive phase of the NAO, the amplification of the NTA impact on ENSO mainly arises from strengthening of the boreal spring mean precipitation over the equatorial Atlantic and enhancement of the persistence of NTA SST anomalies, which enhance the NTA influence by exciting stronger and more persistent subtropical teleconnections. Our findings show that multidecadal variability of the NAO is key to understanding the impacts of the NTA SST on the tropical Pacific Ocean.

Two-dimensional MXenes, exfoliated from their parental precursors-MAX phases, exhibit several outstanding properties and have achieved several accomplishments in a vast range of fields. Developing novel and high-performance MXenes has become a vital task in materials science, so estimating the possibilities for exfoliation is a topic positioned at the research frontier. Here, the likelihood of exfoliating 36 M(2)AC MAX phases was explored by using density functional theory. For MAX phases, the composition-dependent mechanical performances were investigated, highlighting evident trends, and, more essentially, improving MAX phases toughness, which can be achieved via modulating the A site. Two novel criteria were then introduced to assess the probability of exfoliating MXenes from MAX phases, having less complexity and lower computational cost than the prior studies. The excellent agreement provided by the new criteria with the reported results demonstrates that they are feasible, reliable as well as easily accessible. Furthermore, some key features that were previously suggested to be related to exfoliation are instead determined to be weakly correlated with it. We thus performed a detailed numerical analysis to locate representative and correlated features that are fundamental for the exfoliation. Our findings provide deep insight into the synthesis process and accelerate the discovery of new MXenes.

Mucin glycoproteins are essential components of the mucosal barrier, which protects the host from pathogens. Throughout evolution, bacteria have developed strategies to modulate and penetrate this barrier, and cause virulence by interacting with mucin O-glycans at the epithelial cell-surface. O-fucosylated glycan epitopes on mucins are key ligands of many bacterial lectins. Here, a chemoenzymatic synthesis strategy is described to prepare a library of fucosylated mucin core glycopeptides to enable studies of mucin-interacting and fucose-binding bacterial lectins. Glycan cores with biologically important Lewis and H-antigens were prepared decorating the peptide backbone at different sites and densities. The fucosylated mucin glycopeptides were applied in microarray binding studies to explore the importance of glycan core and peptide backbone presentation of these antigens in binding interactions with the P. aeruginosa lectin LecB and the C. difficile toxin A.

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.

Jun Ni, Liusha Zhou, Hua Wang, Jin Yu, Mengli Tong, Dongrong Yu Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine (Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University), Hangzhou, Zhejiang, 310007, People’s Republic of ChinaCorrespondence: Hua Wang, Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, No. 453 Tiyuchang Road, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 13858061992, Email wanghua932@126.comBackground: This study aims to investigate the clinical characteristics of enterococcus-associated peritonitis in patients with peritoneal dialysis (PD).Methods: In this retrospective study, patients with PD-associated enterococcal peritonitis (Group E) who were treated in our center between January 2010 and September 2020 were included. Patients with PD-associated streptococcus peritonitis (Group S) and patients with coagulase-negative staphylococcus peritonitis (Group CNS) were matched 1:1 as cohort-control groups. The clinical characteristics and prognosis of these patients were analyzed.Results: A total of 21 peritonitis episodes were noted in nine males and nine females, with an average age of 60.33± 14.79 years and an average dialysis duration of 63.56± 35.23 months. Mixed infection was observed in 7 out of 21 cases. A total of 22 strains of enterococci were identified in bacterial culture, all sensitive to vancomycin. There were significant differences in white blood cell (WBC) count and blood urea nitrogen (BUN) level among three groups on admission (p< 0.05). In all three groups, WBC count on the second and third day post-treatment was higher in Group E than in other groups (p< 0.05). The cure rate in Group E was lower than in other groups (p< 0.01). The mortality rate in Group E was slightly higher than in other groups (p> 0.05). Kaplan–Meier analysis revealed a significant difference in the cumulative survival among three groups (p< 0.05).Conclusion: En

Bin Cao,1,2,&ast; Xiaokaiti Mijiti,3,&ast; Le-Le Deng,2,4 Quan Wang,3 Jin-Jie Yu,1,2 Aiketaguli Anwaierjiang,5 Chengyu Qian,2,6 Machao Li,2 Dan-Ang Fang,2,6 Yi Jiang,2 Li-Li Zhao,2 Xiuqin Zhao,2 Kanglin Wan,2 Haican Liu,2 Guilian Li,2 Xiuqin Yuan1 1School of Public Health, University of South China, Hengyang, 421001, People’s Republic of China; 2State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People’s Republic of China; 3The Eighth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, People’s Republic of China; 4National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 5College of Xinjiang Uyghur Medicine, Hetian, 848000, People’s Republic of China; 6Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuqin Yuan; Guilian Li, Email wtjysh@126.com; liguilian@icdc.cnBackground: Ethionamide (ETH), a structural analogue of isoniazid (INH), is used for treating multidrug-resistant tuberculosis (MDR-TB). Due to the common target InhA, INH and ETH showed cross-resistance in M. tuberculosis. This study aimed to explore the INH and ETH resistant profiles and genetic mutations conferring independent INH- or ETH-resistance and INH-ETH cross-resistance in M. tuberculosis circulating in south of Xinjiang, China.Methods: From Sep 2017 to Dec 2018, 312 isolates were included using drug susceptibility testing (DST), spoligotyping, and whole genome sequencing (W

This study identifies seasonally-reversed trends in Kuroshio strength and sea surface temperatures (SSTs) within the western North Pacific (WNP) since the 1990s, specifically in the 22° N-28° N region. These trends are characterized by increases during summer and decreases during winter. The seasonally-reversed trends are a result of the asymmetric responses of the WNP to a shift towards the positive phase of the Atlantic multidecadal oscillation (AMO) around the same period. The positive AMO induces an anomalous descent over the North Pacific during summer, leading to the direct strengthening of the gyre. However, during winter, it triggers an anomalous descent over the tropical Pacific, which excites a poleward wavetrain impacting the WNP and causing gyre weakening. The associated responses of the East Asian monsoon and China Coastal Current contribute to the observed seasonally-reversed SST trends. It is noteworthy that the seasonally-reversed trends in gyre strength and SSTs are predominantly observed north of 20° N in the WNP. This limitation arises because the anomalous cyclone within the winter poleward wavetrain is located north of this latitude boundary. Specifically, the clearest trends in gyre strength are observed in the northern segment of the Kuroshio, while the manifestation of SST trends in the Taiwan Strait could potentially be attributed to the influence and enhancement of the East Asian monsoon and the China Coastal Current. Due to the limited length of observational data, statistical significance of some of the signals discussed is rather limited. A CESM1 pacemaker experiments is further conducted to confirm the asymmetric responses of the North Pacific to the AMO between the summer and winter seasons.

By exciting subtropical teleconnections, sea surface temperature (SST) anomalies in the North Tropical Atlantic (NTA) during boreal spring can trigger El Niño-Southern Oscillation (ENSO) events in the following boreal winter, thereby providing a precursor for ENSO predictability. However, this NTA-ENSO connection is not stationary, and it varies considerably over multidecadal timescales, which cannot be directly explained by the Atlantic multidecadal oscillation or the global warming trend. Here we show that multidecadal changes in the NTA-ENSO connection are principally controlled by multidecadal variability associated with the North Atlantic Oscillation (NAO). During the positive phase of the NAO, the amplification of the NTA impact on ENSO mainly arises from strengthening of the boreal spring mean precipitation over the equatorial Atlantic and enhancement of the persistence of NTA SST anomalies, which enhance the NTA influence by exciting stronger and more persistent subtropical teleconnections. Our findings show that multidecadal variability of the NAO is key to understanding the impacts of the NTA SST on the tropical Pacific Ocean.

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) serves as a highly promising antiviral drug target such as for a Remdesivir nucleotide analogue (RDV-TP or RTP). In this work, we mainly used alchemical all-atom simulations to characterize relative binding free energetics between the nucleotide analogue RTP and natural cognate substrate ATP upon initial binding and pre-catalytic insertion into the active site of SARS-CoV-2 RdRp. Natural non-cognate substrate dATP and mismatched GTP were also examined for computation control. We first identified significant differences in dynamical responses between nucleotide initial binding and subsequent insertion configurations to the open and closed active sites of the RdRp, respectively, though the RdRp protein conformational changes between the active site's open and closed states are subtle. Our alchemical simulations indicated that upon initial binding (active site open), RTP and ATP show similar binding free energies to the active sites while in the insertion state (active site closed), ATP is more stabilized (∼-2.4 kcal mol-1) than RTP in free energetics. Additional analyses show, however, that RTP is more stabilized in binding energetics than ATP, in both the insertion and initial binding states, with RTP more stabilized due to the electrostatic energy in the insertion state and due to vdW energy in the initial binding state. Hence, it appears that natural cognate ATP still excels at association stability with the RdRp active site due to that ATP maintains sufficient flexibilities e.g., in base pairing with the template, which exemplifies an entropic contribution to the cognate substrate stabilization. These findings highlight the importance of substrate flexibilities in addition to energetic stabilization in antiviral nucleotide analogue design.

Previous studies have emphasized the significance of a strong El Niño preceding La Niña (LN) in the formation of multi-year LN events due to the slow recharge-discharge ocean heat content process. However, observational analyses from 1900 to 2022 reveal that the majority (64%) of multi-year LN events did not necessitate a preceding strong El Niño to generate their second LN, suggesting an overemphasis on traditional views. Instead, here we show that a negative phase of the North Pacific Meridional Mode (PMM) during spring, when the first LN begins to decay, activates the mechanism responsible for triggering another LN and producing a multi-year event. The westward extension of the first LNs cold anomalies, which interact directly with the eastern edge of the western Pacific warm pool, is highlighted as a crucial factor in the occurrence of a negative PMM. Additionally, the PMM mechanism can create a third LN, leading to triple-dip events.

Using panel data for the years 2013, 2015, and 2017 collected through field surveys in eight counties in the North China Plain, we examine the relationship between smallholders’ land rental behavior and their (agricultural) incomes, with a particular focus on heterogeneous specialization among smallholders. We find that farming-specialized households experience a significant higher increase in agricultural income and a larger decrease in poverty incidence by renting in land than nonspecialized households. Off-farm specialized households had a decreased likelihood of being poor by renting out land, whereas nonspecialized households experienced no decrease in poverty incidence after renting out land.

Meng Cai,1,&ast; Jie Liu,2,&ast; Xiao-Feng Lei,1 Yun-Long Li,3 Jin Yu1 1Department of Anesthesiology, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China; 2Department of Respiratory, The Affiliated Banan Hospital of Chongqing Medical University, People’s Hospital of Chongqing Banan District, Chongqing, People’s Republic of China; 3Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin Yu, Department of Anesthesiology, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, No. 120, Longshan Road, Yubei District, Chongqing, 401147, People’s Republic of China, Tel +86-18623117820, Fax +86-23-63702844, Email dodoes@qq.comBackground: Intravenous labor analgesia is recommended as an alternative for parturients who have contraindications to epidural analgesia. There are several opioid analgesics and different administering regimens used in the clinic. This study aimed to compare the effectiveness and safety of two intravenous remifentanil dosage regimens in the first labor stage.Patients and Methods: One hundred and fifteen parturients with a contraindication to epidural analgesia but were willing to receive systemic labor analgesia were randomized into group A received a fixed dose of remifentanil throughout the first stage of labor, and group B received an elevated dose of remifentanil during the active phase of the first stage both by patient-controlled analgesia (PCA). Maternal numerical rating scale (NRS) pain score and oxygen desaturation, sedation efficacy, satisfaction, as well as maternal and fetal adverse reactions were recorded and compared.Results: The mean NRS pain scores before an

In the recent literature, energy efficiency got the attention of scholars due to its discouraging impact on CO2 emissions, which is considered the most prevalent greenhouse gas that human activities produce. Data reports that China is the leading CO2 emitting country across the globe, and still the environmental degradation is in progress. Thus, the current paper empirically investigates the impact of energy efficiency (ENEF), financial inclusion (FD), GDP, export diversification (EXD), and human capital index (HCI) on the environmental degradation of China over the period from 1988 to 2018. This study uses various time-series tests to empirically investigate the determinant of CO2 emissions, including normality tests, unit root tests, and combined cointegration tests. Besides, the long-run coefficients are analyzed via the fully modified ordinary least square (FMOLS), dynamic OLS (DOLS), and the Canonical Cointegrating Regression (CCR) estimators. The empirical findings reveal that all the variables are cointegrated in the long run. However, the coefficient estimate shows that ENEF and HCI significantly promote environmental sustainability. While GDP, FD, and EXD significantly promote environmental degradation by enhancing the CO2 level in the atmosphere. This study recommends practical policy implications based on the empirical findings: energy-efficient products and energy sources could be promoted.

Magnetic hot stars refer to the stars, which effective temperatures approximately in the range from 7,000 to 50,000 K, and with large-scale globally organized magnetic fields. These magnetic fields exhibit strengths ranging from tens of Gauss to tens of kilo-Gauss. They are key in understanding the effects caused by magnetic fields in the stellar evolution. However, there are only three magnetic hot stars studied via a combination of spectropolarimetric and asteroseismic modeling. Combined with $Transiting\;Exoplanet\;Survey\;Satellite\;(TESS)$ 1-56 sectors data sets, we provided a photometric variability and stochastic low frequency (SLF) variability study of 118 magnetic hot stars. 9 new rotating variable stars are identified. Using the Bayesian Markov Chain Monte Carlo (MCMC) framework, we fitted the morphologies of SLF variability for magnetic hot stars. Our analysis reveals that the magnetic hot stars in our sample have $\gamma < 5.5$ with the vast majority having $1 \leq \gamma \leq 3$. The $\nu_{\rm char}$ is primarily in the ranges of $0\;\text{d}^{-1} < \nu_{\rm char} < 6.3\;\text{d}^{-1}$. The amplitude of SLF variability, log$\alpha_{\rm 0}$, shows a dominant distribution ranging from 0.8 to 3. No significant correlations are observed between the luminosity and fitting parameters, suggesting no clear dependence of SLF variability on stellar mass for our sample of magnetic hot stars with masses between approximately $1.5 M_{\odot}< M < 20 M_{\odot}$. We found a significant negative correlation between the $B_{\rm p}$ and $\nu_{char}$. This suppression effect of magnetic fields on $\nu_{\rm char}$ may be a result of their inhibition of macroturbulence., Comment: 46 pages, 25 figures, Accepted by ApJ

Despite the success of deep neural network (DNN) on sequential data (i.e., scene text and speech) recognition, it suffers from the over-confidence problem mainly due to overfitting in training with the cross-entropy loss, which may make the decision-making less reliable. Confidence calibration has been recently proposed as one effective solution to this problem. Nevertheless, the majority of existing confidence calibration methods aims at non-sequential data, which is limited if directly applied to sequential data since the intrinsic contextual dependency in sequences or the class-specific statistical prior is seldom exploited. To the end, we propose a Context-Aware Selective Label Smoothing (CASLS) method for calibrating sequential data. The proposed CASLS fully leverages the contextual dependency in sequences to construct confusion matrices of contextual prediction statistics over different classes. Class-specific error rates are then used to adjust the weights of smoothing strength in order to achieve adaptive calibration. Experimental results on sequence recognition tasks, including scene text recognition and speech recognition, demonstrate that our method can achieve the state-of-the-art performance.

Meng Cai,1 Hao Liu,2 Yong Peng,2 Jing-Kun Miao,2 Xiao-Feng Lei,1 Jin Yu1 1Department of Anesthesiology, Chongqing Health Center for Women and Children, Women and Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Pediatrics, Chongqing Health Center for Women and Children, Women and Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Jin Yu, Department of Anesthesiology, Chongqing Health Center for Women and Children, Women and Children’s Hospital of Chongqing Medical University, No. 120, Longshan Road, Yubei District, Chongqing, 401147, People’s Republic of China, Tel +86-18623117820, Email dodoes@qq.comObjective: Remifentanil, in combination with etomidate and sevoflurane, is commonly used in clinics for general anesthesia induction in cesarean section (CS). This study aimed to evaluate the correlation between the induction to delivery (I-D) time and neonatal plasma drug concentration and anesthesia, as well as its effects on neonates.Methods: Fifty-two parturients in whom general anesthesia was induced for CS were divided into group A (I-D< 8 min) and group B (I-D≥ 8 min). Maternal arterial (MA), umbilical venous (UV), and umbilical arterial (UA) blood samples were collected at delivery to analyze the remifentanil and etomidate concentrations using liquid chromatography-tandem mass spectrometry.Results: There were no statistically significant differences between the two groups in terms of plasma concentrations of remifentanil in the MA, UA, and UV blood (P > 0.05). The plasma concentration of etomidate in MA and UV was higher in group A than that in group B (P< 0.05), whereas the UA/UV ratio of etomidate was higher in group B than that in group A (P< 0.05). The Spearman rank correlation test showed no correlation between the I-D time and plasma remifentanil concentration in the MA, UA, and UV plasma (P> 0.05). The concentration

RGB-T tracking involves the use of images from both visible and thermal modalities. The primary objective is to adaptively leverage the relatively dominant modality in varying conditions to achieve more robust tracking compared to single-modality tracking. An RGB-T tracker based on mixed attention mechanism to achieve complementary fusion of modalities (referred to as MACFT) is proposed in this paper. In the feature extraction stage, we utilize different transformer backbone branches to extract specific and shared information from different modalities. By performing mixed attention operations in the backbone to enable information interaction and self-enhancement between the template and search images, it constructs a robust feature representation that better understands the high-level semantic features of the target. Then, in the feature fusion stage, a modality-adaptive fusion is achieved through a mixed attention-based modality fusion network, which suppresses the low-quality modality noise while enhancing the information of the dominant modality. Evaluation on multiple RGB-T public datasets demonstrates that our proposed tracker outperforms other RGB-T trackers on general evaluation metrics while also being able to adapt to longterm tracking scenarios., Comment: 14 pages, 10 figures

We present GrooveMeter, a novel system that automatically detects vocal and motion reactions to music via earable sensing and supports music engagement-aware applications. To this end, we use smart earbuds as sensing devices, which are already widely used for music listening, and devise reaction detection techniques by leveraging an inertial measurement unit (IMU) and a microphone on earbuds. To explore reactions in daily music-listening situations, we collect the first kind of dataset, MusicReactionSet, containing 926-minute-long IMU and audio data with 30 participants. With the dataset, we discover a set of unique challenges in detecting music listening reactions accurately and robustly using audio and motion sensing. We devise sophisticated processing pipelines to make reaction detection accurate and efficient. We present a comprehensive evaluation to examine the performance of reaction detection and system cost. It shows that GrooveMeter achieves the macro F1 scores of 0.89 for vocal reaction and 0.81 for motion reaction with leave-one-subject-out cross-validation. More importantly, GrooveMeter shows higher accuracy and robustness compared to alternative methods. We also show that our filtering approach reduces 50% or more of the energy overhead. Finally, we demonstrate the potential use cases through a case study.

Bridge detection in remote sensing images (RSIs) plays a crucial role in various applications, but it poses unique challenges compared to the detection of other objects. In RSIs, bridges exhibit considerable variations in terms of their spatial scales and aspect ratios. Therefore, to ensure the visibility and integrity of bridges, it is essential to perform holistic bridge detection in large-size very-high-resolution (VHR) RSIs. However, the lack of datasets with large-size VHR RSIs limits the deep learning algorithms' performance on bridge detection. Due to the limitation of GPU memory in tackling large-size images, deep learning-based object detection methods commonly adopt the cropping strategy, which inevitably results in label fragmentation and discontinuous prediction. To ameliorate the scarcity of datasets, this paper proposes a large-scale dataset named GLH-Bridge comprising 6,000 VHR RSIs sampled from diverse geographic locations across the globe. These images encompass a wide range of sizes, varying from 2,048*2,048 to 16,38*16,384 pixels, and collectively feature 59,737 bridges. Furthermore, we present an efficient network for holistic bridge detection (HBD-Net) in large-size RSIs. The HBD-Net presents a separate detector-based feature fusion (SDFF) architecture and is optimized via a shape-sensitive sample re-weighting (SSRW) strategy. Based on the proposed GLH-Bridge dataset, we establish a bridge detection benchmark including the OBB and HBB tasks, and validate the effectiveness of the proposed HBD-Net. Additionally, cross-dataset generalization experiments on two publicly available datasets illustrate the strong generalization capability of the GLH-Bridge dataset., Comment: 16 pages, 11 figures, 6 tables; due to the limitation "The abstract field cannot be longer than 1,920 characters", the abstract appearing here is slightly shorter than that in the PDF file

ObjectiveIn this review, we provide examples of applications of fluorescence imaging in urologic, gynecologic, general, and endocrine surgeries.BackgroundWhile robotic-assisted surgery has helped increase the availability of minimally invasive procedures across surgical specialties, there remains an opportunity to reduce adverse events associated with open, laparoscopic, and robotic-assisted methods. In 2011, fluorescence imaging was introduced as an option to the da Vinci Surgical System, and has been standard equipment since 2014. Without interfering with surgical workflow, this fluorescence technology named Firefly® allows for acquisition and display of near-infrared fluorescent signals that are co-registered with white light endoscopic images. As a result, robotic surgeons of all specialties have been able to explore the clinical utility of fluorescence guided surgery.MethodsLiterature searches were performed using the PubMed and MEDLINE databases using the keywords "robotic-assisted fluorescence surgery", "ICG robotic surgery", and "fluorescence guided surgery" covering the years 2011-2020.ConclusionsReal-time intraoperative fluorescence guidance has shown great potential in helping guide surgeons in both simple and complex surgical interventions. Indocyanine green is one of the most widely-used imaging agents in fluorescence guided surgery, and other targeted, near-infrared imaging agents are in various stages of development. Fluorescence is becoming a reliable tool that can help surgeons in their decision-making process in some specialties, while explorations continue in others.

A method designed to facilitate prediction of mechanism and products by developing critical thinking skills and reducing memorization is presented. The mechanistic disc method requiring students to utilize their understanding of charge stabilization, structural organic chemistry, and the fundamental mechanisms of aliphatic substitution and elimination to logically develop a predictive model is demonstrated.

The RecQ family of helicases are important for maintenance of genomic integrity. Although functions of constructive subdomains of this family of helicases have been extensively studied, the helical hairpin (HH) in the RecQ-C-terminal domain (RQC) has been underappreciated and remains poorly understood. Here by using single-molecule fluorescence resonance energy transfer, we found that HH in the human BLM transiently intercepts different numbers of nucleotides when it is unwinding a double-stranded DNA. Single-site mutations in HH that disrupt hydrogen bonds and/or salt bridges between DNA and HH change the DNA binding conformations and the unwinding features significantly. Our results, together with recent clinical tests that correlate single-site mutations in HH of human BLM with the phenotype of cancer-predisposing syndrome or Bloom's syndrome, implicate pivotal roles of HH in BLM's DNA unwinding activity. Similar mechanisms might also apply to other RecQ family helicases, calling for more attention to the RQC helical hairpin.

DNA supercoils are generated in genome regulation processes such as transcription and replication and provide mechanical feedback to such processes. Under tension, a DNA supercoil can present a coexistence state of plectonemic and stretched phases. Experiments have revealed the dynamic behaviors of plectonemes, e.g., diffusion, nucleation, and hopping. To represent these dynamics with conformational changes, we demonstrated first the fast dynamics on the DNA to reach torque equilibrium within the plectonemic and stretched phases, and then identified the two-phase boundaries as collective slow variables to describe the essential dynamics. According to the timescale separation demonstrated here, we developed a two-phase model on the dynamics of DNA supercoiling, which can capture physiologically relevant events across timescales of several orders of magnitudes. In this model, we systematically characterized the slow dynamics between the two phases and compared the numerical results with those from the DNA polymer physics-based worm-like chain model. The supercoiling dynamics, including the nucleation, diffusion, and hopping of plectonemes, have been well represented and reproduced, using the two-phase dynamic model, at trivial computational costs. Our current developments, therefore, can be implemented to explore multiscale physical mechanisms of the DNA supercoiling-dependent physiological processes.

One-dimensional (1-D) sliding of transcription factor (TF) protein along DNA is essential for facilitated diffusion of the TF to locate target DNA site for genetic regulation. Detecting base-pair (bp) resolution of the TF sliding or stepping on the DNA is still experimentally challenging. We have recently performed all-atom molecular dynamics (MD) simulations capturing spontaneous 1-bp stepping of a small WRKY domain TF protein along DNA. Based on the 10 µs WRKY stepping path obtained from such simulations, the protocol here shows how to conduct more extensive conformational samplings of the TF-DNA systems, by constructing the Markov state model (MSM) for the 1-bp protein stepping, with various numbers of micro- and macro-states tested for the MSM construction. In order to examine processive 1-D diffusional search of the TF protein along DNA with structural basis, the protocol further shows how to conduct coarse-grained (CG) MD simulations to sample long-time scale dynamics of the system. Such CG modeling and simulations are particularly useful to reveal the protein-DNA electrostatic impacts on the processive diffusional motions of the TF protein above tens of microseconds, in comparison with sub-microseconds to microseconds protein stepping motions revealed from the all-atom simulations.

The Indian and Pacific Oceans surround the Maritime Continent (MC). Major modes of sea surface temperature variability in both oceans, including the Indian Ocean Dipole (IOD) and El Niño-Southern Oscillation (ENSO), can strongly affect precipitation on the MC. The prevalence of fires in the MC is closely associated with precipitation amount and terrestrial water storage in September and October. Precipitation and terrestrial water storage, which is a measurement of hydrological drought conditions, are significantly modulated by Indian Ocean Dipole (IOD) and El Niño events. We utilize long-term datasets to study the combined effects of ENSO and the IOD on MC precipitation during the past 100 years (1900-2019) and find that the reductions in MC precipitation and terrestrial water storage are more pronounced during years when El Niño and a positive phase of the IOD (pIOD) coincided. The combined negative effects are produced mainly through an enhanced reduction of upward motion over the MC. Coincident El Niño-pIOD events have occurred more frequently after 1965. However, climate models do not project a higher occurrence of coincident El Niño-pIOD events in a severely warming condition, implying that not the global warming but the natural variability might be the leading cause of this phenomenon.

Multi-year El Niño events induce severe and persistent floods and droughts worldwide, with significant socioeconomic impacts, but the causes of their long-lasting behaviors are still not fully understood. Here we present a two-way feedback mechanism between the tropics and extratropics to argue that extratropical atmospheric variability associated with the North Pacific Oscillation (NPO) is a key source of multi-year El Niño events. The NPO during boreal winter can trigger a Central Pacific El Niño during the subsequent winter, which excites atmospheric teleconnections to the extratropics that re-energize the NPO variability, then re-triggers another El Niño event in the following winter, finally resulting in persistent El Niño-like states. Model experiments, with the NPO forcing assimilated to constrain atmospheric circulation, reproduce the observed connection between NPO forcing and the occurrence of multi-year El Niño events. Future projections of Coupled Model Intercomparison Project phases 5 and 6 models demonstrate that with enhanced NPO variability under future anthropogenic forcing, more frequent multi-year El Niño events should be expected. We conclude that properly accounting for the effects of the NPO on the evolution of El Niño events may improve multi-year El Niño prediction and projection.

The emergence of MAX borides as well as MAB phases attracted great attention because of the renewable developments of ternary ceramics and offering great opportunities in potential applications. However, the number of borides remains limited, and further fundamental descriptions and detailed investigations on various properties are still lacking. In this report, we employ an integrated computational scheme that combines density functional theory with the evolutional algorithm to search for the favorable structures of P- and S-glued ternary borides terminated by Nb metal. We discover that the structures of 212-type, as e.g. Nb2PB2 and Nb2SB2, belong to the P‾6m2 space group, while those of 211-type, as e.g. Nb2PB and Nb2SB, prefer to crystallize in the P63/mmc space group, and the corresponding carbides Nb2PC and Nb2SC are also considered for the sake of completeness and comparative analsys. The predicted Nb2PB2, Nb2PB, Nb2SB, Nb2PC and Nb2SC are energetically stable, as revealed by the negative formation energies and by the proposed reaction paths with respect to the most competing phases, as well as dynamically stable, as suggested by the non-imaginary phonon spectra. The thermal conductivities of the six materials show unusual behaviors, particularly for the acoustic and optical contributions, and are accompanied by a strong anisotropy. Most importantly, Nb2PB2 is found to be an excellent thermal conductor with a total thermal conductivity of ~65 W/(m K), while Nb2SC is found to be an ultra-low thermal conductor, with a total thermal conductivity of ~5 W/(m K). These values are clearly outside the currently reported range of thermal conductivities, which makes Nb2PB2 and Nb2SC extremely interesting for fundamental research as well as prospective applications with the aid of artificial tunings on the almost independent MB block and the A layer. The discovery of these novel materials is expected to contribute substantially to the rapid development of ternary ceramic

Picosecond optical and X-ray absorption spectroscopies with time- dependent density functional theory revealed the reaction pathways, electronic and structural conformations of Ir–Co hydrogen evolution photocatalysts. The dyad bearing 2-phenylpyridine ancillary ligands produced more photoreduced Co(II) than its 2-phenylisoquinoline analogue. These findings are important for designs of earth- abundant photosensitizers for photocatalytic applications.

DNA glycosylase, as one member of DNA repair machineries, plays an essential role in correcting mismatched/damaged DNA nucleotides by cleaving the N-glycosidic bond between the sugar and target nucleobase through the base excision repair (BER) pathways. Efficient corrections of these DNA lesions are critical for maintaining genome integrity and preventing premature aging and cancers. The target-site searching/recognition mechanisms and the subsequent conformational dynamics of DNA glycosylase, however, remain challenging to be characterized using experimental techniques. In this review, we summarize our recent studies of sequential structural changes of thymine DNA glycosylase (TDG) during the DNA repair process, achieved mostly by molecular dynamics (MD) simulations. Computational simulations allow us to reveal atomic-level structural dynamics of TDG as it approaches the target-site, and pinpoint the key structural elements responsible for regulating the translocation of TDG along DNA. Subsequently, upon locating the lesions, TDG adopts a base-flipping mechanism to extrude the mispaired nucleobase into the enzyme active-site. The constructed kinetic network model elucidates six metastable states during the base-extrusion process and suggests an active role of TDG in flipping the intrahelical nucleobase. Finally, the molecular mechanism of product release dynamics after catalysis is also summarized. Taken together, we highlight to what extent the computational simulations advance our knowledge and understanding of the molecular mechanism underlying the conformational dynamics of TDG, as well as the limitations of current theoretical work.

The variability of the northern westerlies has been considered as one of the key elements for modern and past climate evolution. Their multiscale behavior and underlying control mechanisms, however, are incompletely understood, owing to the complex dynamics of Atlantic sea-level pressures. Here, we present a multi-annually resolved record of the westerly drift over the past 6,500 years from northern Italy. In combination with more than 20 other westerly-sensitive records, our results depict the non-stationary westerly-affected regions over mainland Europe on multi-decadal to multi-centennial time scales, showing that the direction of the westerlies has changed with respect to the migrations of the North Atlantic centers of action since the middle Holocene. Our findings suggest the crucial role of the migrations of the North Atlantic dipole in modulating the westerly-affected domain over Europe, possibly modulated by Atlantic Ocean variability.

BackgroundMutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion.MethodsVarious mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration.ResultsPiezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouti

Meng Mei Li,1 Wen Cheng Shen,2 Yu Jin Li,1 Jun Teng1 1Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, People’s Republic of China; 2Department of Emergency, Qingdao Municipal Hospital (Group), Qingdao, People’s Republic of ChinaCorrespondence: Jun Teng, Email owen-145@163.comBackground: Linezolid is classed as oxazolidinone antibiotics which can be used to treat severe infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired pneumonia caused by Staphylococcus aureus, complicated skin, and uncomplicated skin structure infections (SSSIs) caused by methicillin-susceptible S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by Streptococcus pneumoniae. However, many studies have suggested it can also cause thrombocytopenia and pancytopenia.Patients and Methods: We report on three patients with linezolid-pancytopenia. Patients in cases 1 and 2 were diagnosed with heart failure with preserved ejection fraction (HFpEF) and were both administered with dapagliflozin, one of the sodium-dependent glucose transporters 2 inhibitors (SHLT-2i).Results: Two patients were diagnosed with type 2 diabetes, pneumonia, and hyponatremia. Severe myelosuppression occurred in both patients, with a severe decrease in leukocytes and platelets and a moderate decrease in hemoglobin, who eventually passed away despite the discontinuation of linezolid and adopting appropriate treatment measures. The patient in case 3 was diagnosed with pneumonia, type 2 diabetes, and sequelae of cerebral thrombosis. After twelve days of treatment, the patient developed moderate thrombocytopenia and anemia. She recovered without any additional treatment after the discontinuation of linezolid.Conclusion: In this case series, two patients with irreversible myelosuppression were treated with both linezolid and SGLT-2i, and one diabetic patient with single linezolid use presented with reversible pancytopenia

Direct molecular editing of heteroarene carbon-hydrogen (C-H) bonds through consecutive selective C-H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry1. In contrast to electronically biased heterocyclic C-H bonds2-9, remote benzocyclic C-H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases10-12. Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C-H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C-H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage molecular editing strategy to directly modify bicyclic aza-arenes at any given site in different orders.

We report genome-wide data from 33 Ashkenazi Jews (AJ), dated to the 14th century, obtained following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genet-ically similar to modern AJ, but they show more variability in Eastern European-related ancestry than mod-ern AJ. A third of the Erfurt individuals carried a mitochondrial lineage common in modern AJ and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. The Erfurt bottleneck was more severe, implying substructure in medieval AJ. Overall, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

Analyzing the behavior of complex interdependent networks requires complete information about the network topology and the interdependent links across networks. For many applications such as critical infrastructure systems, understanding network interdependencies is crucial to anticipate cascading failures and plan for disruptions. However, data on the topology of individual networks are often publicly unavailable due to privacy and security concerns. Additionally, interdependent links are often only revealed in the aftermath of a disruption as a result of cascading failures. We propose a scalable nonparametric Bayesian approach to reconstruct the topology of interdependent infrastructure networks from observations of cascading failures. Metropolis-Hastings algorithm coupled with the infrastructure-dependent proposal are employed to increase the efficiency of sampling possible graphs. Results of reconstructing a synthetic system of interdependent infrastructure networks demonstrate that the proposed approach outperforms existing methods in both accuracy and computational time. We further apply this approach to reconstruct the topology of one synthetic and two real-world systems of interdependent infrastructure networks, including gas-power-water networks in Shelby County, TN, USA, and an interdependent system of power-water networks in Italy, to demonstrate the general applicability of the approach.