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Drilling carbon fiber reinforced polymers (CFRPs) presents significant challenges due to high cutting forces and surface defects. To address this, laser-assisted drilling (LAD) has emerged as a pioneering technique, surpassing conventional drilling (CD). Experimental results unequivocally establish LAD's superiority. Notably, the cutting mechanism in CFRP transitions from compression fracture in CD to shear cutting in LAD, remarkably reducing cutting force by about 26%. This reduction is explained comprehensively, accounting for surface energy, frictional energy, and chip fracture energy. We introduce an innovative simulation model replicating the machined CFRP surface after laser processing, enabling detailed surface quality analysis in LAD. Drawing on elastic foundation beam theory, we formulate a mathematical model for orthogonal cutting in LAD, characterizing cutting forces. Combining these findings with experiments, we elucidate LAD's CFRP drilling mechanism, identifying six drilling stages by tool depth. Our investigation covers facets including cutting forces, temperatures, exit delamination, and hole surface quality, holistically evaluating LAD's benefits. This research sheds light on LAD's intrinsic drilling characteristics for CFRP, highlighting its potential for innovation and application in CFRP drilling. The combination of experimental validation, innovative modeling, and comprehensive analysis solidifies LAD as a breakthrough in advancing CFRP drilling. This study enhances our understanding of LAD's mechanics and its promise for broader industrial use. [ABSTRACT FROM AUTHOR]

To design and construct a hydrogel drug-controlled release system loaded with gentamicin on a titanium surface, and to evaluate the in vitro drug release behaviour and antibacterial properties and biocompatibility of the controlled release system. Titanium (Ti) surface was coated with poly dopamine (PDA) substrate, and then polyethylene glycol (PEG) was attached to PDA. The composite drug microsphere controlled release layer formed by gentamicin (GEN) and cross-linked starch (CSt) were subsequently covered with poly lactic⁃co⁃glycolic acid (PLGA) as a barrier to construct a Ti-GEN-Cst-PLGA anti-infective drug controlled release system. The hydrogel drug release system was successfully constructed. The results of in vitro anti-staphylococcus aureus (SAU) assay, anti-staphylococcus epidermidis (SEP) assay and anti-Escherichia coli (ECO) assay showed that Ti-GEN-Cst-PLGA could effectively inhibit the growth of three bacteria. Assay in the New Zealand rabbit found that Ti-GEN-Cst-PLGA could promote wound healing at the 3rd week after implantation, and the pathology assay found that the Ti-GEN-Cst-PLGA group had less inflammatory reactions and significant tissue proliferation at the endophyte contact surface. Ti-GEN-Cst-PLGA can effectively inhibit the inflammatory response and promote wound healing, or may be a potential treatment for orthopaedic endophytes. [ABSTRACT FROM AUTHOR]

Mobile machines using a hydrostatic transmission is highly efficient under lower working-speed condition but less capable at higher transport velocities. To enhance overall efficiency, we have improved the powertrain design by combining a hydrostatic transmission with a dual-clutch transmission (DCT). Compared with other mechanical gearboxes, the DCT avoids the interruption of torque transmission in the process of shifting without sacrificing more transmission efficiency. However, there are some problems of unstable torque transmission during the shifting process, and an excessive torque drop occurring at the end of the gear shift, which result in a poor drive comfort. To enhance the performance of the novel structural possibility of powertrain design, we designed a novel control strategy, which maintains the sliding in the torque phase and reduces the difference before and after the engagement, for the motor torque and the clutch torques during the shifting process, and then validated the control effect with model-based simulation. As a result, the control strategy employing clutch and motor torque control achieve a smooth shifting process since the drive torque is well tracked, and highly dynamical actuators are not required. As another benefit, only two calibration parameters are designed and actually needed to adjust the control performance systematically, even for any different sizes machines. Our research indicates the possibility to adopt dual-clutch in the field of construction machines. [ABSTRACT FROM AUTHOR]

Background: Studies on the associations between ambient temperature and asthma hospitalizations are limited, and the results are controversial. We aimed to assess the short-term effects of ambient temperature on the risk of asthma hospitalizations and quantify the hospitalization burdens of asthma attributable to non-optimal temperature in adults in Beijing, China. Methods: We collected daily asthma hospitalizations, meteorological factors and air quality data in Beijing from 2012 to 2015. We applied a time-stratified case-crossover design and fitted a distributed lag non-linear model with a conditional quasi-Poisson regression to explore the association between ambient temperature and adult asthma hospitalizations. The effect modifications of these associations by gender and age were assessed by stratified analyses. We also computed the attributable fractions and numbers with 95% empirical confidence intervals (eCI) of asthma hospitalizations due to extreme and moderate temperatures. Results: From 2012 to 2015, we identified a total of 18,500 hospitalizations for asthma among adult residents in Beijing, China. Compared with the optimal temperature (22 °C), the cumulative relative risk (CRR) over lag 0–30 days was 2.32 with a 95% confidence interval (CI) of 1.57–3.42 for extreme cold corresponding to the 2.5th percentile (− 6.5 °C) of temperature distribution and 2.04 (95% CI 1.52–2.74) for extreme heat corresponding to the 97.5th percentile (29 °C) of temperature distribution. 29.1% (95% eCI 17.5–38.0%) of adult asthma hospitalizations was attributable to non-optimum temperatures. Moderate cold temperatures yielded most of the burdens, with an attributable fraction of 20.3% (95% eCI 9.1–28.7%). The temperature-related risks of asthma hospitalizations were more prominent in females and younger people (19–64 years old). Conclusions: There was a U-shaped association between ambient temperature and the risk of adult asthma hospitalizations in Beijing, China. Females and younger patients were more vulnerable to the effects of non-optimum temperatures. Most of the burden was attributable to moderate cold. Our findings may uncover the potential impact of climate changes on asthma exacerbations. [ABSTRACT FROM AUTHOR]

A sensitive amperometric sensor for norfloxacin (NF) was introduced. The receptor layer was prepared by molecularly imprinted photopolymerization of acrylamide and trimethylolpropane trimethacrylate on the surface of a gold electrode. The binding mechanism of the molecularly imprinted polymer was explored by ultraviolet (UV) and infrared (IR) spectroscopy. The chemosensor was characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), electrochemical impedance (EI), and scanning electron microscopy (SEM). The electrode prepared by photopolymerization has a better recognition ability to template molecules than that of electropolymerization and NIP. Some parameters affecting sensor response were optimized. Norfloxacin was detected by measurements of an amperometric i- t curve. The linear relationships between current and logarithmic concentration are obtained from 1.0 × 10 to 1.0 × 10 mol L. The detection limit of the sensor was 1.0 × 10 mol L. The proposed method is sensitive, simple, and cheap, and is applied to detect NF in human urine successfully. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/ CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L11 HRS cells, PD-L11 TAMs, and PD-11 T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L11 and PD-11 cells in the tumor microenvironment (TME) of cHL.Wefind that the majority of PD-L1 in theTMEis expressed by the abundant PD-L11 TAMs, which physically colocalize with PD-L11 HRS cells in a microenvironmental niche. PD-L11 TAMs are enriched for contacts with T cells, and PD-L11 HRS cells are enriched for contacts with CD41 T cells, a subset of which are PD-11. Our data define a unique topology of cHL in which PD-L11 TAMs surround HRS cells and implicate CD41 T cells as a target of PD-1 blockade. [ABSTRACT FROM AUTHOR]

Human gene expression patterns are controlled and coordinated by the activity of a diverse array of epigenetic regulators, including histone methyltransferases, acetyltransferases, and chromatin remodelers. Deregulation of these epigenetic pathways can lead to genome-wide changes in gene expression, with serious disease consequences. In recent years, research has suggested that cross talk between genomic (i.e., for example, mutations, translocations) and epigenomic factors may drive the etiology of both hematologic malignancies and solid tumors. Current work in translational research seeks to identify epigenetic regulators whose aberrant activity contributes to oncogenesis, including the histone methyltransferases DOT1L and EZH2 and the bromodomain-containing BET family, and to develop drugs that inhibit the aberrant activity of these regulators. Preclinical and clinical studies using small-molecule inhibitors of epigenetic regulators have underscored their value for therapeutic intervention, and these inhibitors can also be used to drive further studies into dissecting the functions of epigenetic factors in normal and cancer cells. [ABSTRACT FROM AUTHOR]

More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild-type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches, we have addressed the mechanism by which ER antagonizes the proapoptotic function of p53. Interestingly, both ER agonists such as estradiol and the selective ER modulator (SERM) tamoxifen promote p53 antagonism. In contrast, the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This inhibition works through a mechanism involving the modulation of a subset of p53 and ER target genes that can predict the relapse-free survival of patients with ER+ breast cancer. These findings suggest an improved strategy for the treatment of ER+ breast cancer using antagonists that completely block ER action together with drugs that activate p53-mediated cell death. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of studies investigating extreme cold events and asthma exacerbations. This study examined whether an association exists between cold spells and daily hospital admissions for asthma in Beijing, China from 2012 to 2016.Methods: Daily hospital admissions for asthma, meteorological variables and air quality data were collected during 2012-2016 in Beijing. A cold spell was defined as a period of at least two consecutive days with the daily mean temperature below or at the 5th percentile (-7 °C) in cold seasons (November to March) during the study period. We applied a time-series design using quasi-Poisson regression combined with a distributed lag model to estimate the risk of asthma hospital admissions associated with cold spells. Stratified analyses by gender and age groups were conducted to identify the potential susceptible subpopulations to cold spells. We also explored the effect modification by air quality by dividing the daily air quality index (AQI) into two levels (high and low) based on the median value.Results: Cold spells increased the risk of asthma hospital admissions, with the maximum cumulative relative risk (CRR) over three weeks (Lag0-21) in the total population. The highest single-day relative risk (RR) was found on the days of cold spells (Lag0) with the RR = 1.059 (95% CI: 1.008-1.113), and the CRR at Lag0-21 was 1.333 (95% CI: 1.049-1.693). Across different gender and age groups, younger people (<65 years) were more sensitive to cold spells. No significant effect modification by AQI was detected.Conclusion: Short-term exposure to cold spells is associated with an increased risk of hospital admissions for asthma in Beijing. During the cold spells, younger people aged <65 years were at particular risk for asthma exacerbations. Our results suggest that extreme cold events have a significant impact on asthma. [ABSTRACT FROM AUTHOR]

Computational data-centric research techniques play a prevalent and multi-disciplinary role in life science research. In the past, scientists in wet labs generated the data, and computational researchers focused on creating tools for the analysis of those data. Computational researchers are now becoming more independent and taking leadership roles within biomedical projects, leveraging the increased availability of public data. We are now able to generate vast amounts of data, and the challenge has shifted from data generation to data analysis. Here we discuss the pitfalls, challenges, and opportunities facing the field of data-centric research in biology. We discuss the evolving perception of computational data-driven research and its rise as an independent domain in biomedical research while also addressing the significant collaborative opportunities that arise from integrating computational research with experimental and translational biology. Additionally, we discuss the future of data-centric research and its applications across various areas of the biomedical field., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) remains a formidable challenge, lacking effective treatments. Following SCI, neural stem cells (NSCs) migrate to SCI sites, offering a potential avenue for nerve regeneration, but the effectiveness of this intrinsic repair mechanism remains suboptimal. Salidroside has demonstrated pro-repair attributes in various pathological conditions, including arthritis and cerebral ischemia, and the ability to curtail early-stage inflammation following SCI. However, the specific role of salidroside in the late-stage repair processes of SCI remains less defined. In this investigation, we observed that continuous salidroside treatment in SCI mice improved motor function recovery. Immunofluorescence-staining corroborated salidroside's capacity to stimulate nerve regeneration and remyelination, suppress glial scar hyperplasia, reduce the activation of neurotoxic A1 astrocytes, and facilitate NSCs migration towards the injured region. Mechanistically, in vitro experiments elucidated salidroside's significant role in restraining astrocyte proliferation and A1 polarization. It was further established that A1 astrocytes hinder NSCs proliferation while inducing their differentiation into astrocytes. Salidroside effectively ameliorated this inhibition of NSCs proliferation through diminishing c-Jun N-terminal kinase (JNK) pathway phosphorylation and restored their differentiation into neurons by suppressing the signal transducer and activator of transcription 3 (STAT3) pathway. In summary, our findings suggest that salidroside holds promise as a therapeutic agent for traumatic SCI treatment., (© 2024. The Author(s).)

The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC) n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC) n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC) n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC) n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC) n . In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC) n , its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC) n and its influence on partner binding. Given the crucial role of r(GGGGCC) n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC) n RNA.

We performed a meta-analysis to evaluate the effect of minimally invasive surgery and laparotomy on wound infection and postoperative and intraoperative complications in the management of cervical cancer. A systematic literature search up to July 2022 was performed and 10 231 subjects with cervical cancer at the baseline of the studies; 4307 of them were using the minimally invasive surgery, and 5924 were using laparotomy. Odds ratio (OR) with 95% confidence intervals (CIs) were calculated to assess the effect of minimally invasive surgery and laparotomy on wound infection and postoperative and intraoperative complications in the management of cervical cancer using the dichotomous methods with a random or fixed-effect model. The minimally invasive surgery had significantly lower wound infection (OR, 0.20; 95% CI, 0.13-0.30, P < .001), and postoperative complications (OR, 0.48; 95% CI, 0.37-0.64, P < .001) in subjects with cervical cancer compared laparotomy. However, minimally invasive surgery compared with laparotomy in subjects with cervical cancer had no significant difference in intraoperative complications (OR, 1.04; 95% CI, 0.80-1.36, P = 0.76). The minimally invasive surgery had significantly lower wound infection, and postoperative complications however, had no significant difference in intraoperative complications in subjects with cervical cancer compared with laparotomy. The analysis of outcomes should be with caution because of the low sample size of 22 out of 41 studies in the meta-analysis and a low number of studies in certain comparisons., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Sound-induced flash illusion (SiFI) is typical auditory dominance phenomenon in multisensory illusion. Although a number of studies have explored the SiFI in terms of age-related effects, the reasons for the enhanced SiFI in older adults are still controversial. In the present study, older and younger adults with equal visual discrimination were selected to explore age differences in SiFI effects, and to explore the neural indicators by resting-state functional magnetic resonance imaging (rs-fMRI) signals. A correlation analysis was calculated to examine the relationship between regional homogeneity (ReHo) and the SiFI. The results showed that both younger and older adults experienced significant fission and fusion illusions, and fission illusions of older adults were greater than that of younger adults. In addition, our results showed ReHo values of the left middle frontal gyrus (MFG), the right inferior frontal gyrus (IFG) and right superior frontal gyrus (SFG) were significantly positively correlated with the SiFI in older adults. More importantly, the comparison between older and younger adults showed that ReHo values of the right superior temporal gyrus (STG) decreased in older adults, and this was independent of the SiFI. The results indicated that when there was no difference in unisensory ability, the enhancement of multisensory illusion in older adults may not always be explained by compensation mechanisms.

Background: In the context of global climate changes, increasing extreme weather events have aroused great public concern. Limited evidence has focused on the association between extreme precipitation and hospitalizations for acute myocardial infarction (AMI). Our study aimed to examine the effect of extreme precipitation on AMI hospitalizations., Methods: Daily AMI hospitalizations, weather variables and air pollution data in Beijing from 2013 to 2018 were obtained. We used a time-series analysis with a distributed lag model to evaluate the association of extreme precipitation (≥95th percentile of daily precipitation) with AMI hospitalizations. Subgroup analysis was conducted to identify the vulnerable subpopulations and further assessed the attributable burden., Results: Extreme precipitation increased the risk of AMI hospitalizations with significant single-day effects from Lag 4 to Lag 11, and the maximum cumulative effects at Lag 0-14 (CRR = 1.177, 95% CI: 1.045, 1.326). Older people (≥65 years) and females were more vulnerable to extreme precipitation. The attributable fraction and numbers of extreme precipitation on AMI hospitalizations were 0.68% (95% CI: 0.20%, 1.12%) and 854 (95% CI: 244, 1,395), respectively., Conclusion: Extreme precipitation is correlated with a higher risk of AMI hospitalizations. The elderly (≥65 years) and females are more susceptible to AMI triggered by extreme precipitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Chang, Zhao, Liu, Fu, Liu, Liu, Kong, Han, Tang and Fan.)

We aimed to assess the effects of serratus anterior plane block (SAPB) and thoracic paravertebral nerve block (TPVB) on analgesia, immune function and serum tumor markers in patients after thoracoscopic radical resection of lung cancer. A total of 132 patients enrolled from February 2019 to November 2020 were prospectively selected and randomly divided into 3 groups (n=44). Control group received general anesthesia. After induction of general anesthesia, TPVB or SAPB group was given TPVB or SAPB. Their clinical data, operation conditions, Visual Analogue Scale (VAS) score, immune function, serum tumor markers and adverse reactions were compared. TPVB and SAPB groups had lower dosage of sufentanil during operation, later time of first pressing patient-controlled intravenous analgesia (PCA) pump after operation and smaller number of pressing PCA pump within 48 h after operation than those of control group (P<0.05). VAS scores at rest and coughing decreased 6 and 12 h after operation in TPVB and SAPB groups compared with that in control group (P<0.05). Cluster of differentiation 3 (CD3) + , CD4 + and CD4 + /CD8 + ratio were higher, while CD8 + was lower 24 and 48 h after operation in TPVB and SAPB groups than those of control group (P<0.05). TPVB and SAPB groups had lower serum tumor marker levels 24 h after operation than those of control group (P<0.05). The three groups had similar incidence rates of adverse reactions (P>0.05). SAPB and TPVB can markedly improve postoperative analgesic effect, enhance immune function and decrease serum tumor marker levels in patients receiving thoracoscopic radical resection of lung cancer, without increasing adverse reactions. However, TPVB may puncture the pleura., Competing Interests: The authors have no conflicts of interest.

Pairing a single visual stimulus with multiple auditory stimuli will lead to the illusory perception of multiple visual stimuli, which is known as sound-induced flash illusion (SIFI). The present study adopted the classic SIFI paradigm to investigate whether value-associated tasks could affect the SIFI. By adjusting the sequence of reward and nonreward conditions, we also examined the effect of reward history on SIFI. The results showed that the fission illusion was reduced when associated with momentary reward, demonstrating significantly higher accuracy and discriminability than the nonreward condition. However, the fusion illusion was not affected by the momentary reward, and the explanation was that the fusion illusion was not as stable as the fission illusion and disappeared across different trials and conditions. Moreover, the robustness of reward history in the present study was not as strong as previous studies have suggested, indicating that the effect of sound on the perceptual representation of visual stimuli is strong and robust to reward history. These findings demonstrated that the reward could reduce the SIFI and broaden the existing dichotomy of SIFI. New evidence for the operation of value-driven attention mechanisms is also provided, suggesting that the underlying value-driven attention operates across multiple sensory systems.

Background: Previous studies suggested that exposure to air pollution could increase risk of asthma attacks in children. The aim of this study is to investigate the short-term effects of exposure to ambient air pollution on asthma hospital admissions in children in Beijing, a city with serious air pollution and high-quality medical care at the same time. Methods: We collected hospital admission data of asthma patients aged ≤ 18 years old from 56 hospitals from 2013 to 2016 in Beijing, China. Time-stratified case-crossover design and conditional Poisson regression were applied to explore the association between risk of asthma admission in children and the daily concentration of six air pollutants [particulate matter ≤ 2.5 μm (PM 2.5 ), particulate matter ≤ 10 μm (PM 10 ), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), carbon monoxide (CO), and ozone (O 3 )], adjusting for meteorological factors and other pollutants. Additionally, stratified analyses were performed by age, gender, and season. Results: In the single-pollutant models, higher levels of PM 2.5 , SO 2 , and NO 2 were significantly associated with increased risk of hospital admission for asthma in children. The strongest effect was observed in NO 2 at lag06 ( RR = 1.25, 95%CI: 1.06-1.48), followed by SO 2 at lag05 ( RR = 1.17, 95%CI: 1.05-1.31). The robustness of effects of SO 2 and NO 2 were shown in two-pollutant models. Stratified analyses further indicated that pre-school children (aged ≤ 6 years) were more susceptible to SO 2 . The effects of SO 2 were stronger in the cold season, while the effects of NO 2 were stronger in the warm season. No significant sex-specific differences were observed. Conclusions: These results suggested that high levels of air pollution had an adverse effect on childhood asthma, even in a region with high-quality healthcare. Therefore, it will be significant to decrease hospital admissions for asthma in children by controlling air pollution emission and avoiding exposure to air pollution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Kong, Fu, Zhang, Chen, Liu, Chang, Liu, Liu, Xu, Jiang and Fan.)

Purpose: Immunoprofiling to identify biomarkers and integration with clinical trial outcomes are critical to improving immunotherapy approaches for patients with cancer. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assay performance further limits comparison and interpretation of data across studies and laboratories., Experimental Design: To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer Moonshot SM Initiative of the National Cancer Institute (NCI) and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the NIH., Results: The CIMAC-CIDC Network is composed of four academic centers with multidisciplinary expertise in cancer immunotherapy that perform validated and harmonized assays for immunoprofiling and conduct correlative analyses. A data coordinating center (CIDC) provides the computational expertise and informatics platforms for the storage, integration, and analysis of biomarker and clinical data., Conclusions: This overview highlights strategies for assay harmonization to enable cross-trial and cross-site data analysis and describes key elements for establishing a network to enhance immuno-oncology biomarker development. These include an operational infrastructure, validation and harmonization of core immunoprofiling assays, platforms for data ingestion and integration, and access to specimens from clinical trials. Published in the same volume are reports of harmonization for core analyses: whole-exome sequencing, RNA sequencing, cytometry by time of flight, and IHC/immunofluorescence., (©2021 American Association for Cancer Research.)

Animal pose estimation tools based on deep learning have greatly improved animal behaviour quantification. These tools perform pose estimation on individual video frames, but do not account for variability of animal body shape in their prediction and evaluation. Here, we introduce a novel multi-frame animal pose estimation framework, referred to as OptiFlex. This framework integrates a flexible base model (i.e., FlexibleBaseline), which accounts for variability in animal body shape, with an OpticalFlow model that incorporates temporal context from nearby video frames. Pose estimation can be optimised using multi-view information to leverage all four dimensions (3D space and time). We evaluate FlexibleBaseline using datasets of four different lab animal species (mouse, fruit fly, zebrafish, and monkey) and introduce an intuitive evaluation metric-adjusted percentage of correct key points (aPCK). Our analyses show that OptiFlex provides prediction accuracy that outperforms current deep learning based tools, highlighting its potential for studying a wide range of behaviours across different animal species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Yu, Flierman, Loyola, Kamermans, Hoogland and De Zeeuw.)

Objectives: Our work aimed at exploring the relationship between cold spells and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalisations in Beijing, China, and assessing the moderating effects of the intensities and the durations of cold spells, as well as identifying the vulnerable., Design: A time-series study., Setting: We obtained time-series data of AECOPD hospitalisations, meteorological variables and air quality index in Beijing, China during 2012-2016., Participants: All AECOPD hospitalisations among permanent residents in Beijing, China during the cold seasons (November-March) of 2012-2016 were included (n=84 571)., Primary and Secondary Outcome Measures: A quasi-Poisson regression with a distributed lag model was fitted to investigate the short-term effects of cold spells on AECOPD hospitalisations by comparing the counts of AECOPD admissions during cold spell days with those during non-cold spell days., Results: Cold spells under different definitions were associated with increased risk of AECOPD hospitalisations, with the maximum cumulative relative risk (CRR) over 3 weeks (lag0-21). The cumulative effects at lag0-21 increased with the intensities and the durations of cold spells. Under the optimal definition, the most significant single-day relative risk (RR) was found on the days of cold spells (lag0) with an RR of 1.042 (95% CI 1.013 to 1.072), and the CRR at lag0-21 was 1.394 (95% CI 1.193 to 1.630). The elderly (aged ≥65) were more vulnerable to the effects of cold spells on AECOPD hospitalisations., Conclusion: Cold spells are associated with increased AECOPD hospitalisations in Beijing, with the cumulative effects increased with intensities and durations. The elderly are at particular risk of AECOPD hospitalisations triggered by cold spells., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo , validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states., (©2020 American Association for Cancer Research.)

The sound-induced flash illusion (SiFI) is a classical auditory-dominated multisensory integration phenomenon in which the observer misperceives the number of visual flashes due to the simultaneous presentation of a different number of auditory beeps. Although the SiFI has been documented to correlate with perceptual sensitivity, to date there is no consensus as to how it corresponds to sensitivity with aging. The present study was based on the SiFI paradigm (Shams et al., 2000), adding repeated auditory stimuli prior to the appearance of audiovisual stimuli to investigate the effects of repetition suppression (RS) on the SiFI with aging. The repeated auditory stimuli consisted of one or two of the same auditory stimuli presented twice in succession, which were then followed by the audiovisual stimuli. By comparing the illusions in old and young adults, we aimed to explore the influence of aging on the RS of auditory stimuli on the SiFI. The results showed that both age groups showed SiFI effects, however, the RS performance of the two age groups had different effects on the fusion and fission illusions. The illusion effect in old adults was weaker than in young adults. Specifically, RS only affected fission illusions in the old adults but both fission and fusion illusions in young adults. Thus, the present study indicated that the decreased perceptual sensitivity based on auditory RS could weaken the SiFI effect in multisensory integration and that old adults are more susceptible to RS, showing that old adults perceived the SiFI effect weakly under auditory RS., (Copyright © 2020 Sun, Liu, Li, Sava-Segal, Wang and Zhang.)

Alkali lignin is a component of the waste black liquor produced by the paper-making industry that is difficult to degrade. In recent years, the biological activities of lignin, such as free-radical scavenging and antioxidant capacity, have received increasing attention. Here, we prepared H 3 PW 12 O 40 /ZrO 2 and used this catalyst together with the ionic liquid 1-butyl-3-methylimidazolium chloride ([BMIM]Cl) as a double-effect catalyst for the degradation of alkali lignin. Single-factor and orthogonal tests showed that the best degradation conditions were as follows: reaction time, 2 h; reaction temperature, 100 °C; mass ratio of H 3 PW 12 O 40 /ZrO 2 to lignin, 1:4; and substrate concentration, 2.5%. The phenolic hydroxyl group content of the lignin degradation product increased by 231.2% and the total hydroxyl group content increased by 337.1% when the double-effect catalyst was used rather than [BMIM]Cl alone. Analysis by gel permeation chromatography showed that both the weight-average molecular weight and the number-average molecular weight of the product were reduced and that the lignin was degraded into small-molecular-weight compounds by the macromolecule. The product after the catalytic degradation of lignin showed a markedly increased antioxidant capacity, which was similar to that of the commercial antioxidant, 2,6-ditert-butyl-4-methylphenol. The study opens up a new direction for the better utilization of lignin., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature., Competing Interests: W.G.K. receives consulting income and equity from Peloton Therapeutics, which is developing HIF2 inhibitors for treatment of kidney cancer.

When attention is oriented to a peripheral cue, the processing of nearby stimuli is facilitated. This brief period of facilitation is followed by a long-lasting inhibitory effect, during which there is a delayed response to stimuli presented at a previously cued location. Although the mechanisms underlying the facilitatory effect of attentional orienting/reorienting in three-dimensional (3-D) space have been documented, there is not yet consensus as to how attention orients/reorients in depth during the later inhibitory phase (i.e., inhibition of return [IOR]). In the present study, by incorporating the Posner exogenous cueing paradigm into a virtual 3-D environment, we aimed to investigate whether an IOR effect occurs when attention orients and reorients at the uncued depth in the same hemispace, and whether the IOR effects are the same or different when attention orients/reorients along different trajectories in 3-D space. Our results showed asymmetrical spatial IOR effects when attention was oriented/reoriented at the uncued depth in the same hemispace. Spatial IOR was depth-specific when targets appeared in the near depth plane, whereas it was not depth-specific when targets appeared in the far depth plane. Apart from these results, we also found that attention oriented/reoriented at the same depth but in a different hemispace experienced a reduction in IOR size, thus indicating that the direction-specific spatial IOR mechanisms when attention orients/reorients along different trajectories are different. Taken together, our results suggest that spatial IOR is not entirely "depth-blind," and that the ecological importance of the 3-D world influences the direction of attentional shifts of spatial IOR in 3-D space.

Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancer-associated TFs, we comprehensively integrated 686 ENCODE ChIP-seq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNA-binding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3'UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators.

Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R(2) = 0.6213, P < 5 × 10(-11)) and KLK2 (R(2) = 0.5893, P < 5 × 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.

Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ∼3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/.

Type I human hepatic 3alpha-hydroxysteroid dehydrogenase (AKR1C4) plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism. Utilization of a hidden Markov model for predictive modeling of nuclear hormone receptor response elements coupled with chromatin immunoprecipitation/microarray technology revealed a putative binding site in the AKR1C4 promoter for the nuclear hormone receptor known as liver X receptor alpha, (LXRalpha [NR1H3]), which is the physiological receptor for oxidized cholesterol metabolites. The putative LXRalpha response element (LXRE), identified by chromatin immunoprecipitation, was approximately 1.5 kilobase pairs upstream of the transcription start site. LXRalpha was shown to bind specifically to this LXRE and mediate transcriptional activation of the AKR1C4 gene, leading to increased AKR1C4 protein expression. These data suggest that LXRalpha may modulate the bile acid biosynthetic pathway at a unique site downstream of CYP7A1 and may also modulate the metabolism of steroid hormones and certain xenobiotics.