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Mass spectrometry imaging (MSI) technologies are widely used today to study the in situ spatial distributions for a variety of analytes. As these technologies advance, the pursuit of higher resolution in MSI has intensified. The limitation of direct desorption/ionization is its insufficient ionization, posing a constraint on the advancement of high-resolution MSI technologies. The introduction of postionization process compensates the low ionization efficiency caused by sacrificing the desorption area while pursuing high spatial resolution, resolving the conflict between high spatial resolution and high sensitivity in direct desorption/ionization method. Here, we discuss the sampling and ionization steps of MSI separately, and review the postionization methods in MSI according to three different sampling modes: laser sampling, probe sampling, and ion beam sampling. Postionization technology excels in enhancing ionization efficiency, boosting sensitivity, mitigating discrimination effect, simplifying sample preparation, and expanding the scope of applicability. These advantages position postionization technology as a promising tool for biomedical sciences, materials sciences, forensic analysis and other fields., (© 2024 John Wiley & Sons Ltd.)

Aims: To investigate the epidemiological and clinical characteristics of children with Mycoplasma pneumoniae pneumonia (MPP) in Hubei, China., Methods: We retrospectively analyzed inpatients with MPP from 20 hospitals in Hubei, China from January 2021 to December 2022. The co-detected pathogens of Mycoplasma pneumoniae ( M. pneumoniae ) were investigated using targeted next-generation sequencing (tNGS), and 23S rRNA gene mutations were analyzed to assess the macrolide resistance., Results: M. pneumoniae infected 20.7% of patients with CAP, with cough (96.59%) and fever (80.28%) being the most prevalent symptoms. The infection rates in children younger than 1, 1-2, 3-6, 7-12, and older than 12 years were 6.17%, 19.98%, 26.97%, 43.93%, and 2.95%, respectively. Among 1,349 patients undergoing tNGS, the overall co-detection rate was 59.45%, with Streptococcus pneumoniae (29.30%), Haemophilus influenzae (23.57%), and Human rhinovirus (17.21%) being the most commonly co-detected pathogens. In 635 patients undergoing the 23S rRNA gene mutation test, 86.30% exhibited positive mutations (A2063G, 98.00%; A2064G, 1.50%; A2067G, 0.50%). Despite a significant age difference ( P  = 0.037) between macrolide-resistant M. pneumoniae and macrolide-sensitive M. pneumoniae groups, there were no significant differences in symptoms, lab data, or disease severity., Conclusions: In Hubei Province, the prevalence of exhibited consistent changes during the COVID-19 pandemic. MPP was prevalent year-round, particularly in summer and autumn, with school-age children being more susceptible. Co-detections of viruses and bacteria were frequent in MPP cases, and macrolide resistance exceeded 85%. Ongoing surveillance of M. pneumoniae in children is crucial for understanding the healthcare impact of MPP., 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., (© 2024 Du, Li, Li, Zhao, Lu, Zhang, Liu, Luo, Lu, Hu, Ma, He, Sha, Zhang, Wu, Yang, Li, Chen, Li, Li, Lin, Liu, Wu, Liu, Li and Lu.)

Dielectric barrier discharge ionization is increasingly used for rapid detection in ambient mass spectrometry, although more often for gaseous and highly volatile samples than for solids and liquids. In this project, we present a rapid and sensitive method for detecting mycotoxins and demonstrate its capability for the detection of aflatoxin B1, zearalenone, and ochratoxin A in food samples. Our method is based on thermal desorption coupled to dielectric barrier discharge ionization mass spectrometry (TD-DBDI-MS), which we show generates minimal interferences and produces almost exclusively molecular ions. We detected mycotoxins in various food samples, including corn, peanuts, millet, and rice. Our method has a linear dynamic range of 1 μg kg -1 to 100 μg kg -1 for all three mycotoxins and a limit of detection (LOD) of 0.31 μg kg -1 , 0.28 μg kg -1 and 0.43 μg kg -1 , respectively. It is simple, rapid, reduces the pretreatment steps and has significant potential for practical applications.

Introduction: Thalassemia represents a significant public health challenge globally. However, the global burden of thalassemia and the disparities associated with it remain poorly understood. Our study aims to uncover the long-term spatial and temporal trends in thalassemia at global, regional, and national levels, analyze the impacts of age, time periods, and birth cohorts, and pinpoint the global disparities in thalassemia burden., Methods: We extracted data on the thalassemia burden from the Global Burden of Disease Study (GBD) 2019. We employed a joinpoint regression model to assess temporal trends in thalassemia burden and an age-period-cohort model to evaluate the effects of age, period, and cohort on thalassemia mortality., Results: From 1990 to 2019, the number of thalassemia incident cases, prevalent cases, mortality cases, and disability-adjusted life years (DALYs) decreased by 20.9%, 3.1%, 38.6%, and 43.1%, respectively. Age-standardized rates of incidence, prevalence, mortality, and DALY declined across regions with high, high-middle, middle, and low-middle sociodemographic index (SDI), yet remained the highest in regions with low SDI and low-middle SDI as well as in Southeast Asia, peaking among children under five years of age. The global prevalence rate was higher in males than in females. The global mortality rate showed a consistent decrease with increasing age., Conclusion: The global burden of thalassemia has significantly declined, yet notable disparities exist in terms of gender, age groups, periods, birth cohorts, SDI regions, and GBD regions. Systemic interventions that include early screening, genetic counseling, premarital health examinations, and prenatal diagnosis should be prioritized in regions with low, and low-middle SDI, particularly in Southeast Asia. Future population-based studies should focus specifically on thalassemia subtypes and transfusion requirements, and national registries should enhance data capture through newborn screening., (© 2024 Wiley Periodicals LLC.)

Background: Studies have been conducted on the relationship between depression and thyroid diseases and function, its causal relationship remains unclear., Methods: Using summary statistics of genome-wide association studies of European and East Asian ancestry, we conducted 2-sample bidirectional Mendelian randomization to estimate the association between MDD and thyroid function (European: normal range TSH, T4, T3, fT4, TPOAb levels and TPOAb-positives; East Asian: T4) and thyroid diseases (hypothyroidism, hyperthyroidism, and Hashimoto's thyroiditis), and used Mediation analysis to evaluate potential mediators (alcohol intake, antidepressant) of the association and calculate the mediated proportions., Results: It was observed a significant causal association between MDD on hypothyroidism (P = 8.94 × 10 -5 ), hyperthyroidism (P = 8.68 × 10 -3 ), and hashimoto's thyroiditis (P = 3.97 × 10 -5 ) among European ancestry, which was mediated by Alcohol intake (alcohol intake versus 10 years previously for hypothyroidism (P = 0.026), hashimoto's thyroiditis (P = 0.042), and alcohol intake frequency for hypothyroidism (P = 0.015)) and antidepressant (for hypothyroidism (P = 0.008), hashimoto's thyroiditis (P = 0.010)), but not among East Asian ancestry (P MDD-hypothyroidism  = 0.016, but β direction was different; P MDD-hyperthyroidism  = 0.438; P MDD-hashimoto ' s thyroiditis  = 0.496). There was no evidence for bidirectional causal association between thyroid function mentioned above and MDD among both ancestry (all P > 0.05)., Conclusion: We importantly observed a significant causal association between MDD on risk of hypothyroidism, hyperthyroidism, and hashimoto's thyroiditis among European ancestry, and Alcohol intake and antidepressant as mediators for prevention of hypothyroidism, hashimoto's thyroiditis attributable to MDD., Competing Interests: Declaration of competing interest 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The economic burden of brucellosis care on patients can lead to significant financial strain, despite partial coverage by medical insurance. However, there is limited research on the out-of-pocket costs faced by brucellosis patients. Therefore, our study aimed to investigate the costs and out-of-pocket expenses of brucellosis care, specifically examining the varying socioeconomic status of patients in Xinjiang, China. We collected cost and demographic data from 563 respondents and their hospital bills and employed latent variable analysis to assess socioeconomic status. The majority of patients belonged to the middle and lower socioeconomic status categories (85.97%), and they were primarily farmers and herders (82.77%). The median direct cost per brucellosis episode was USD 688.65, with out-of-pocket expenses amounting to USD 391.44. These costs exceeded both the 2020 Xinjiang and national per capita health expenditures (USD 233.66 and USD 267.21, respectively). Notably, the overall medical reimbursement rate was 48.60%, and for outpatient costs, it was merely 12.82%. Despite higher out-of-pocket costs among high socioeconomic status patients, the percentage of income spent was higher (37.23%) for patients in the lower socioeconomic status group compared to other groups (16.25% and 12.96%). In conclusion, our findings highlight that brucellosis patients are predominantly from the middle and lower socioeconomic status, with high out-of-pocket expenses placing them under significant financial pressure. Moreover, there is notable inequity in economic consequences across different socioeconomic status groups. These results call for policy interventions aimed at reducing brucellosis-related poverty and promoting equitable access to care., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Hai-Bo He et al.)

A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous determination of doxorubicin (DOX) in mouse plasma and tissues, including the heart, liver, spleen, lung, kidney and tumor, and to investigate the pharmacokinetics and distribution in mice. In this study, daunorubicin (DNR) was used as an internal standard, and the mobile phase consisted of ammonium formate 2 mM containing 0.1 % formic acid (A) and acetonitrile (B), the chromatographic column was ACQUITY UPLC BEHTM C18 with a gradient elution at a flow rate of 0.2 mL/min. Electrospray ionization (ESI) in positive ion pattern was utilized for the ion separation of DOX, with the ions used for quantitative analysis being DOX m/z 544.28 → 397.10 and DNR m/z 528.35 → 321.08, respectively. The results showed that a good linear relationship in the calibration curve range of 1-800 ng/mL in mouse plasma and 1-2500 ng/g in tissues (R 2  > 0.99) with the limits of quantification of 1 ng/mL in plasma and tissues. The method exhibited good matrix effect and extraction recovery, with the intra-day and inter-day precision of plasma and tissue were less than 10.3 % and 15.4 %, and the relative error (RE) were both less than ±14.8 % and ±18.9 %, respectively. The stability results under different conditions were found to be accurate. It also revealed the distribution of DOX in various tissues of mice, with the concentration ranking as liver > heart > kidney > spleen > lung > tumor. This method was successfully used to the study for the pharmacokinetics in plasma and drug distribution in tissues of BALB/c mice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells., Methods: Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro "condition medium of fibroblasts + MCF-7" cell model and in vivo "4T1/NIH-3T3" co-implantation mice model were established to evaluate the anti-tumor effect of drugs., Results: The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect., Conclusion: In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wu et al.)

Aims: Caused by multiple risk factors, heavy burden of major depressive disorder (MDD) poses serious challenges to public health worldwide over the past 30 years. Yet the burden and attributable risk factors of MDD were not systematically known. We aimed to reveal the long-term spatio-temporal trends in the burden and attributable risk factors of MDD at global, regional and national levels during 1990-2019., Methods: We obtained MDD and attributable risk factors data from Global Burden of Disease Study 2019. We used joinpoint regression model to assess the temporal trend in MDD burden, and age-period-cohort model to measure the effects of age, period and birth cohort on MDD incidence rate. We utilized population attributable fractions (PAFs) to estimate the specific proportions of MDD burden attributed to given risk factors., Results: During 1990-2019, the global number of MDD incident cases, prevalent cases and disability-adjusted life years (DALYs) increased by 59.10%, 59.57% and 58.57%, respectively. Whereas the global age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR) and age-standardized DALYs rate (ASDR) of MDD decreased during 1990-2019. The ASIR, ASPR and ASDR in women were 1.62, 1.62 and 1.60 times as that in men in 2019, respectively. The highest age-specific incidence, prevalence and DALYs rate occurred at the age of 60-64 in women, and at the age of 75-84 in men, but the maximum increasing trends in these age-specific rates occurred at the age of 5-9. Population living during 2000-2004 had higher risk of MDD. MDD burden varied by socio-demographic index (SDI), regions and nations. In 2019, low-SDI region, Central sub-Saharan Africa and Uganda had the highest ASIR, ASPR and ASDR. The global PAFs of intimate partner violence (IPV), childhood sexual abuse (CSA) and bullying victimization (BV) were 8.43%, 5.46% and 4.86% in 2019, respectively., Conclusions: Over the past 30 years, the global ASIR, ASPR and ASDR of MDD had decreased trends, while the burden of MDD was still serious, and multiple disparities in MDD burden remarkably existed. Women, elderly and populations living during 2000-2004 and in low-SDI regions, had more severe burden of MDD. Children were more susceptible to MDD. Up to 18.75% of global MDD burden would be eliminated through early preventing against IPV, CSA and BV. Tailored strategies-and-measures in different regions and demographic groups based on findings in this studywould be urgently needed to eliminate the impacts of modifiable risk factors on MDD, and then mitigate the burden of MDD.

Diabetes is a common chronic metabolic disease. The frequent fluctuation of glucose is the main cause of most diabetes complications, which in turn causes harm to the health of patients. Surface-enhanced Raman scattering (SERS) spectroscopy has attracted much attention in the rapid detection of glucose due to its unique molecular fingerprinting ability, ultra-high sensitivity and fast response. However, due to the low affinity between glucose and SERS substrate, poor signal, susceptibility to complex environmental interference, and poor stability of SERS detection, it is still a challenge for SERS to accurately and sensitively determine glucose in complex environments. In this work, we encapsulated 4-mercaptobutyronitrile (4-MBN) as an internal standard (IS) in Au@Ag NRs inside and then Au@4-MBN@Ag NRs, Leucomalachite Green (LMG), glucose oxidase (GOx) and horseradish peroxidase (HPR) were encapsulated in ZIF-8 to prepare a tandem enzyme catalytic ratiometric SERS sensor Au@4-MBN@Ag@LMG@ZIF-8(GOx, HPR) for the detection of glucose in saliva. Because ZIF-8 enhanced the catalytic activity of the enzyme, the ability of glucose enrichment, and weakens the aggregation of Ag NRs. The internal standard signal molecule improves the accuracy and sensitivity of detection. The ratiometric Raman signal I 412 /I 2233 of glucose has a good linear relationship with the concentration in the range of 0.1-100 μM, and the limit of detection (LOD) could be down to 0.03 μM. At the same time, it has excellent selectivity, repeatability and accuracy. The recovery rate of glucose in saliva is 96.50%-105.56 %, which proves the feasibility of the method. The Au@4-MBN@Ag@LMG@ZIF-8(GOx, HPR) sensor prepared in this study showed excellent SERS performance, which was able to detect glucose quickly, sensitively and accurately. This work provides a new strategy for the design of enzyme-catalyzed SERS sensors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases., Competing Interests: Competing interests statement:Authors are inventors on intellectual property related to this work that is owned by Stanford University and New York University. J.W. is on the Scientific Advisory Board of Rootpath Genomics and is a consultant for BMS (Relatlimab Advisory Council) and Beijing Hanmi Pharmaceutical Co., LTD. J.R.C. is a cofounder and equity holder of Combangio, Inc. (now Kala Bio), xCella Biosciences (now OmniAb), Charged Biotherapeutics, TwoStep Therapeutics, and Red Tree Venture Capital; has financial interests in Aravive, Inc.; is a member of the Board of Directors of OmniAb, Revel Pharmaceuticals, Excellergy Therapeutics, Rondo Therapeutics, Tachyon Therapeutics, and Biograph 55; and is a Board Observer at Acrigen Biosciences. The other authors have no competing interests.

The MHC-I antigen presentation (AP) pathway is key to shaping mammalian CD8 + T cell immunity, with its aberrant expression closely linked to low tumor immunogenicity and immunotherapy resistance. While significant attention has been given to genetic mutations and downregulation of positive regulators that are essential for MHC-I AP, there is a growing interest in understanding how tumors actively evade MHC-I expression and/or AP through the induction of MHC-I inhibitory pathways. This emerging field of study may offer more viable therapeutic targets for future cancer immunotherapy. Here, we explore potential mechanisms by which cancer cells evade MHC-I AP and function and propose therapeutic strategies that might target these MHC-I inhibitors to restore impaired T cell immunity within the tumor microenvironment (TME)., Competing Interests: Declaration of interests J.W. is on the Scientific Advisory Board of Rootpath Genomics and is a consultant for Bristol Myers Squibb (Relatlimab Advisory Council) and Hanmi Pharmaceutical Co., Ltd. The other authors have no interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background Detection of extranodal extension (ENE) at pathology is a poor prognostic indicator for rectal cancer, but whether ENE can be identified at pretreatment MRI is, to the knowledge of the authors, unknown. Purpose To evaluate the performance of pretreatment MRI in detecting ENE using a matched pathologic reference standard and to assess its prognostic value in patients with rectal cancer. Materials and Methods This single-center study included a prospective development data set consisting of participants with rectal adenocarcinoma who underwent pretreatment MRI and radical surgery (December 2021 to January 2023). MRI characteristics were identified by their association with ENE-positive nodes (χ 2 test and multivariable logistic regression) and the performance of these MRI features was assessed (area under the receiver operating characteristic curve [AUC]). Interobserver agreement was assessed by Cohen κ coefficient. The prognostic value of ENE detected with MRI for predicting 3-year disease-free survival was assessed by Cox regression analysis in a retrospective independent validation cohort of patients with locally advanced rectal cancer (December 2019 to July 2020). Results The development data set included 147 participants (mean age, 62 years ± 11 [SD]; 87 male participants). The retrospective cohort included 110 patients (mean age, 60 years ± 9; 79 male participants). Presence of vessel interruption and fusion (both P < .001), heterogeneous internal structure, and the broken-ring and tail signs (odds ratio range, 4.10-23.20; P value range, <.001 to .002) were predictors of ENE at MRI, and together achieved an AUC of 0.91 (95% CI: 0.88, 0.93) in detecting ENE. Interobserver agreement was moderate for the presence of vessel interruption and fusion (κ = 0.46 for both) and substantial for others (κ = 0.61-0.67). The presence of ENE at pretreatment MRI was independently associated with worse 3-year disease-free survival (hazard ratio, 3.00; P = .02). Conclusion ENE can be detected at pretreatment MRI, and its presence was associated with worse prognosis for patients with rectal cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Eberhardt in this issue.

With its high resolving power and sensitivity, mass spectrometry is considered the most informative technique for metabolite qualitation and quantification in the plant sciences. However, the spatial location information, which is crucial for the exploration of plant physiological mechanisms, is lost. Mass spectrometry imaging (MSI) is able to visualize the spatial distribution of a large number of metabolites from the complex sample surface in a single experiment. In this paper, a flexible and low-cost laser desorption-dielectric barrier discharge ionization-MSI (LD-DBDI-MSI) platform was constructed by combining an LD system with an in-line DBDI source, a high-precision sample translation stage, and an ambient mass spectrometer. It can be operated at a spatial resolution of 20 μm in an atmospheric environment and requires minimal sample preparation. This study presents images of in-situ metabolic profiling of two kinds of plants from different origins, a wild and a farmed Rheum palmatum L. From the screen of these two root sections, the wild one presented five more endogenous molecules than the farmed one, which provides information about the differences in metabolomics.

Background: Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients., Methods: A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation., Results: A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5-58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906-8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176-2.384), arthralgia (OR = 3.197, 95% CI 1.986-5.148), eye bulging pain (OR = 3.482, 95% CI 1.349-8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310-2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145-2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%)., Conclusions: More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers., (© 2024. The Author(s).)

This paper demonstrates a high-energy, single-longitudinal-mode (SLM), actively Q -switched fiber laser based on the injection seeding technique. The large-mode-area double-cladding fiber is used as the gain medium to improve energy storage. Simultaneously, by using the linear electro-optic effect of the negative uniaxial crystal ( β - B a B 2 O 4 , BBO), a matching frequency-shift-free Q -switch with high damage threshold and high extinction-ratio is designed. Before reaching the stimulated Brillouin scattering threshold, the SLM Q -switched pulses can be achieved with energy higher than 15 µJ over a wide range of repetition rates from 10 to 80 kHz, and the maximum output power reaches 1.2 W at the repetition rate of 80 kHz, which may be the highest output pulse energy for such a SLM Q -switched fiber laser so far, to our best knowledge.

Breeding has dramatically changed the plant architecture of wheat (Triticum aestivum), resulting in the development of high-yielding varieties adapted to modern farming systems. However, how wheat breeding shaped the genomic architecture of this crop remains poorly understood. Here, we performed a comprehensive comparative analysis of a whole-genome resequencing panel of 355 common wheat accessions (representing diverse landraces and modern cultivars from China and the United States) at the phenotypic and genomic levels. The genetic diversity of modern wheat cultivars was clearly reduced compared to landraces. Consistent with these genetic changes, most phenotypes of cultivars from China and the United States were significantly altered. Of the 21 agronomic traits investigated, 8 showed convergent changes between the 2 countries. Moreover, of the 207 loci associated with these 21 traits, more than half overlapped with genomic regions that showed evidence of selection. The distribution of selected loci between the Chinese and American cultivars suggests that breeding for increased productivity in these 2 regions was accomplished by pyramiding both shared and region-specific variants. This work provides a framework to understand the genetic architecture of the adaptation of wheat to diverse agricultural production environments, as well as guidelines for optimizing breeding strategies to design better wheat varieties., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Polycyclic aromatic hydrocarbons (PAHs) and halogenated derivatives are a series of environmental pollutants with potential toxicity and health risks on biosystems and the ecosystem. Rapid and sensitive analysis of trace PAHs and halogenated PAHs in complex environmental samples is a challenging topic for analytical science. Here we report the development of a nanospray laser-induced plasma ionization MS method for rapid and sensitive analysis of trace PAHs and halogenated PAHs under ambient and open-air conditions. A nanospray tip was applied for loading samples and placed pointing to the MS inlet, being a nanospray emitter with the application of a high voltage. A beam of laser was focused to induce energetic plasma between the nanospray emitter and the MS inlet for ionization of PAHs and halogenated PAHs for mass spectrometric analysis. Meanwhile, an inner-wall naphthyl-coated nanospray emitter was developed and applied as a solid-phase microextraction (SPME) probe for highly selective enrichment of trace PAHs and halogenated PAHs in complex environmental samples, and some organic solvent was applied to desorb the analytes for nanospray laser-induced plasma ionization MS analysis. Satisfactory linearity for each target PAH and halogenated PAH was obtained, with correlation coefficient values ( r ) no less than 0.9917. The method showed extremely high sensitivity for analysis of trace PAHs and halogenated PAHs in water, with limits of detection (LODs) and quantification (LOQs) of 0.0001-0.02 and 0.0003-0.08 μg/L, respectively. By using the inner-wall naphthyl-coated nanospray laser-induced plasma ionization MS method, sensitive detection of trace PAHs and halogenated PAHs in real sewage and wastewater samples was successfully achieved.

Key Message: Five environmentally stable QTLs for spikelet number per spike and days to heading were identified using a high-genetic map containing 95,444 SNPs, among which QSns.ucas-5B was validated using residual heterozygous line at multiple environments. Spikelet number per spike (SNS) and days to heading (DTH) play pivotal roles in the improvement of wheat yield. In this study, a high-density genetic map for a recombinant inbred lines (RILs) population derived from Zhengnong 17 (ZN17) and Yangbaimai (YBM) was constructed using 95,444 single-nucleotide polymorphism (SNP) markers from the Wheat660K SNP array. Our study identified a total of five environmentally stable QTLs for SNS and DTH, one of which was named QSns.ucas-5B, with a physical interval of approximately 545.4-552.1 Mb on the 5BL chromosome arm. Importantly, the elite haplotype within QSns.ucas-5B showed a consistent and positive effect on SNS, grain number and weight per spike, without extending the days to heading. These findings provide a foundation for future efforts to map and clone the gene(s) responsible for QSns.ucas-5B and further indicate the potential application of the developed and validated InDel marker of QSns.ucas-5B for molecular breeding purposes, aimed at improving wheat grain yield., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: At present, the relationship between sleep and inflammatory factors is not clear. The aim of this study was to investigate the relationship between specific inflammatory factors and sleep in MDD patients., Methods: We measured and compared clinical features and 10 peripheral blood inflammatory factors in 40 MDD patients with sleep disorders, 80 MDD patients without sleep disorders, and 80 healthy controls. Correlation analysis and multiple linear regression analysis were used to explore the relationship between sleep and inflammatory factors., Result: The levels of IL-1β, IL-2, IL-6, IL-8, IL-10, CRP, TNF-α, CXCL-1, CXCL-2, and IFN-γ were different among the three groups(all p<0.05).Poor sleep quality was significantly negatively correlated with IL-2 and IL-8 (all p<0.01), and significantly positively correlated with IL-6, IL-10, CRP, TNF-α, CXCL-1, CXCL-2 and IFN-γ (all p<0.01). IL-8 could significantly negatively predict the deterioration of sleep quality (p<0.001), and TNF-a and IFN-γ could significantly positively predict the deterioration of sleep quality (all p<0.05)., Limitations: The self-rating scale was used in this study., Conclusions: Inflammatory factors are disrupted in patients with sleep disorders. The lower the level of IL-8 in peripheral blood of MDD patients, the higher the TNF-a and IFN-γ, and the worse the quality of sleep., Competing Interests: Declaration of Competing Interest The author declares that there is no potential conflict of interest of employment, consultancies, etc. among all the authors of this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8 + T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers., Competing Interests: Declaration of interests J.W., I.A., X.C., and Q.L. are named inventors on a patent application related to this study. J.W. is on the Scientific Advisory Board of RootPath Inc. and is a consultant for Bristol Myers Squibb (Relatlimab Advisory Council). D.S. is currently an employee at Rubius Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Local anesthetics, drugs that only affect a restricted area of the body, are widely used in daily clinical practice. Less studied but equally important is the distribution of local anesthetics inside organisms. Here, we present a rapid in situ testing method of drug distribution in various organs. The temporal and spatial distribution of anesthetics in mice was measured by solid-phase microextraction (SPME), thermal desorption (TD), and dielectric barrier discharge ionization (DBDI) atmospheric pressure mass spectrometry. A coated SPME probe using a tungsten wire as the support covered with a carbonaceous material was prepared by a simple, low-cost flame method. An in-line structure of the inlet allows TD and DBDI to share the same capillary tube, which greatly improves the transmission efficiency. Nine kinds of anesthetics, such as lidocaine and dyclonine, were detected, and the limit of detection was determined to be as low as 13 pg/mL. In addition, the time-dependent distribution of drugs in mice organs was studied. We also found that macromolecules in organisms do not noticeably interfere with the detection. This method is convenient and efficient because it does not require tissue homogenates and allows direct in situ detection. Compared with the conventional analytical methods, this method is simple and rapid, works in situ, and allows microscale analysis of trace analytes in biological organisms with high sensitivity.

All‑trans retinoic acid (ATRA) has been implicated in the differentiation of hepatic stellate cells (HSCs). In the present study, the liver‑targeting hyaluronic acid micelles (ADHG) were prepared for co‑delivery of ATRA and doxorubicin (DOX) to block the HSC‑hepatoma interrelation. To simulate the tumor microenvironment, an in vitro dual‑cell model and an in vivo co‑implantation mouse model were established for anticancer studies. The experimental methods involved the MTT assay, wound‑healing assay, cellular uptake, flow cytometry and and in vivo antitumor study. The results revealed that the HSCs in the research models notably promoted tumor proliferation and migration. Furthermore, ADHG were readily internalized by cancer cells and HSCs simultaneously, and widely distributed in cancer regions. The in vivo antitumor studies demonstrated that ADHG could notably decrease HSC activation and extracellular matrix deposition, as well as constrain tumor growth and metastasis. Therefore, ATRA could facilitate DOX‑induced anti‑proliferation and anti‑metastasis effects, and ADHG are a promising nano‑sized formulation for the combination therapy of hepatocellular carcinoma.

The intestinal epithelial cells (IECs) constitute the primary barrier between host cells and numerous foreign antigens; it is unclear how IECs induce the protective immunity against pathogens while maintaining the immune tolerance to food. Here, we found IECs accumulate a less recognized 13-kD N-terminal fragment of GSDMD that is cleaved by caspase-3/7 in response to dietary antigens. Unlike the 30-kD GSDMD cleavage fragment that executes pyroptosis, the IEC-accumulated GSDMD cleavage fragment translocates to the nucleus and induces the transcription of CIITA and MHCII molecules, which in turn induces the Tr1 cells in upper small intestine. Mice treated with a caspase-3/7 inhibitor, mice with GSDMD mutation resistant to caspase-3/7 cleavage, mice with MHCII deficiency in IECs, and mice with Tr1 deficiency all displayed a disrupted food tolerance phenotype. Our study supports that differential cleavage of GSDMD can be understood as a regulatory hub controlling immunity versus tolerance in the small intestine., Competing Interests: Declaration of interests S.Z. is a cofounder of Ibiome which studies microbial regulation of immune responses. R.A.F. is a cofounder of Ventus, which studies inflammatory pathways. Both in topics unrelated to the subject of this work., (Copyright © 2023. Published by Elsevier Inc.)

Recent efforts have focused on preparing drug-loaded hydrogel for wound healing. In order to obtain an ideal hydrogel dressing for skin wound repair, a carboxymethyl chitosan-gelatin hydrogel was prepared for co-delivery of SP (substance P) and DMOG (dimethyloxallyl glycine) by a chemical cross-linking method using genipin as the cross-linking agent. The synthesized hydrogels have good biocompatibility and physicochemical properties due to the low toxicity of the hydrogel material. The three-dimensional network structure of the hydrogels supports cell migration and proliferation, and the combination of SP and DMOG drugs exhibited strong effects on cell proliferation. Moreover, the co-loaded drug hydrogels could significantly promote wound healing in vivo, and provide a potential hydrogel for wound healing., (© 2022 Wiley Periodicals LLC.)

Curcumin is a dietary spice and coloring agent widely used in food and herbal medicine. Herein, we visualized the distribution of curcumin in fresh Curcuma longa (turmeric) root sections using the state-of-the-art vacuum-ultraviolet (VUV, 118 nm) single photon-postionization mass spectrometric imaging method. Compared with other mass spectrometric imaging methods, the proposed method does not require any sample pre-treatment. The proposed approach could be more conducive to in situ detection of small molecules. The mass spectroscopic imaging (MSI) images of curcumin sections with a lateral resolution of 100 μm indicated that the concentrations of curcumin decreased from the phloem to the xylem of the root. We also show MS imaging of curcumin in the turmeric root at different maturity periods, revealing the transformation of this endogenous species. The result of quantitative analysis indicates that the total curcumin content of the mature turmeric root is estimated to be 3.43%, which is consistent with the previous report that the content of curcumin in the turmeric root is estimated between 3% and 5%. The report indicated that the proposed method of VUV single photon postionization MSI can be used to explore the metabolic process of plants, which is critical for herbal farming, harvest, and its ingredient extraction.

Background Accurate restaging of rectal cancer is crucial in the selection of candidates for local excision after neoadjuvant chemotherapy and radiation therapy (NCRT). The conventional approach of combined T2-weighted imaging and diffusion-weighted imaging (DWI) at MRI has been found to have limitations in restaging. Purpose To determine the diagnostic performance of contrast-enhanced MRI in distinguishing between pathologic stage ypT0-1 and ypT2-4 rectal cancer after NCRT compared with T2-weighted imaging and DWI by using surgical pathologic specimens as the reference standard. Materials and Methods This retrospective study evaluated MRI scans in all consecutive patients with locally advanced rectal cancer who underwent total mesorectal excision after NCRT in Peking University Cancer Hospital (Beijing, China) from January 2014 to October 2018. All MRI features obtained before and after NCRT were evaluated by two experienced radiologists, independently and blinded to personal, clinical, and histopathologic information. The post-NCRT yT stage was assigned based on high b value ( b = 1000 sec/mm 2 ) DWI with T2-weighted imaging (protocol 1) in the first round and on contrast-enhanced MRI scans (protocol 2) in a second round. The diagnostic accuracies for the differentiation of pathologic stage ypT0-1 from ypT2-4 tumors with the two protocols were compared. Multivariable regression analysis was used to explore the independent predictors of pathologic stage ypT0-1 tumors. Results A total of 328 patients (mean age, 57 years ± 10 [SD]; 227 men; 69%) were enrolled. The area under the receiver operating characteristic curve of the contrast-enhanced MRI protocol in predicting pathologic stage ypT0-1 tumors was 0.81 (95% CI: 0.77, 0.85), which was better than that of the T2-weighted DWI protocol (0.66; 95% CI: 0.60, 0.71; P < .001). Multivariable logistic regression analysis showed that yT stage after NCRT on contrast-enhanced MRI scans was the only independent predictor of pathologic stage ypT0-1 tumors ( P < .001). Conclusion Contrast-enhanced MRI provides accurate differentiation of ypT0-1 from ypT2-4 tumors after neoadjuvant chemotherapy and radiation therapy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Zins and Santiago in this issue.

Background: Myocardial ischemia-reperfusion injury (MIRI) caused by the reperfusion therapy of myocardial ischemic diseases is a kind of major disease that threatens human health and lives severely. There are lacking of effective therapeutic measures for MIRI. MicroRNAs (miRNAs) are abundant in mammalian species and play a critical role in the initiation, promotion, and progression of MIRI. However, the biological role and molecular mechanism of miRNAs in MIRI are not entirely clear., Methods: We used bioinformatics analysis to uncover the significantly different miRNA by analyzing transcriptome sequencing data from myocardial tissue in the mouse MIRI model. Multiple miRNA-related databases, including miRdb, PicTar, and TargetScan were used to forecast the downstream target genes of the differentially expressed miRNA. Then, the experimental models, including male C57BL/6J mice and HL-1 cell line, were used for subsequent experiments including quantitative real-time polymerase chain reaction analysis, western blot analysis, hematoxylin and eosin staining, flow cytometry, luciferase assay, gene interference, and overexpression., Results: MiR-582-5p was found to be differentially upregulated from the transcriptome sequencing data. The elevated levels of miR-582-5p were verified in MIRI mice and hypoxia/reperfusion (H/R)-induced HL-1 cells. Functional experiments revealed that miR-582-5p promoted apoptosis of H/R-induced HL-1 cells via downregulating cAMP-response element-binding protein 1 (Creb1). The inhibiting action of miR-582-5p inhibitor on H/R-induced apoptosis was partially reversed after Creb1 interference., Conclusions: Collectively, the research findings reported that upregulation of miR-582-5p promoted H/R-induced cardiomyocyte apoptosis by inhibiting Creb1. The potential diagnostic and therapeutic strategies targeting miR-582-5p and Creb1 could be beneficial for the MIRI treatment., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Directly modulated vector beam lasers are increasingly desirable for wide applications ranging from optical manipulation to optical communications. We report the first, to our knowledge, high-speed directly modulated vector beam laser with azimuthally polarized emission. It is a microcylinder cavity interacted with a proper second-order grating on top, which enables single mode lasing and efficient surface emission. Through theoretical and numerical analysis, the laser is designed in detail. With an optimized top grating, the emission of the laser is an azimuthally polarized vector beam. With high-differential-gain material and a small active region, the laser can be directly modulated with a high 3 dB bandwidth reach of 40 GHz in simulation. The proposed high-speed directly modulated semiconductor laser with an azimuthally polarized vector beam is promising for applications in fiber space communications or quantum information.

Background and Aims: Ribonucleotide reductase (RNR), functioning in the de novo synthesis of deoxyribonucleoside triphosphates (dNTPs), is crucial for DNA replication and cell cycle progression. In most plants, the large subunits of RNR have more than one homologous gene. However, the different functions of these homologous genes in plant development remain unknown. In this study, we obtained the mutants of two large subunits of RNR in tomato and studied their functions., Methods: The mutant ylc1 was obtained by ethyl methyl sulfonate (EMS) treatment. Through map-based cloning, complementation and knock-out experiments, it was confirmed that YLC1 encodes a large subunit of RNR (SlRNRL1). The expression level of the genes related to cell cycle progression, chloroplast biogenesis and photosynthesis was assessed by RNA-sequencing. In addition, we knocked out SlRNRL2 (a SlRNRL1 homologue) using CRISPR-Cas9 technology in the tomato genome, and we down-regulated SlRNRL2 expression in the genetic background of slrnrl1-1 using a tobacco rattle virus-induced gene silencing (VIGS) system., Key Results: The mutant slrnrl1 exhibited dwarf stature, chlorotic young leaves and smaller fruits. Physiological and transcriptomic analyses indicated that SlRNRL1 plays a crucial role in the regulation of cell cycle progression, chloroplast biogenesis and photosynthesis in tomato. The slrnrl2 mutant did not exhibit any visible phenotype. SlRNRL2 has a redundant function with SlRNRL1, and the double mutant slrnrl1slrnrl2 is lethal., Conclusions: SlRNRL1 is essential for cell cycle progression, chloroplast biogenesis and photosynthesis. In addition, SlRNRL1 and SlRNRL2 possess redundant functions and at least one of these RNRLs is required for tomato survival, growth and development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Key Message: A tiller inhibition gene TIN5 was delimited to an approximate 2.1 Mb region on chromosome Tu7 that contains 24 annotated genes. Grain yield in wheat (Triticum aestivum L.) is a polygenic trait representing many developmental processes and their interactions with the environments. Among them, tillering capacity is an important agronomic trait for plant architecture and grain yield, but the genetic basis of tiller formation in wheat remains largely unknown. In this study, we identified a tiller inhibition 5 (tin5) mutant from ethyl methane sulfonate treated G1812 (Triticum urartu Thumanjan ex Gandilyan). A mapping population was constructed with tin5/G3146. Based on the sequence differences between G1812 and G3146, large insertions and deletions (≥ 5 bp) were selected and verified, and a skeleton physical map was constructed with genome-wide 168 polymorphic InDel markers. Genetic analysis revealed that the low-tiller phenotype was controlled by a single recessive locus, which we named TIN5. This locus was mapped to a 2.1-Mb region that contained 24 annotated genes on chromosome Tu7. Among these annotated genes, only TuG1812G0700004539 showed a non-synonymous polymorphism between tin5 and the wild type. Our finding will facilitate its map-based cloning and pave the way for an in-depth analysis of the underlying genetic basis of tiller formation and regulation patterns., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The widespread deficiency of iron (Fe) and sulfur (S) is becoming a global concern. The underlying mechanisms regulating Fe and S sensing and signaling have not been well understood. We investigated the crosstalk between Fe and S using mutants impaired in Fe homeostasis, sulfate assimilation, and glutathione (GSH) biosynthesis. We showed that chlorosis symptoms induced by Fe deficiency were not directly related to the endogenous GSH levels. We found dynamic crosstalk between Fe and S networks and more interestingly observed that the upregulated expression of IRT1 and FRO2 under S deficiency in Col-0 was missing in the cad2-1 mutant background, which suggests that under S deficiency, the expression of IRT1 and FRO2 was directly or indirectly dependent on GSH. Interestingly, the bottleneck in sulfite reduction led to a constitutively higher IRT1 expression in the sir1-1 mutant. While the high-affinity sulfate transporter ( Sultr1;2 ) was upregulated under Fe deficiency in the roots, the low-affinity sulfate transporters ( Sultr2;1, and Sultr2;2 ) were down-regulated in the shoots of Col-0 seedlings. Moreover, the expression analysis of some of the key players in the Fe-S cluster assembly revealed that the expression of the so-called Fe donor in mitochondria ( AtFH ) and S mobilizer of group II cysteine desulfurase in plastids ( AtNFS2 ) were upregulated under Fe deficiency in Col-0. Our qPCR data and ChIP-qPCR experiments suggested that the expression of AtFH is likely under the transcriptional regulation of the central transcription factor FIT., 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 Khan, Lu, Cui, Rajab, Wu, Chai and Ling.)

Background: Tumor microenvironment (TME) plays a vital role in the development of hepatocellular carcinoma (HCC). Mounting evidence indicates that peripheral nerves could induce a shift from quiescent hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) by secreting substance P (SP). The anti-tumor strategy by targeting "SP-HSCs-HCC" axis might be an effective therapy to inhibit tumor growth and metastasis., Objective: In this study, we prepared novel liposomes (CUR-APR/HA&GA-LPs) modified with hyaluronic acid (HA) and glycyrrhetinic acid (GA) for co-delivery aprepitant (APR) and curcumin (CUR), in which APR was chosen to inhibit the activation of HSCs by blocking SP/neurokinin-1 receptor (NK-1R), and CUR was used to induce apoptosis of tumor cells., Results: To mimic the TME, we established "SP+HSCs+HCC" co-cultured cell model in vitro. The results showed that CUR-APR/HA&GA-LPs could be taken up by CAFs and HCC simultaneously, and inhibit tumor cell migration. Meanwhile, the "SP+m-HSCs+HCC" co-implanted mice model was established to evaluate the anti-tumor effect in vivo. The results showed that CUR-APR/HA&GA-LPs could inhibit tumor proliferation and metastasis, and reduce extracellular matrix (ECM) deposition and tumor angiogenesis, indicating a superior anti-HCC effect., Conclusion: Overall, the combination therapy based on HA&GA-LPs could be a potential nano-sized formulation for anti-HCC therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Li et al.)

Purpose: Current low anterior resection syndrome (LARS) score is lagging behind and only based on clinical symptoms patient described. Preoperative imaging indicators which can be used to predict LARS is unknown. We proposed preoperative MRI parameters for identifying major LARS., Methods: Patients receiving curative restorative anterior resection from Sept. 2007 to Sept. 2015 were collected to complete LARS score (median 75.7 months since surgery). MRI measurements associated with LARS were tested, and a multivariate logistic model was conducted for predicting LARS. Receiver operating characteristic curve was used to evaluate the model., Results: Two hundred fifty-five patients undergoing neoadjuvant chemoradiotherapy and 72 patients undergoing direct surgery were enrolled. The incidence of major LARS in NCRT group was significantly higher (53.3% vs.34.7%, P = 0.005). In patients with neoadjuvant chemoradiotherapy, the thickness of ARJ (TARJ), the distance between the tumor's lower edge and anal rectal joint (DTA), and sex were independent factors for predicting major LARS; ORs were 0.382 (95% CI, 0.198-0.740), 0.653 (95% CI, 0.565-0.756), and 0.935 (95% CI, 0.915-0.955). The AUC of the multivariable model was 0.842 (95% CI, 0.794-0.890). In patients with direct surgery, only DTA was the independent factor for predicting major LARS; OR was 0.958 (95% CI, 0.930-0.988). The AUC was 0.777 (95% CI: 0.630-0.925)., Conclusions: Baseline MRI measurements have the potential to predict major LARS in rectal cancer, which will benefit the decision-making and improve patients' life quality., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Atrial fibrillation (AF) is the most common sustained arrhythmia with a high rate of recurrence after catheter ablation. The gene encoding transcription factor 21 ( TCF21 ) has been linked to coronary artery disease risk by human genome-wide association studies in multiple racial ethnic groups. However, the association of TCF21 with AF remains unclear., Patients and Methods: Circulating leukocytes in patients with paroxysmal AF (PAF) and 92 age-matched controls without a history of cardiovascular disease, AF and other arrhythmias were collected. A total of 224 PAF patients receiving radiofrequency ablation had an 18-month scheduled follow-up study for recurrence of AF. Three single-nucleotide polymorphisms (SNPs) of TCF21 ( rs2327429, rs2327433 and rs12190287 ) were genotyped by PCR, and serum levels of TCF21 were measured by ELISA., Results: More males and smokers were observed in the PAF group compared with controls. C allele of rs2327429 , G allele and GG genotype of rs12190287 were markedly associated with the increased onset of PAF. The levels of serum TCF21 were significantly higher in PAF group than those in control group (1.96 ± 0.85 vs 0.86 ± 0.49 ng/mL, P <0.001). Based on logistic regression analysis, we confirmed that risk allele at rs12190287 and serum TCF21 concentration were independently correlated with the incidence of PAF. Furthermore, GG genotype of rs12190287 enhanced the susceptibility of AF recurrence after ablation., Conclusion: G allele and GG genotype of rs12190287 in TCF21 and elevated TCF21 concentration are significantly associated with the onset of PAF and recurrence after ablation., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Zhang et al.)

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein-altering de novo coding variants in complex cases (p = 3.3 × 10 -4 ), especially in genes that are intolerant of loss-of-function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein-altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. Our results suggest significant genetic heterogeneity of EA/TEF and may have implications for the mechanisms of other rare congenital anomalies., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Purpose: To explore the association between CT-detected extramural vascular invasion (ctEMVI) and lymph-vascular invasion (LVI) in colon cancer, and analyze the prognostic value of ctEMVI in different conditions of LVI., Methods: This single-center, retrospective study included 448 colon cancer patients from January 2015 to December 2017. Preoperative CT features and clinical and pathological data were collected. Associations between ctEMVI and LVI were tested. Univariate and multivariate logistic regression was performed. Multivariate Cox regression was performed adjusted with propensity score(PS). Kaplan-Meier method was used to compare survival differences between the ctEMVI and LVI groups. A 1:1 patient pairing was conducted using PS matching to assess the prognostic effect of ctEMVI in LVI subgroups., Results: Among the 448 patients, there were 261 men and 187 women, with an average age of 63 ± 12 years. The coincidence rate of ctEMVI and LVI was 73.9%. The k coefficient for identifying ctEMVI was 0.84. ctEMVI and LVI were both independent risk factors for overall survival (ctEMVI: HR 2.8, 95% CI 1.5-5.5; LVI: HR 2.2, 95% CI 1.2-4.1) and metastasis-free survival (ctEMVI: HR 3.3, 95% CI 1.7-6.4; LVI: HR 2.4, 95% CI 1.3-4.5) adjusted with PS. In the LVI(+) subgroup, the prognosis of ctEMVI(+) was significantly worse than that of ctEMVI(-); in the LVI(-) subgroup, the prognosis of different ctEMVI states was similar., Conclusion: ctEMVI is an independent prognostic risk factor and has different prognostic value in different LVI states. It is recommended to perform the evaluation in routine work, especially for patients with positive LVI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The cT3 substage criteria based on extramural depth of tumor invasion in rectal cancer have several limitations., Objective: This study proposed that the distance between the deepest tumor invasion and mesorectal fascia on pretherapy MRI can distinguish the prognosis of patients with cT3 rectal cancer., Design: This is a cohort study., Setting: This study included a prospective, single-center, observational cohort and a retrospective, multicenter, independent validation cohort., Patient: Patients who had cT3 rectal cancer with negative mesorectal fascia undergoing neoadjuvant chemoradiotherapy followed by radical surgery were included in 4 centers in China from January 2013 to September 2014., Intervention: Baseline MRI with the distance between the deepest tumor invasion and mesorectal fascia, extramural depth of tumor invasion, and mesorectum thickness were measured., Main Outcome Measures: The cutoff of the distance between the deepest tumor invasion and mesorectal fascia was determined by time-dependent receiver operating characteristic curves, supported by a 5-year progression rate from the prospective cohort, and was then validated in a retrospective cohort., Results: There were 124 and 274 patients included in the prospective and independent validation cohorts. The distance between the deepest tumor invasion and mesorectal fascia was the only predictor for cancer-specific death (HR, 0.1; 95% CI, 0.0-0.7) and was also a significant predictor for distant recurrence (HR, 0.4; 95% CI, 0.2-0.9). No statistically significant difference was observed in prognosis between patients classified as T3a/b and T3c/d., Limitations: The sample size is relatively small, and the study focused on cT3 rectal cancers with a negative mesorectal fascia., Conclusions: A cutoff of 7 mm of the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI can distinguish cT3 rectal cancer from a different prognosis. We recommend using the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI for local and systemic risk assessment and providing a tailored schedule of neoadjuvant treatment. See Video Abstract at http://links.lww.com/DCR/B682.CORRELACIÓN ENTRE LA DISTANCIA DE LA FASCIA MESORRECTAL Y EL PRONÓSTICO DEL CÁNCER DE RECTO cT3: RESULTADOS DE UN ESTUDIO MULTICÉNTRICO DE CHINAANTECEDENTES:Los criterios de subestadificación cT3 basados en la profundidad extramural de invasión tumoral en el cáncer de recto tienen varias limitaciones.OBJETIVO:Este estudio propuso que la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética preterapia puede distinguir el pronóstico de los pacientes con cT3.DISEÑO:Estudio de cohorte.ENTORNO CLINICO:El estudio incluyó una cohorte observacional, prospectiva, unicéntrica, y una cohorte de validación retrospectiva, multicéntrica e independiente.PACIENTE:Se incluyeron pacientes con cáncer de recto cT3 con fascia mesorrectal negativa sometidos a quimio-radioterapia neoadyuvante seguida de cirugía radical en cuatro centros de China desde enero de 2013 hasta septiembre de 2014.INTERVENCIÓN:Imágenes de resonancia magnética de referencia fueron medidas con la distancia entre la invasión tumoral más profunda y la fascia mesorrectal; la profundidad extramural de la invasión tumoral y el grosor del mesorrecto.PRINCIPALES MEDIDAS DE VALORACION:El límite de la distancia entre la invasión tumoral más profunda y la fascia mesorrectal se determinó mediante curvas características operativas del receptor dependientes del tiempo y se apoyó en la tasa de progresión a 5 años de la cohorte prospectiva, y luego se validó en una cohorte retrospectiva.RESULTADOS:Se incluyeron 124 y 274 pacientes en la cohorte de validación prospectiva e independiente, respectivamente. La distancia entre la invasión tumoral más profunda de la fascia mesorrectal fue el único predictor de muerte específica por cáncer (Hazard ratio: 0.1, 95% CI, 0,0-0,7); y también fue un predictor significativo de recurrencia distante Hazard ratio: 0,4, 95% CI, 0,2-0,9). No se observaron diferencias estadísticamente significativas en el pronóstico entre los pacientes clasificados como T3a/b y T3c/d.LIMITACIONES:El tamaño de la muestra es relativamente pequeño y el estudio se centró en los cánceres de recto cT3 con fascia mesorrectal negativa.CONCLUSIONES:Un límite de 7 mm de distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia puede distinguir el cáncer de recto cT3 de diferentes pronósticos. Recomendamos la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia para la evaluación del riesgo local y sistémico, proporcionando un programa personalizado de tratamiento neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B682. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2022.)

The CRISPR-Cas9 system acts as the prokaryotic immune system and has important applications in gene editing. The protein Cas9 is one of its crucial components. The role of Cas9 is to search for specific target sequences on the DNA and cleave them. In this Letter, we introduce a model of facilitated diffusion for Cas9 and fit its parameters to single-molecule experiments. Our model confirms that Cas9 search for targets by sliding, but shows that its sliding length is rather short. We then investigate how Cas9 explores a long stretch of DNA containing randomly placed targets. We solve this problem by mapping it into the theory of Anderson localization in condensed matter physics. Our theoretical approach rationalizes experimental evidence on the distribution of Cas9 molecules along the DNA.

Atmospheric pressure mass spectrometry imaging (AP-MSI) is a powerful tool in many fields; however, there are still some difficulties to achieve high spatial resolution for AP-MSI, one of them being the need for a small ablation crater. Here, a fiber probe laser ablation (FPLA) system is introduced that uses an etched optical fiber with a sharp tip (o.d. 200 nm) to deliver ablation laser pulses to a sample surface to ablate materials with high spatial resolution. The tip-to-sample distance was adjusted to ∼10 μm using a micro-actuator having a stepping motor with submicron accuracy. The laser-ablated neutrals were post-ionized using a home-built in-line dielectric barrier discharge source, which can be interfaced to any mass spectrometer with an AP interface. Using MSI on a standard sample with a striped pattern and sections of fingernails treated with the drug methyl green zinc chloride salt, a FPLA-DBDI-MSI spatial resolution of ≈5 μm was demonstrated.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, P meta  = 8.36 × 10 -8 , OR = 1.29; rs7259428, 19q12, ZNF536, P meta  = 7.58 × 10 -8 , OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, P meta  = 1.95 × 10 -8 ; rs2414487, 15q21.3, LOC145783, P meta  = 4.53 × 10 -9 ; rs2106525, 7q31.1, MDFIC, P meta  = 6.24 × 10 -9 ). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice., (© 2021. The Author(s).)

Background and Objective: Since the classification of gaming disorder (GD) by the World Health Organization (WHO) as "mental disorder caused by addictive behaviors," there has been controversy regarding whether online game behaviors can lead to mental disorder. This study aims to clarify the correlation between the online game behaviors of college students and anxiety, depression, and executive function of college students in China, from a questionnaire-based investigation. Methods: Based on the whole class random sampling method, a questionnaire survey was conducted among college students in Northern Anhui, China from March 7 to March 27, 2020. The questionnaires included the Internet Game Addiction (IGA) Scale, Behavior Rating Inventory of Executive Function (Adult Version, BRIEF-A), Generalized Anxiety Disorder Scale (GAD-7) and Patient Health Questionnaire Scale (PHQ-9). Results: A total of 850 participants completed the survey, including 353 males (41.53%) and 497 females (58.47%). The primary age group was 18-27 years (91.53%), and the educational background was a bachelor's degree (94.7%). The study found that the online behavior of 17.76% of college students was online game behavior. This study did not identify any students who met the criteria for IGA, and 3% met the criteria for indulgent behavior. A dual role of online games was identified; moderate online game activities can improve the emotional state and executive function of college students, while excessive online game behaviors that may not reach the degree of addiction can also harm emotional state and executive function. Conclusions: This study suggests that although IGA has been regarded as a mental disease, online game behavior should be treated differently. Online game activities should not be entirely denied, but mental disorders caused by excessive gaming activities deserve attention. In particular, the emotional state and executive function of students with excessive online game behaviors should be monitored and intervened in advance to avoid game behaviors turning into indulgent behaviors or addiction. As a cognitive control process, executive function may play a key role in regulating IGA and emotional state., 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, Wei, Zhou, Wang, Wang, Ren, Shao, Luo, Zhou, Chen, Lu, Song, Zhang, Fang, Zhang and Jiao.)

Hybrid necrosis, caused by complementary genes Ne1 and Ne2, is a serious barrier for combining desirable traits from different genotypes of wheat, affecting the full utilisation of heterosis. To date, both Ne1 and Ne2 are still not isolated although they were documented decades ago. We report here the map-based cloning and functional characterisation of Ne2, encoding a coiled coil-nucleotide-binding site-leucine-rich repeat (CC-NBS-LRR) protein. Homozygous frameshift mutations generated using the CRISPR/Cas9 approach confirmed the Ne2-inducing hybrid necrosis in wheat. Upregulated expression of Ne2 induced by Ne1 and excess hydrogen peroxide accumulation are associated with the necrosis formation. Genetic analyses of a Ne2 allele (Ne2 m ) and leaf rust resistance gene LrLC10/Lr13 revealed that they might be the same gene. Furthermore, we demonstrated that the frequency of the Ne2 allele was much lower in landraces (2.00%) compared with that in modern cultivars (13.62%), suggesting that Ne2 allele has been partially applied in wheat genetic improvement. Our findings open opportunities of thoroughly investigating the molecular mechanism of hybrid necrosis, selecting Lr13 and simultaneously avoiding hybrid necrosis in wheat breeding through marker-assisted selection., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~10 3 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 10 6 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion., (© 2021. The Author(s).)

Recent advances in communication enable individuals to use phones and computers to access information on the web. E-commerce has seen rapid development, e.g., Alibaba has nearly 12 hundred million customers in China. Click-Through Rate (CTR) forecasting is a primary task in the e-commerce advertisement system. From the traditional Logistic Regression algorithm to the latest popular deep neural network methods that follow a similar embedding and MLP, several algorithms are used to predict CTR. This research proposes a hybrid model combining the Deep Interest Network (DIN) and eXtreme Deep Factorization Machine (xDeepFM) to perform CTR prediction robustly. The cores of DIN and xDeepFM are attention and feature cross, respectively. DIN follows an adaptive local activation unit that incorporates the attention mechanism to adaptively learn user interest from historical behaviors related to specific advertisements. xDeepFM further includes a critical part, a Compressed Interactions Network (CIN), aiming to generate feature interactions at a vectorwise level implicitly. Furthermore, a CIN, plain DNN, and a linear part are combined into one unified model to form xDeepFM. The proposed end-to-end hybrid model is a parallel ensemble of models via multilayer perceptron. CIN and xDeepFM are trained in parallel, and their output is fed into a multilayer perceptron. We used the e-commerce Alibaba dataset with the focal loss as the loss function for experimental evaluation through online complex example mining (OHEM) in the training process. The experimental result indicates that the proposed hybrid model has better performance than other models., Competing Interests: Qiao Lu, Silin Li and Tuo Yang are employed by Taicu Music co Ltd., (©2021 Lu et al.)

Peripheral nerves have emerged as the important components in tumor microenvironment (TME), which could activate hepatic stellate cells (HSCs) by secreting substance P (SP), leading to hepatocellular carcinoma (HCC) invasion and metastasis. Herein, we proposed a novel anti-HCC concept of blocking "SP-HSCs-HCC" axis for omnidirectional inhibition of HCC development. To pursue this aim, the novel CAP/GA-sHA-DOX NPs were developed for targeted co-delivery of capsaicin (CAP) and doxorubicin (DOX) using glycyrrhetinic acid (GA) modified sulfated-HA (sHA) as nanocarriers. Among that, CAP could inhibit the activation of HSCs as an inhibitor of SP. Notably, to real mimic "SP-HSCs-HCC" axis for in vitro and in vivo evaluation, both "SP + LX-2+BEL-7402" co-cultured cell model and "SP + m-HSC + H22" co-implantation mice model were attempted for the first time. Furthermore, in vivo anti-HCC effects were performed in three different tumor-bearing models: subcutaneous implantation of H22 or "SP + m-HSC + H22", intravenous injection of H22 for lung metastasis, and orthotopic implantation of H22 for primary HCC. Our results showed that CAP/GA-sHA-DOX NPs could be efficiently taken up by tumor cells and activated HSCs (aHSCs) simultaneously, and effectively inhibit tumor drug-resistance and migration by blocking SP-induced HSCs activation. In addition, CAP/GA-sHA-DOX NPs exhibited low ECM deposition, less tumor angiogenesis, and superior in vivo anti-HCC effects. The anti-HCC mechanisms revealed that CAP/GA-sHA-DOX NPs could down-regulate the expression level of Vimentin and P-gp, reverse epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nano-sized combination therapy based on GA-sHA-DOX polymers could effectively inhibit drug-resistance and metastasis of HCC by blocking "SP-HSCs-HCC" axis, which provides a promising approach for cancer therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)