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Local animal health services in rural communities in Cambodia are mainly provided by village animal health workers (VAHWs), although the participation and contribution of VAHWs to livestock disease prevention are uncertain. The participation of the VAHWs as identified by their 'dropout rate' was examined in a desktop review in December 2020 of the national data on VAHWs recorded between 2011 and 2020. The contribution and involvement of VAHWs in disease prevention programmes were examined in a survey conducted between February and March 2014, then analyzed in the context of other surveys of VAHW knowledge, attitudes and practices. The survey involved guided group discussion with VAHWs (n = 198) from the two Cambodian provinces of Kampong Cham and Pursat. This study identified that VAHWs generated less than 22% of their annual household incomes from animal health services. Less than one-third had vaccinated livestock against foot-and-mouth disease (FMD), with none having vaccinated cattle every 6 months during the study period, and nearly half of the VAHWs having never vaccinated their own cattle against FMD. As no privately provided FMD vaccination services occurred in these communities, with all vaccines delivered through the government-subsidized programme, the findings confirmed that VAHWs only vaccinated animals against FMD when vaccines were made available by the Government. The desktop review found that the number of VAHWs in 2020 declined by more than 24% since 2017, and the proportion of female VAHWs was consistently low, with a mean of 8.26 (±1.019). These findings confirm findings from previous studies that identified considerable weaknesses in the VAHW system in Cambodia, particularly in contributing to FMD control. Cambodian animal health authorities require more effective policies to strengthen the current VAHW system, improving their services delivery; their retention as 'active'; their development of more sustainable roles with lower 'dropout' rates and the prolonged gender inequity. With the limited availability of government-subsidized FMD vaccination currently, extension programmes that engage VAHWs and farmers in seeking privately funded and delivered FMD vaccination that incorporates appropriate multivalent FMD serotype vaccines of high quality, delivered in small dose vials from a robust cold chain, is suggested. This strategy would assist VAHWs to contribute to the provision of private livestock vaccination services that are likely essential for sustainable FMD prevention and control in Cambodia., (© 2021 Wiley-VCH GmbH.)

Food-and-mouth disease (FMD) is endemic in Cambodia. The control programme for FMD has relied on vaccination, with poor vaccination uptake by smallholder farmers becoming an increasing concern. A study to improve the understanding of farmer knowledge, attitudes and practices of FMD control and vaccination was conducted in two Cambodian provinces (Kampong Cham and Pursat). The aim was to identify opportunities to improve the livestock disease control programmes provided by both the government and private sectors. The survey comprised 300 smallholder farmers using a one-on-one interview technique and was completed between January to February 2014. Results identified that over two-thirds of the respondent farmers had not vaccinated their cattle over 2 years (2011-2013). Of those who did, most cattle were vaccinated either once a year or once every 3 years. A booster had never been administered. It was concluded that the FMD vaccine had only been administered through an unreliable and limited government vaccination programme, and private FMD vaccination services were not accessed in the study areas. FMD outbreaks occurred every year during the study period, with a morbidity rate of over 30%. Isolation of first infected cattle from the household herd was not practiced, with treatment identified as the first preference intervention. Farmers often assisted other farmers to restrain and treat infected cattle both before (57%) and after (43%) their own cattle were infected. This indicated that most farmers did not practice basic biosecurity measures and chose to report FMD outbreaks to the village animal health workers (VAHW), friends, neighbours and relatives in preference to government officials. It was concluded that poor knowledge of disease transmission and biosecurity, with low FMD vaccination coverage and a focus on treatment, contribute to regular FMD outbreaks in these communities. Improvement of FMD control requires the cooperation of villagers, VAHWs and village leaders in disease reporting, with either improved funding of government vaccination services or establishing a private FMD vaccination service. Training programmes for farmers on disease transmission, and the importance of biosecurity and vaccination, including information on the cost-benefits of treatment versus full fee bi-annual FMD vaccination, are required., (© 2021 Wiley-VCH GmbH.)

Data-independent acquisition (DIA)-mass spectrometry (MS)-based proteome strategies are increasingly used for detecting and validating protein biomarkers and therapeutic targets. Here, based on an in-depth proteome analysis of seven pancreatic cancer cell lines, we built a pancreas-specific mass spectrum library containing 10633 protein groups and 184551 peptides. The proteome difference among the seven pancreatic cancer cells was significant, especially for the divergent expression of proteins related to epithelial-mesenchymal transition (EMT). The spectra library was applied to explore the proteome difference of PANC-1 and BxPC-3 cells upon gemcitabine (GEM) treatment, and potential GEM targets were identified. The cytotoxicity test and GEM target analysis found that HPAC, CFPAC-1, and BxPC-3 were sensitive to GEM treatment, whereas PANC-1 and AsPC-1 were resistant. Finally, we found EMT was significant for CFPAC-1, AsPC-1, and PANC-1 cells, whereas BxPC-3 and HPAC cells showed more typical epithelial features. This library provides a valuable resource for in-depth proteomic analysis on pancreatic cancer cell lines, meeting the urgent demands for cell line-dependent protein differences and targeted drug analysis., (© 2022. The Author(s).)

Background: Solute carrier family 2 member 3 (SLC2A3), is a member of a superfamily of transport protein genes. SLC2A3 played an important role in embryonic development. Previous research reported SLC2A3 duplication was reportedly associated with congenital syndromic heart defects. However, it is not clear whether the gene is associated with non-syndromic congenital heart disease. Our study aimed to elucidate the relationship between its variation and congenital heart disease., Methods: Genomic DNA extracted from the peripheral blood leukocytes of two families with CHD were sequenced with whole-exome sequencing to identify variations, used Sanger sequencing to investigate SLC2A3 variants in 494 Chinese patients with CHD and 576 healthy unrelated individuals., Results: In members from the two families, three with CHD had the SLC2A3 (rs3931701) C > T variant. Of the 494 patients with CHD, 394 had gene variants (86 had the TT type and 308 had the CT type). Of the 576 healthy controls, 272 participants had gene variants (36 had the TT type and 236 had the CT type). The TT type [p < 0.0001, odds ratio (OR) =7.262, 95% confidence interval (CI) =4.631-11.388] and CT type (p < 0.0001, OR =3.967, 95% CI =2.991-5.263) of SLC2A3 (rs3931701) significantly increased the risk of sporadic ASD in a Chinese Yunnan population., Conclusions: Single nucleotide variations of SLC2A3, particularly, the SLC2A3 (rs3931701) C > T variant increased the risk of CHD among the studied population., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Hepatitis B virus (HBV)/Hepatitis C virus (HCV) coinfection is frequently observed because of the common infection routine. Despite the reciprocal inhibition exerted by HBV and HCV genomes, the coinfection of HBV and HCV is associated with more severe forms of liver diseases. However, the complexity of viral interference and underlying pathological mechanism is still unclarified. With the demonstration of absence of direct viral interplay, some in vitro studies suggest the indirect effects of viral-host interaction on viral dominance outcome. Here, we comprehensively investigated the viral replication and host immune responses which might mediate the interference between viruses in HBV/HCV coinfected Huh7-NTCP cells and immunocompetent HCV human receptors transgenic ICR mice. We found that presence of HCV significantly inhibited HBV replication in vitro and in vivo irrespective of the coinfection order, while HBV did not affect HCV replication. Pathological alteration was coincidently reproduced in coinfected mice. In addition to the participation of innate immune response, an involvement of HCV in up-regulating HBV-specific immune responses was described to facilitate HBV clearance. Our systems partially recapitulate HBV/HCV coinfection and unveil the uncharacterized adaptive anti-viral immune responses during coinfection, which renews the knowledge on the nature of indirect viral interaction during HBV/HCV coinfection., Competing Interests: Conflict of interest All authors have no competing interests to declare., (Copyright © 2022 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Background: To determine the congenital heart defect (CHD) prevalence and identify the associated risk factors in children within the multi-ethnic Yunnan Region of China., Methods: This is a prospective matched case-control screening study. Screening for CHD in children residing within 28 county districts of Yunnan Province during the period of January 2001 to December 2016 was conducted. A total of 2,421 and CHD cohort and 24,210 control cohort were derived from a total population of 400,855 children (under 18 years of age)., Results: A total of 2,421 children were diagnosed with CHD, yielding a CHD prevalence of 6.04 cases per 1,000 children. The prevalence of CHD by sex was 6.54 per 1,000 females versus 5.59 per 1,000 males. The ethnic groups displaying the highest CHD prevalence were the Lisu (15.51 per 1,000), Achang (13.18 per 1,000), Jingpo (12.32 per 1,000), Naxi (9.68 per 1,000), and Tibetan (8.57 per 1,000), respectively. The most common CHD was atrial septal defect, amounting to 1.94 instances per 1,000 children. We identified a number of child-associated parameters that significantly correlated with greater CHD risk, such as lower mass at birth, shorter duration of gestation, and younger age at the time of screening. We also identified a number of maternal and familial risk factors., Conclusions: This ultrasonic color Doppler imaging study revealed a relatively commonplace prevalence of CHD. Moreover, the prevalence of CHD in Yunnan Region significantly varied with sex and ethnic status. Certain child-associated, maternal, and familial risk factors may contribute to CHD risk., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-21-371/coif). The authors have no conflicts of interest to declare., (2022 Translational Pediatrics. All rights reserved.)

Pancreaticobiliary carcinomas is a highly malignant gastrointestinal tumor. Most pancreaticobiliary cancers arise from epithelial proliferation within the pancreaticobiliary ducts, referred to as pancreatic intraepithelial neoplasias (PanINs). Some PanINs are benign metaplasia, while others progress to invasive duct adenocarcinoma (IDAC). However, there is no standard program to diagnose the progression from PanINs to IDAC. In this study, we present a tri-modality imaging system, which integrates ultrasound (US), optical coherence tomography (OCT), and near-infrared fluorescence (NIRF) for pancreaticobiliary duct imaging. This system can obtain OCT, US, and NIRF images in real-time with a frame rate of 30 frames per second. For the endoscopy probe with an outer diameter of 0.9 mm, the US transducer and fiber ball lens were placed back to back. In vivo experiments were performed on the rectums of Sprague-Dawley rats to demonstrate the imaging performance of US, OCT, and fluorescence angiography. An ex vivo experiment on a human pancreatic duct was performed for a more accurate assessment of the pancreaticobiliary duct. The tomography images of rat rectums and human pancreatic ducts were correlated with hematoxylin and eosin (H&E) histology to check the measurement accuracy. The integrated tri-modality system has great clinical potential in mechanism studies, early diagnosis, and prognosis evaluation of malignant pancreaticobiliary carcinomas.

Ustiloxins, a group of bioactive metabolites produced by the pathogen of rice false smut (RFS), have emerged as ubiquitous contaminants in RFS-occurred paddy fields and could accumulate in rice. Nevertheless, the prevalence of ustiloxins in rice and exposure risks of humans are limited. In this study, concentrations of ustiloxin A (UA) and ustiloxins B (UB), which are two predominant ustiloxins, were measured in 240 rice samples from China and 72 rice samples from 12 other counties. The detection rates (DRs) of UA and UB were 82.1% and 49.3%, respectively, and their concentrations in rice ranged from below detection limit (LOD: 0.22 μg/kg) to 85.96 μg/kg dw. Furthermore, for the first time, we reported the occurrence of UA (DR = 22.8%) in urine collected from residues of Enshi city, China. Urinary UA were significantly correlated with the activities of alanine aminotransferase in male, and this male-biased hepatotoxicity was further confirmed in mice exposure experiment. This study for the first time reported the widespread geographical distribution of ustiloxins in rice, as well as emphasized the occurrence of internal exposure and potential health risk in humans., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adult tissue homeostasis is maintained by residential stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced to avoid excessive proliferation or premature differentiation. However, how stem cell proliferation is properly controlled remains elusive. Here, we find that auxilin (Aux) restricts intestinal stem cell (ISC) proliferation mainly through EGFR signaling. aux depletion leads to excessive ISC proliferation and midgut homeostasis disruption, which is unlikely caused by defective Notch signaling. Aux is expressed in multiple types of intestinal cells. Interestingly, aux depletion causes a dramatic increase in EGFR signaling, with a strong accumulation of EGFR at the plasma membrane and an increased expression of EGFR ligands in response to tissue stress. Furthermore, Aux co-localizes and associates with EGFR. Finally, blocking EGFR signaling completely suppresses the defects caused by aux depletion. Together, these data demonstrate that Aux mainly safeguards EGFR activation to keep a proper ISC proliferation rate to maintain midgut homeostasis., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Preoperative anaemia is a risk factor for adverse postoperative outcomes after cardiac surgery. Iron deficiency is a frequent cause of low preoperative haemoglobin. An effective treatment for preoperative anaemia associated with iron deficiency has not been determined., Methods: We conducted a single-centre, open-label, pragmatic randomised trial, enrolling 156 elective cardiac surgery patients who had low preoperative haemoglobin (100-130 g L -1 ) with iron deficiency (serum ferritin <100 μg L -1 or transferrin saturation <30%) to compare intravenous ferric derisomaltose 1000 mg and darbepoetin 200 μg subcutaneously (intervention group) with oral ferrous sulphate 600 mg daily (control group). The primary outcome was transfusion of at least one unit of allogeneic red cells during surgery and within the following 5 days. Secondary outcomes included the change in haemoglobin concentration between randomisation and surgery, red cell transfusion volume, postoperative blood loss, pre-specified postoperative complications, length of hospital stay, and in-hospital death., Results: The odds of red cell transfusion were lower in the intervention group compared with the control group (adjusted odds ratio=0.33; 95% confidence interval [CI], 0.15-0.75; P=0.008). Of the secondary outcomes, the only significant difference was the increase in haemoglobin between randomisation and surgery, intervention vs control 9.5 g L -1 (95% CI, 6.8-12.2; P<0.001)., Conclusions: In patients with a low preoperative haemoglobin and iron deficiency, preoperative treatment with a single dose of ferric derisomaltose and darbepoetin decreased the proportion of participants who received a perioperative blood transfusion as a consequence of a greater increase in haemoglobin compared with treatment with oral ferrous sulphate., Clinical Trial Registration: ISRCTN Number: 41421863; EUDRACT number: 2011-003695-36., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Stem cells maintain adult tissue homeostasis under physiological conditions. Uncontrolled stem cell proliferation will lead to tumorigenesis. How stem cell proliferation is precisely controlled is still not fully understood. Phosphorylation of Yun is essential for ISC proliferation. Yun is essential for the proliferation of normal and transformed intestinal stem cells. Our mass spectrometry and biochemical data suggest that Yun can be phosphorylated at multiple residues in vivo. Interestingly, we show that the phosphorylation among these residues is likely interdependent. Furthermore, phosphorylation of each residue in Yun is important for its function in ISC proliferation regulation. Thus, our study unveils the important role of post-translational modification of Yun in stem cell proliferation., (© 2022 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

A perylene five-membered ring diimide, PDI39, was developed as a new electron-deficient building block for n-type semiconductors. The π-expanded conjugated molecules containing azulenes were synthesized from PDI39. These conjugated molecules show helical geometry and near-infrared absorption up to 810 nm.

High-temperature nitridation is commonly thought of as a necessary process to obtain N-polar GaN films on a sapphire substrate. In this work, high-quality N-polar GaN films were grown on a vicinal sapphire substrate with a 100 nm high-temperature (HT) AlN buffer layer (high V/III ratio) and without an intentional nitriding process. The smallest X-ray full width at half maximum (FWHM) values of the (002)/(102) plane were 237/337 arcsec. On the contrary, N-polar GaN film with an intentional nitriding process had a lower crystal quality. In addition, we investigated the effect of different substrate treatments 1 min before the high-temperature AlN layer's growth on the quality of the N-polar GaN films grown on different vicinal sapphire substrates.

We proposed a method to intelligently design two-spherical-mirror-based multipass cells (MPCs) and optimize multiple objectives simultaneously. By integrating the K-means algorithm into the particle swarm optimization (PSO) algorithm, an efficient method is developed to optimize MPC configurations possessing characteristics of both long optical path lengths (OPLs) and circle patterns. We built and tested an MPC with four concentric circle patterns, which achieved an OPL of 54.1 m in a volume of 273.1 cm 3 . We demonstrated the stability and detection precision of the developed gas sensor. Continuous measurement of methane in ambient laboratory air was realized, with a detection precision of 8 ppb and an averaging time of 13 s. The combination of K-means and PSO algorithms is effective in optimizing MPCs with multiple objectives, which makes it suitable for designing versatile MPCs satisfying various requirements of field applications, including pollution and greenhouse gas emission monitoring and high-sensitivity measurements of other trace gases.

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma., (© 2022. The Author(s).)

Antioxidant-defense systems of tumor cells protect them from oxidative damage. Herein, a carrier-free nanomedicine is developed based on chlorine e6 (Ce6) and coniferyl ferulate (Con), which inhibits glutathione S-transferase (GST) activity to hamper antioxidant systems and amplify intracellular oxidative stress for enhanced photodynamic therapy.

As a typical third-generation semiconductor material, silicon carbide (SiC) has been increasingly used in recent years. However, the outstanding performance of SiC component can only be obtained when it has a high-quality surface and low-damage subsurface. Due to the hard-brittle property of SiC, it remains a challenge to investigate the ductile machining mechanism, especially at the nano scale. In this study, a three-dimensional molecular dynamics (MD) simulation model of nanometric cutting on monocrystalline 3C-SiC was established based on the ABOP Tersoff potential. Multi-group MD simulations were performed to study the removal mechanism of SiC at the nano scale. The effects of both cutting speed and undeformed cutting thickness on the material removal mechanism were considered. The ductile machining mechanism, cutting force, hydrostatic pressure, and tool wear was analyzed in depth. It was determined that the chip formation was dominated by the extrusion action rather than the shear theory during the nanocutting process. The performance and service life of the diamond tool can be effectively improved by properly increasing the cutting speed and reducing the undeformed cutting thickness. Additionally, the nanometric cutting at a higher cutting speed was able to improve the material removal rate but reduced the quality of machined surface and enlarged the subsurface damage of SiC. It is believed that the results can promote the level of ultraprecision machining technology.

From 2011 to 2020, there were 111 213 cases of rabies exposed people recruited from the rabies immunization clinic of a hospital in Beijing. The monthly distribution of patients in each year was not statistically significant ( P >0.05). The distribution of patients showed remarkable seasonality, with the exposure peak from May to October. The ratio of male to female was 1∶1.3. The majority of patients were aged 20-29 years old (39.1%) and in-service personnel (56.5%). Level-Ⅱ wounds (84.2%) were more common than level-Ⅲ wounds (14.9%). The number of visits to level-Ⅲwounds increased rapidly since 2017. The most common injured body part was hand (60.7%). Dogs were the most common animal for injuries (60.6%), followed by cats (32.3%), of which most were host animals (75.5%). The vaccination rate from 2016 to 2020 [49.8% (24 276/48 703)] was significantly higher than that from 2011 to 2015[18.6% (6 559/35 272)]( χ²= 8597.18, P <0.001).

Hepatitis B virus (HBV) infection is an important problem threatening human health. After HBV virus invades human body, it may assemble a complete virus particle in the cytoplasm to trigger the immune reaction, especially the interaction between the HBV virus and the host that mediated by CD8 + T cell. We collected the sequences of HBV from the HBVdb database, then screened candidate mutation sites in Chinese, European and American populations based on conservation and physicochemical properties. After that we constructed the three-dimensional structure of Major histocompatibility complex class I (MHC I) -peptide complexes, performed molecular docking, run molecular dynamics to compare the binding free energy, stability, and affinity of MHC I-peptide complexes with the aim to estimate the effect of peptide mutation. The specific HBV virus subtypes of the Chinese, European and American population were studied and the candidate mutation sites were used to predict the mutant peptide antigen. Finally, based on physical and chemical properties and peptide antigen prediction scores, 21 HBV mutation sites were selected. Then combined with specific Human lymphocyte antigen (HLA) subtypes, 11 mutations were found to have a significant negative impact on affinity, stability and binding free energy. Overall, our work found important potential mutations, which provide an evaluation of HBV mutations and a clue of it in immunotherapy. Communicated by Ramaswamy H. Sarma.

Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However, the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94/VCP/p97, components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its C-terminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1- or TER94-deficient progenitors. Further removal of reactive oxygen species (ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance (ER protein quality control) in tissue homeostasis and tumor development., Competing Interests: Conflict of interest The authors declare no competing of interest., (Copyright © 2021 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Hair remains the most common type of physical evidence found in most crime scenes. However, the amount of hair found at a crime scene is limited and analysis of drugs in hair by gas chromatography mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) is laborious and time-consuming. In this study, a rapid and simple method is developed using thermal desorption ionization mass spectrometry (TDI-MS) to analyze drugs directly in a single hair. A single hair is put onto a heated metal ceramic heater (MCH) and then a high voltage direct current and solvent are applied to the single hair. The drugs in the hair are thermally desorbed and ionized, and subsequently transferred to the MS inlet and detected. A typical hair analysis can be completed in a few minutes. This novel technique provides a new orientation for forensic scientists to study drugs in a single hair that is found at a crime scene, on a suspect, or on a victim.

Background: Peroxisome proliferator-activated receptor-beta/delta (PPARδ) was considered as the key regulator involved in the evolution of various tumors. Given that PPARδ potential role in hepatocellular carcinoma (HCC) is still obscure, we comprehensively assessed its expression pattern, prognosis, functions and correlation with tumor microenvironment in HCC using public database data and in vitro studies., Methods: Transcriptional data and clinical data in the TCGA and GEO database were analyzed in R software. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry were used to detect the expression level of related RNA and proteins. The malignant biological characteristics were explored by cell counting Kit-8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU) assay and wound healing assay., Results: Our results illustrated that PPARδ expression was significantly higher in HCC tissues and HCC cell lines. Elevated expression of PPARδ suggested poor clinical staging and prognosis in HCC. Ligand-activated PPARδ expression promoted the proliferation and invasion of HCC cells via PDK1/AKT/GSK3β signaling pathway. The expression of PPARδ was closely related to the HCC tumor microenvironment., Conclusions: PPARδ plays an important part in HCC progression, penetrating investigation of the related regulatory mechanism may shed light upon further biological and pharmacological value., (© 2022. The Author(s).)

Blocking the pyrimidine nucleotide de novo synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) results in the cell cycle arrest and/or differentiation of rapidly proliferating cells including activated lymphocytes, cancer cells, or virally infected cells. Emvododstat (PTC299) is an orally bioavailable small molecule that inhibits DHODH. We evaluated the potential for emvododstat to inhibit the progression of acute myeloid leukemia (AML) using several in vitro and in vivo models of the disease. Broad potent activity was demonstrated against multiple AML cell lines, AML blasts cultured ex vivo from patient blood samples, and AML tumor models including patient-derived xenograft models. Emvododstat induced differentiation, cytotoxicity, or both in primary AML patient blasts cultured ex vivo with 8 of 10 samples showing sensitivity. AML cells with diverse driver mutations were sensitive, suggesting the potential of emvododstat for broad therapeutic application. AML cell lines that are not sensitive to emvododstat are likely to be more reliant on the salvage pathway than on de novo synthesis of pyrimidine nucleotides. Pharmacokinetic experiments in rhesus monkeys demonstrated that emvododstat levels rose rapidly after oral administration, peaking about 2 hours post-dosing. This was associated with an increase in the levels of dihydroorotate (DHO), the substrate for DHODH, within 2 hours of dosing indicating that DHODH inhibition is rapid. DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias., Competing Interests: Authors AB, LC, BF, CT, JG, JM, BR, WL, JS, AM, SY, RK, JB, KO’K, RSp, EG, SK and MW are or were employed by PTC Therapeutics and have received salary compensation for time, effort, and hold or held financial interest in the company. Author MS was employed by Notable Labs and RSh was employed by InSeption Group. The authors declare that this study received funding from PTC Therapeutics, Inc. The funder had the following involvement with the study: funded the entire study, including all experiments and outside editorial support., (Copyright © 2022 Branstrom, Cao, Furia, Trotta, Santaguida, Graci, Colacino, Ray, Li, Sheedy, Mollin, Yeh, Kong, Sheridan, Baird, O’Keefe, Spiegel, Goodwin, Keating and Weetall.)

Stem cells constantly divide and differentiate to maintain adult tissue homeostasis, and uncontrolled stem cell proliferation leads to severe diseases such as cancer. How stem cell proliferation is precisely controlled remains poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Yun, required for proliferation of normal and transformed ISCs. Yun is mainly expressed in progenitors; our genetic and biochemical evidence suggest that it acts as a scaffold to stabilize the Prohibitin (PHB) complex previously implicated in various cellular and developmental processes and diseases. We demonstrate that the Yun/PHB complex is regulated by and acts downstream of EGFR/MAPK signaling. Importantly, the Yun/PHB complex interacts with and positively affects the levels of the transcription factor E2F1 to regulate ISC proliferation. In addition, we find that the role of the PHB complex in cell proliferation is evolutionarily conserved. Thus, our study uncovers a Yun/PHB-E2F1 regulatory axis in stem cell proliferation., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Emvododstat was identified as a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19. The objective of this paper is to evaluate the metabolism, pharmacokinetics, and drug interaction potentials of emvododstat.Emvododstat showed high binding to plasma protein with minimal distribution into blood cells in mouse, rat, dog, monkey, and human whole blood. O -Demethylation followed by glucuronidation appeared to be the major metabolic pathway in rat, dog, monkey, and human hepatocytes. CYP2C8, 2C19, 2D6, and 3A4 were involved in O -desmethyl emvododstat metabolite formation. Both emvododstat and O -desmethyl emvododstat inhibited CYP2D6 activity and induced CYP expression to different extents in vitro .Emvododstat and O -desmethyl emvododstat inhibited BCRP transporter activity but did not inhibit bile salt transporters and other efflux or uptake transporters. Neither emvododstat nor O -desmethyl emvododstat was a substrate for common efflux or uptake transporters investigated.Emvododstat is bioavailable in mice, rats, dogs, and monkeys following a single oral dose. The absorption was generally slow with the mean plasma T max ranging from 2 to 5 h; plasma exposure of O -desmethyl emvododstat was lower in rodents, but relatively higher in dogs and monkeys.

Inflammasome is a molecular platform that is formed in the cytosolic compartment to mediate host immune responses to infection and cellular damage. Inflammasome can activate caspase-1, leading to the maturation of two inflammatory cytokines interleukin 1β (IL-1β) and IL-18 and initiation of a proinflammatory form of cell death called pyroptosis. Among various inflammasome complexes, the NLRP3 inflammasome is by far the most studied inflammasome. NLRP3 inflammasome is a key factor in regulating host immune defense against infectious microbes and cellular damage. However, the dysregulated NLRP3 inflammasome activation also participates in the pathogenesis of many human disorders. NLRP3 inflammasome plays an important role in the pathogenesis of rheumatic disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), Sjögren's syndrome (SS), dermatomyositis/polymyositis (DM/PM), gout, and systemic sclerosis (SSc). For example, NLRP3 inflammasome has been found highly activated in synovial tissues and peripheral blood mononuclear cells from RA patients. In this paper, we will discuss the role of NLRP3 inflammasome in the pathogenesis of rheumatic disease.

Objectives: The prevalence, clinical features, and outcomes of patients with systemic lupus erythematosus (SLE) complicated with or without aortic aneurysm (AA) were compared in a Chinese single-center cohort., Methods: Included in this study were SLE patients who received treatment at Shanghai Changhai Hospital between 2000 and 2020. The prevalence, clinical features, and outcomes of these SLE patients with or without AA were compared by Student's t-tests or Fisher's exact tests as appropriate. Risk factors associated with AA occurrence in SLE were evaluated by univariable and multivariable logistic regression analyses. The survival analysis between SLE patients with or without AA was conducted by the Kaplan-Meier method., Results: Of the 1843 SLE patients included in this study, 16 (0.86%) were identified as having AA, and 160 of the remaining 1825 SLE patients without AA were selected as a simple random sample for comparison. The SLE patients with AA showed a higher proportion of smoking and hypertension as compared with those with no AA. Multivariable logistic regression analysis showed that a long SLE duration and anti-RNP positivity were two independent risk factors associated with AA occurrence in SLE patients. The log rank test showed that SLE patients with AA had a significantly higher risk of progression to death. Renal disorder was associated with an even poorer outcome in SLE patients with AA., Conclusion: The incidence of AA in SLE patients may be underestimated. The association between AA and SLE, especially in patients with multiple risk factors, should not be ignored. Key Points • The risk of SLE patients developing AA may be higher than that previously estimated. • The risk of SLE patients especially with multiple risk factors developing AA should not be ignored. • The diagnosis of AA should not be forgot when SLE patients present with chest, back, or abdominal symptoms with unexplained causes., (© 2021. International League of Associations for Rheumatology (ILAR).)

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.

The prediction of the estrogen receptor (ER) and androgen receptor (AR) activity of a compound is quite important to avoid the environmental exposures of endocrine-disrupting chemicals. The Estrogen and Androgen Receptor Database (EARDB, http://eardb.schanglab.org.cn/) provides a unique collection of reported ERα, ERβ, or AR protein structures and known small molecule modulators. With the user-uploaded query molecules, molecular docking based on multi-conformations of a single target will be performed. Moreover, the 2D similarity search against known modulators is also provided. Molecules predicted with a low binding energy or high similarity to known ERα, ERβ, or AR modulators may be potential endocrine-disrupting chemicals or new modulators. The server provides a tool to predict the endocrine activity for compounds of interests, benefiting for the ER and AR drug design and endocrine-disrupting chemical identification., 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 Wang, Hu, Ma, Li, Li, Liang, Chang and Kong.)

Class B G protein-coupled receptors (GPCRs) are important targets in the treatment of metabolic syndrome and diabetes. Although multiple structures of class B GPCRs-G protein complexes have been elucidated, the detailed activation mechanism of the receptors remains unclear. Here, we combine Gaussian accelerated molecular dynamics simulations and Markov state models (MSM) to investigate the activation mechanism of a canonical class B GPCR, human glucagon receptor-GCGR, including the negative allosteric modulator-bound inactive state, the agonist glucagon-bound active state, and both glucagon- and Gs-bound fully active state. The free-energy landscapes of GCGR show the conformational ensemble consisting of three activation-associated states: inactive, active, and fully active. The structural analysis indicates the high dynamics of GCGR upon glucagon binding with both active and inactive conformations in the ensemble. Significantly, the H8 and TM6 exhibits distinct features from the inactive to the active states. The additional simulations demonstrate the role of H8 in the recruitment of Gs. Gs binding presents a crucial function of stabilizing the glucagon binding site and MSM highlights the absolute requirement of Gs to help the GCGR reach the fully active state. Together, our results reveal the detailed activation mechanism of GCGR from the view of conformational dynamics., 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., (© 2022 The Author(s).)

Rationale: The neuroinflammation is necessary for glial group initiation and clearance of damaged cell debris after nerve injury. However, the proinflammatory polarization of excessive microglia amplifies secondary injury via enhancing cross-talk with astrocytes and exacerbating neurological destruction after spinal cord injury (SCI). The glucagon-like peptide-1 receptor (GLP-1R) agonist has been previously shown to have a neuroprotective effect in neurodegeneration, whereas its potency in microglial inflammation after SCI is still unknown. Methods: The effect and mechanism of GLP-1R activation by exendin-4 (Ex-4) were investigated in in vitro cultured glial groups and in vivo in SCI mice. Alterations in the gene expression after GLP-1R activation in inflammatory microglia were measured using mRNA sequencing. The microglial polarization, neuroinflammatory level, and astrocyte reaction were detected by using western blotting, flow cytometry, and immunofluorescence. The recoveries of neurological histology and function were also observed using imaging and ethological examinations. Results: GLP-1R activation attenuated microglia-induced neuroinflammation by reversing M1 subtypes to M2 subtypes in vitro and in vivo . In addition, activation of GLP-1R in microglia blocked production of reactive astrocytes. We also found less neuroinflammation, reactive astrocytes, corrected myelin integrity, ameliorated histology, and improved locomotor function in SCI mice treated with Ex-4. Mechanistically, we found that Ex-4 rescued the RNA expression of Arf and Rho GAP adapter protein 3 (ARAP3). Knockdown of ARAP3 in microglia reversed activation of RhoA and the pharmacological effect of Ex-4 on anti-inflammation in vitro . Conclusion: Ex-4 exhibited a previously unidentified role in reducing reactive astrocyte activation by mediation of the PI3K/ARAP3/RhoA signaling pathway, by neuroinflammation targeting microglia, and exerted a neuroprotective effect post-SCI, implying that activation of GLP-1R in microglia was a therapeutical option for treatment of neurological injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Taking the maximum fluorescence of an identical fluorophore as a reference, a DNAzyme-based normalized strategy is developed to unify the output signals under external interferences. This makes it possible to directly quantify endogenous zinc in living cells by in situ fluorescence imaging, implying promising potential in fundamental study and early disease diagnosis.

Background: The new coronavirus disease 2019 (COVID-19) is spreading rapidly around the world. Artificial Intelligence (AI) assisted identification and detection of diseases is an effective method of medical diagnosis., Objectives: To present recent advances in AI-assisted diagnosis of COVID-19, we introduce major aspects of AI in the process of diagnosing COVID-19., Methods: In this paper, we firstly cover the latest collection and processing methods of datasets of COVID-19. The processing methods mainly include building public datasets, transfer learning, unsupervised learning and weakly supervised learning, semi-supervised learning methods and so on. Secondly, we introduce the algorithm application and evaluation metrics of AI in medical imaging segmentation and automatic screening. Then, we introduce the quantification and severity assessment of infection in COVID-19 patients based on image segmentation and automatic screening. Finally, we analyze and point out the current AI-assisted diagnosis of COVID-19 problems, which may provide useful clues for future work., Conclusion: AI is critical for COVID-19 diagnosis. Combining chest imaging with AI can not only save time and effort, but also provide more accurate and efficient medical diagnosis results., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We conducted in-the-field choice experiments in China to investigate farmers' willingness to pay for crop insurance and to determine how objective and subjective beliefs affect Willingness to Pay (WTP). We deploy three variants of the choice experiment using a priming mechanism on objective and subjective beliefs plus a control. We find that the cuing frame matters in that there are differences in WTP within five attributes and across variants. In terms of practical policy, our results suggest that farmers' frame of reference toward objective and subjective risks can affect insurance demand., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© International Association for the Study of Insurance Economics 2021.)

Background & Aims: Copy number alterations (CNAs), elicited by genome instability, are a major source of intratumor heterogeneity. How CNAs evolve in hepatocellular carcinoma (HCC) remains unknown., Methods: We performed single-cell DNA sequencing (scDNA-seq) on 1275 cells isolated from 10 patients with HCC, ploidy-resolved scDNA-seq on 356 cells from 1 additional patient, and single-cell RNA sequencing on 27,344 cells from 3 additional patients. Three statistical fitting models were compared to investigate the CNA accumulation pattern., Results: Cells in the tumor were categorized into the following 3 subpopulations: euploid, pseudoeuploid, and aneuploid. Our scDNA-seq analysis revealed that CNA accumulation followed a dual-phase copy number evolution model, that is, a punctuated phase followed by a gradual phase. Patients who exhibited prolonged gradual phase showed higher intratumor heterogeneity and worse disease-free survival. Integrating bulk RNA sequencing of 17 patients with HCC, published datasets of 1196 liver tumors, and immunohistochemical staining of 202 HCC tumors, we found that high expression of CAD, a gene involved in pyrimidine synthesis, was correlated with rapid tumorigenesis and reduced survival. The dual-phase copy number evolution model was validated by our single-cell RNA sequencing data and published scDNA-seq datasets of other cancer types. Furthermore, ploidy-resolved scDNA-seq revealed the common clonal origin of diploid- and polyploid-aneuploid cells, suggesting that polyploid tumor cells were generated by whole genome doubling of diploid tumor cells., Conclusions: Our work revealed a novel dual-phase copy number evolution model, showed HCC with longer gradual phase was more severe, identified CAD as a promising biomarker for early recurrence of HCC, and supported the diploid origin of polyploid HCC., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Synovial mesenchymal stem cell (SMSC)-derived exosomes show treatment potential in osteoarthritis, although their functional mechanism is still unclear. Materials & methods: Osteoarthritis chondrocytes and normal SMSC were cultured. Subsequently, chondrocytes were co-cultured with SMSC or miR-320c -overexpressing SMSC-derived exosomes, or directly transfected with miR-320c mimic. Furthermore, compensate experiments were conducted. Results: SMSC promoted chondrocyte proliferation, migration, COL2A1 and ACAN expressions while suppressing apoptosis by transmitting exosomes. Furthermore, miR-320c -overexpressing SMSC-derived exosomes and direct miR-320c overexpression in chondrocytes presented more significant effect on enhancing chondrogenesis. In addition, miR-320c directly targeted ADAM19, and ADAM19 overexpression compensated the regulation of miR-320c on chondrogenesis. Conclusion: SMSC-derived exosomal miR-320c enhances chondrogenesis through targeting ADAM19, highlighting a potentially novel mechanism of SMSC in treating osteoarthritis.

Allostery is a fundamental and extensive mechanism of intramolecular signal transmission. Allosteric drugs possess several unique pharmacological advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity. However, owing to the complexity of allosteric regulation, experimental approaches for the development of allosteric modulators are traditionally serendipitous. Recently, the reversed allosteric communication theory has been proposed, providing a feasible tool for the unbiased detection of allosteric sites. Herein, we review the latest research on the reversed allosteric communication effect using the examples of sirtuin 6, epidermal growth factor receptor, 3-phosphoinositide-dependent protein kinase 1, and Related to A and C kinases (RAC) serine/threonine protein kinase B and recapitulate the methodologies of reversed allosteric communication strategy. The novel reversed allosteric communication strategy greatly expands the horizon of allosteric site identification and allosteric mechanism exploration and is expected to accelerate an end-to-end framework for drug discovery.

Background: Osteoarthritis (OA) is the most prevalent chronic joint disease globally. Loss of extracellular matrix (ECM) by chondrocytes is a classic feature of OA. Inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), secreted mainly by macrophages, promote expression of matrix degrading proteins and further aggravate progression of OA. 1,25-dihydroxyvitamin D (1,25VD) modulates inflammation thus exerting protective effects on cartilage tissue. However, the underlying mechanisms of 1,25VD activity have not been fully elucidated., Methods: The destabilization of the medial meniscus (DMM)-induced mice model of OA was established to investigate the protective effects of 1,25VD by micro-CT and Safranin-O and Fast Green staining. And the co-culture system between THP-1 cells and primary chondrocytes was constructed to explore the effects of vitamin D receptor (VDR) and 1,25VD on chondrogenic proliferation, apoptosis, and migration. The immunofluorescence staining and Western blot analysis were used to detect the expressions of ECM proteins and matrix degradation-associated proteases. Enzyme-linked immunosorbent assay (ELISA) was used to examine the expression levels of inflammatory cytokines., Results: The findings of the study showed that 1,25VD prevented cartilage degeneration and osteophyte formation by inhibiting secretion of inflammatory cytokines in OA mice model. These protective effects were exerted through the vitamin D receptor (VDR). Further studies showed that 1,25VD increased ubiquitination level of NLRP3 by binding to VDR, resulting in decrease in IL-1β and IL-18 secretion. These findings indicate that 1,25VD binds to VDR thus preventing chondrogenic ECM degradation by modulating macrophage NLRP3 activation and secretion of inflammatory cytokines, thus alleviating OA progression., Conclusion: Here, our study suggests that 1,25VD, targeting to VDR, prevents chondrogenic ECM degradation through regulating macrophage NLRP3 activation and inflammatory cytokines secretion, thereby alleviating OA. These findings provide information on a novel molecular mechanism for application of 1,25VD as OA therapy., Competing Interests: All authors declare that they have no conflicts of interest to report., (© 2021 Duan et al.)

Though alprostadil has been reported to improve the impaired microcirculation of patients with pulmonary arterial hypertension, its effectiveness as a treatment for coronary microvasculature dysfunction (CMD) following ST-segment elevation myocardial infarction (STEMI) is unknown. A total of 18 miniature pigs with CMD following STEMI were randomized into three groups that received an intracoronary injection of 5 ml of normal saline, 2 mg of nicorandil or 10 µg of alprostadil immediately after measurement of the index of microcirculatory resistance (IMR) and then an intravenous drip containing 5 ml of normal saline, 2 mg of nicorandil or 10 µg of alprostadil once a day for 6 days. The IMR, cardiac function using ultrasound, infarct areas and heparanase levels in infarct areas were measured and compared between the three groups. The IMR decreased markedly 10 min after alprostadil or nicorandil intracoronary injection (both P<0.05) but not following saline injection (P>0.05). After 7 days, the IMR was substantially lower in the alprostadil and nicorandil groups compared with the saline group (both P<0.05) and the ejection fraction was considerably higher in the alprostadil and nicorandil groups compared with the saline group (both P<0.05). Differences in infarct areas and the relative heparanase expression levels among the 3 groups were similar to the differences in the ejection fraction. No significant differences in the above assessment indexes were identified in the alprostadil and nicorandil groups. Alprostadil infusion improved coronary microcirculation function, reduced the infarct area and limited left ventricular dilatation in a pig coronary microvasculature dysfunction model following STEMI., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Duan et al.)

Background: Breast Carcinoma (BCa) is the leading cause of cancer among females in Trinidad and Tobago (TnT). This twin-island has a diversified population of 1.3 million individuals that display and are exposed to a variety of lifestyle choices that have been linked to the development of BCa. Therefore, this study aimed to identify the risk factors that influence the development of BCa, analyze the common histopathological details, and categorize BCa based on receptor study., Methods: Cancer information for 120 BCa cases at Eric Williams Medical Sciences Complex from 2012 to 2019 was retrieved, analyzed, and statistically estimated. The clinical details were categorized based on data tabulations, and histological assessment was performed to identify specific features. The receptor analysis was classified based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2neu) staining intensity. A descriptive data analysis and comparison were statistically evaluated in all these cases., Results: Epidemiological factors influencing the development of BCa were age with a peak of 56-65 years 27.5% (n = 33), ethnicity predominated in Indo-Trinidadians 48.33% (n = 58), and marital status primarily in unmarried/single/widowed patients 55% (n = 66). Infiltrating ductal carcinoma was the principal histopathological type 91.66% (n = 110). Receptor analysis revealed ER/PR + HER-2neu as the most common type 40% (n = 18) for therapeutic surveillance., Conclusion: This study highlights various epidemiological factors that influence the development of BCa among females in TnT. Histopathological analysis and receptor studies would provide a useful link between the tumor behavior and its prognosis., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70-75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70-80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands., (© 2021 Wiley Periodicals LLC.)

OCD20015-V009 is an herbal mix of water-extracted Ginseng Radix, Poria (Hoelen), Rehmanniae Radix, Adenophorae Radix, Platycodi Radix, Crataegii Fructus, and Astragali Radix. In this study, its in vitro and in vivo antiviral activity and mechanisms against the influenza A virus were evaluated using a GFP-tagged influenza A virus (A/PR/8/34-GFP) to infect murine macrophages. We found that OCD20015-V009 pre-treatment substantially reduced A/PR/8/34-GFP replication. Also, OCD20015-V009 pre-treatment increased the phosphorylation of type-I IFN-related proteins TBK-1 and STAT1 and the secretion of pro-inflammatory cytokines TNF-α and IL-6 by murine macrophages. Moreover, OCD20015-V009 prophylactic administration increased IFN-stimulated genes-related 15, 20, and 56 and IFN-β mRNA in vitro . Thus, OCD20015-V009 likely modulates murine innate immune response via macrophages. This finding is potentially useful for developing prophylactics or therapeutics against the influenza A virus. Furthermore, pre-treatment with OCD20015-V009 decreased the mortality of the mice exposed to A/PR/8/34-GFP by 20% compared to that in the untreated animals. Thus, OCD20015-V009 stimulates the antiviral response in murine macrophages and mice to viral infections. Additionally, we identified chlorogenic acid and ginsenoside Rd as the antiviral components in OCD20015-V009. Further investigations are needed to elucidate the protective effects of active components of OCD20015-V009 against influenza A viruses., Competing Interests: Authors SM-P and RK were employed by the company Okchungdang. The remaining 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 Kwon, Oh, Hwang, Li, Park, Kong, Kim and Choi.)

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.

In this work, we develop a simple yet robust method to fabricate a bioinspired adhesive coating based on polyethyleneimine (PEI) and tannic acid (TA) complexes, exhibiting excellent antifogging, self-cleaning, and antibacterial properties. The polyethyleneimine-tannic acid (PEI-TA) complexes coating combined with the bioinspired adhesive property from TA can be effectively and stably coated onto various substrates through a one-step deposition process, and the hydrophilicity of the coated substrates can be significantly enhanced with their water contact angle less than 10°. The bioinspired adhesive coating endows the coated substrates with outstanding antifogging and self-cleaning performance. Moreover, it is found that the PEI-TA coated safety goggles display excellent durability and antifogging capability compared to the commercial antifogging safety goggles and commercial antifogging agents coated safety goggles under 65 ℃ vapor condition for 2 h. Furthermore, the PEI-TA coatings show superior antibacterial activities for Gram-negative Escherichiak coli and Gram-positive Staphylococcus aureus. The antifogging, self-cleaning, and antibacterial coating provides widely potential application prospects in optical and medical devices., 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 © 2021 Elsevier Inc. All rights reserved.)

Adult stem cells are critical for the maintenance of tissue homeostasis. However, how the proliferation and differentiation of intestinal stem cells (ISCs) are regulated remains not fully understood. Here, we find a mutant, stum 9-3, affecting the proliferation and differentiation of Drosophila adult ISCs in a forward genetic screen for factors regulating the proliferation and differentiation ISCs. stum 9-3 acts through the conserved Notch signaling pathway, upstream of the S2 cleavage of the Notch receptor. Interestingly, the phenotype of stum 9-3 mutant is not caused by disruption of stumble (stum), where the p-element is inserted. Detailed mapping, rescue experiments and mutant characterization show that stum 9-3 is a new allele of O-fucosyltransferase 1 (O-fut1). Our results indicate that unexpected mutants with interesting phenotype could be recovered in forward genetic screens using known p-element insertion stocks., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Nonsense-mediated mRNA decay (NMD) is a highly regulated quality control mechanism through which mRNAs harboring a premature termination codon are degraded. It is also a regulatory pathway for some genes. This mechanism is subject to various levels of regulation, including phosphorylation. To date only one kinase, SMG1, has been described to participate in NMD, by targeting the central NMD factor UPF1. Here, screening of a kinase inhibitor library revealed as putative NMD inhibitors several molecules targeting the protein kinase AKT1. We present evidence demonstrating that AKT1, a central player in the PI3K/AKT/mTOR signaling pathway, plays an essential role in NMD, being recruited by the UPF3X protein to phosphorylate UPF1. As AKT1 is often overactivated in cancer cells and as this should result in increased NMD efficiency, the possibility that this increase might affect cancer processes and be targeted in cancer therapy is discussed., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Large-scale biophysical circuit models provide mechanistic insights into the micro-scale and macro-scale properties of brain organization that shape complex patterns of spontaneous brain activity. We developed a spatially heterogeneous large-scale dynamical circuit model that allowed for variation in local synaptic properties across the human cortex. Here we show that parameterizing local circuit properties with both anatomical and functional gradients generates more realistic static and dynamic resting-state functional connectivity (FC). Furthermore, empirical and simulated FC dynamics demonstrates remarkably similar sharp transitions in FC patterns, suggesting the existence of multiple attractors. Time-varying regional fMRI amplitude may track multi-stability in FC dynamics. Causal manipulation of the large-scale circuit model suggests that sensory-motor regions are a driver of FC dynamics. Finally, the spatial distribution of sensory-motor drivers matches the principal gradient of gene expression that encompasses certain interneuron classes, suggesting that heterogeneity in excitation-inhibition balance might shape multi-stability in FC dynamics., (© 2021. The Author(s).)