Nucleolar stress induces nucleolar stress body formation via the NOSR-1/NUMR-1 axis in Caenorhabditis elegans.

Environmental stimuli not only alter gene expression profiles but also induce structural changes in cells. How distinct nuclear bodies respond to cellular stress is poorly understood. Here, we identify a subnuclear organelle named the nucleolar stress body (NoSB), the formation of which is induced by the inhibition of rRNA transcription or inactivation of rRNA processing and maturation in C. elegans. NoSB does not colocalize with other previously described subnuclear organelles. We conduct forward genetic screening and identify a bZIP transcription factor, named nucleolar stress response-1 (NOSR-1), that is required for NoSB formation. The inhibition of rRNA transcription or inactivation of rRNA processing and maturation increases nosr-1 expression. By using transcriptome analysis of wild-type animals subjected to different nucleolar stress conditions and nosr-1 mutants, we identify that the SR-like protein NUMR-1 (nuclear localized metal responsive) is the target of NOSR-1. Interestingly, NUMR-1 is a component of NoSB and itself per se is required for the formation of NoSB. We conclude that the NOSR-1/NUMR-1 axis likely responds to nucleolar stress and mediates downstream stress-responsive transcription programs and subnuclear morphology alterations in C. elegans.

Germ granule compartments coordinate specialized small RNA production.

Germ granules are biomolecular condensates present in most animal germ cells. One function of germ granules is to help maintain germ cell totipotency by organizing mRNA regulatory machinery, including small RNA-based gene regulatory pathways. The C. elegans germ granule is compartmentalized into multiple subcompartments whose biological functions are largely unknown. Here, we identify an uncharted subcompartment of the C. elegans germ granule, which we term the E granule. The E granule is nonrandomly positioned within the germ granule. We identify five proteins that localize to the E granule, including the RNA-dependent RNA polymerase (RdRP) EGO-1, the Dicer-related helicase DRH-3, the Tudor domain-containing protein EKL-1, and two intrinsically disordered proteins, EGC-1 and ELLI-1. Localization of EGO-1 to the E granule enables synthesis of a specialized class of 22G RNAs, which derive exclusively from 5' regions of a subset of germline-expressed mRNAs. Defects in E granule assembly elicit disordered production of endogenous siRNAs, which disturbs fertility and the RNAi response. Our results define a distinct subcompartment of the C. elegans germ granule and suggest that one function of germ granule compartmentalization is to facilitate the localized production of specialized classes of small regulatory RNAs.

Coexistence of a novel NDM-1-encoding MDR plasmid and an IMP-4-encoding IncN-IncU hybrid plasmid in a clinical isolate of Citrobacter freundii BC73.

Objectives: To investigate the genetic characteristics and transmission mechanism of the NDM-1-, IMP-4-, and SHV-12-producing multidrug-resistant (MDR) clinical isolate, Citrobacter freundii BC73. Methods: C. freundii BC73 was isolated from a urine specimen of a urological patient diagnosed with bladder cancer at a Chinese teaching hospital. Antimicrobial susceptibility testing was carried out using DL-120E susceptibility cards and DL-96A system. Whole genome sequencing (WGS) of the isolate was performed using the Illumina and Oxford Nanopore platforms to analyze the genetic context of drug resistance genes and plasmid characteristics. The phylogenetic tree was constructed and visualized by KSNP3.0 software and iTOL5.0 online database. Results: C. freundii isolate BC73 co-carrying bla NDM-1, bla IMP-4 and bla SHV-12 were multidrug-resistant. bla NDM-1 and bla IMP-4 were located on a novel IncFIB-like plasmid, pCFBC1, and an IncN-IncU hybrid plasmid, pCFBC2, respectively. The transferability of bla NDM-1 and bla IMP-4 from C. freundii BC73 to E. coli J53 was successfully demonstrated. The genetic context of the bla NDM-1 and bla IMP-4 genes were ISCR27-groEL-∆groES-cutA-dsbD-trpF-ble MBL-bla NDM-1-∆ISAba125-IS3000 and intI1-bla IMP-4-Kl.pn.13-mobC-IS6100, respectively. Additionally, two extensive transposition units (MGE1 in pCFBC1, MGE2 in pCFBC2) were identified and numerous antimicrobial resistance genes were discovered on it. Conclusion: To our knowledge, our study represents the first characterization of a ST22 C. freundii isolate co-harboring bla NDM-1, bla IMP-4, and bla SHV-12, obtained from a urine sample. The dissemination of this MDR isolate should be of close concern in future clinical surveillance.

Integrative transcriptome-proteome approach reveals key hypoxia-related features involved in the neuroprotective effects of Yang Xue oral liquid on Alzheimer's and Parkinson's disease.

Introduction: This study investigates the role of hypoxia-related genes in the neuroprotective efficacy of Yang Xue oral liquid (YXKFY) in Alzheimer's disease (AD) and Parkinson's disease (PD). Methods and results: Using differential expression and weighted gene co-expression network analysis (WGCNA), we identified 106 and 9 hypoxia-associated genes in AD and PD, respectively, that are implicated in the transcriptomic and proteomic profiles. An artificial intelligence-driven hypoxia signature (AIDHS), comprising 17 and 3 genes for AD and PD, was developed and validated across nine independent cohorts (n = 1713), integrating 10 machine learning algorithms and 113 algorithmic combinations. Significant associations were observed between AIDHS markers and immune cells in AD and PD, including naive CD4+ T cells, macrophages, and neutrophils. Interactions with miRNAs (hsa-miR-1, hsa-miR-124) and transcription factors (USF1) were also identified. Single-cell RNA sequencing (scRNA-seq) data highlighted distinct expression patterns of AIDHS genes in various cell types, such as high expression of TGM2 in endothelial cells, PDGFRB in endothelial and mesenchymal cells, and SYK in microglia. YXKFY treatment was shown to repair cellular damage and decrease reactive oxygen species (ROS) levels. Notably, genes with previously dysfunctional expression, including FKBPL, TGM2, PPIL1, BLVRB, and PDGFRB, exhibited significant recovery after YXKFY treatment, associated with riboflavin and lysicamine. Conclusion: The above genes are suggested to be central to hypoxia and neuroinflammation responses in AD and PD, and are potential key mediators of YXKFY's neuroprotective action.

Self-Assembling E2-Based Nanoparticles Improve Vaccine Thermostability and Protective Immunity against CSFV.

Classical swine fever virus (CSFV) is a highly contagious pathogen causing significant economic losses in the swine industry. Conventional inactivated or attenuated live vaccines for classical swine fever (CSF) are effective but face biosafety concerns and cannot distinguish vaccinated animals from those infected with the field virus, complicating CSF eradication efforts. It is noteworthy that nanoparticle (NP)-based vaccines resemble natural viruses in size and antigen structure, and offer an alternative tool to circumvent these limitations. In this study, we developed an innovative vaccine delivery scaffold utilizing self-assembled mi3 NPs, which form stable structures carrying the CSFV E2 glycoprotein. The expressed yeast E2-fused protein (E2-mi3 NPs) exhibited robust thermostability (25 to 70 °C) and long-term storage stability at room temperature (25 °C). Interestingly, E2-mi3 NPs made with this technology elicited enhanced antigen uptake by RAW264.7 cells. In a rabbit model, the E2-mi3 NP vaccine against CSFV markedly increased CSFV-specific neutralizing antibody titers. Importantly, it conferred complete protection in rabbits challenged with the C-strain of CSFV. Furthermore, we also found that the E2-mi3 NP vaccines triggered stronger cellular (T-lymphocyte proliferation, CD8+ T-lymphocytes, IFN-γ, IL-2, and IL-12p70) and humoral (CSFV-specific neutralizing antibodies, CD4+ T-lymphocytes, and IL-4) immune responses in pigs than the E2 vaccines. To sum up, these structure-based, self-assembled mi3 NPs provide valuable insights for novel antiviral strategies against the constantly infectious agents.

Microsatellite markers for genotyping of Kodamaea ohmeri: Demonstrating outbreaks based on a multicenter surveillance study in China.

Kodamaea ohmeri, an emerging human pathogen, caused both sporadic and nosocomial infections among immunocompromised people with high mortality. However, there is limited research on the molecular epidemiology of K. ohmeri. A total of fifty microsatellite loci were designed based on K. ohmeri type strain NRRL Y-1932 and three loci were finally selected for microsatellite analysis. Non-duplicated K. ohmeri isolates and strains of other species were collected across China as a part of CHIF-NET program for sensitivity and specificity verification. Antifungal susceptibility was determined using Sensititre YeastOne TM YO10. The three loci (P10, P11 and P26), with a cumulative discriminatory power of 0.98, exhibited a prospective specificity and reproducibility in the PCR of 92 K. ohmeri strains from different hospitals. A total of 54 microsatellite types (MT) were identified and most of them distributed sporadically. However, six strains of MT12 clustered in HZ hospital and were isolated in the same department within two months, indicating a potential outbreak. Of seven isolates exhibited MIC values of >8 mg/L for fluconazole, three isolates from LR hospital shared the same genotype of MT44. Herein, we established a set of microsatellite loci for K. ohmeri, as a rapid and specific tool for genotyping K. ohmeri, and identified several potential clusters. This study will help us better understand the molecular epidemiology of the emerging pathogen K. ohmeri.

Atroposelective hydroarylation of biaryl phosphines directed by phosphorus centres.

Prized for their ability to generate chemical complexity rapidly, catalytic carbon-hydrogen (C-H) activation and functionalization reactions have enabled a paradigm shift in the standard logic of synthetic chemistry. Directing group strategies have been used extensively in C-H activation reactions to control regio- and enantioselectivity with transition metal catalysts. However, current methods rely heavily on coordination with nitrogen and/or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, we report enantioselective C-H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution. High reactivity and enantioselectivity are derived from modular assembly of an iridium catalyst with an endogenous phosphorus atom and an exogenous chiral phosphorus ligand, as confirmed by detailed experimental and computational studies. This reaction mode significantly expands the pool of enantiomerically enriched functional phosphines, some of which have shown excellent efficiency for asymmetric catalysis.

Rearrangement of a carboxy-substituted spiro[4.4]nonatriene to annulated fulvenes through a Pd(ii)-mediated 1,5-vinyl shift.

A novel synthesis of aryl-substituted, enantioenriched fulvenes from an oxidative Heck cascade and rearrangement of a carboxy-substituted spiro[4.4]nonatriene is disclosed. Mechanistic investigations with density functional theory (DFT) calculations and empirical results support the net transformation occurring through a novel Pd(ii)-mediated 1,5-vinyl shift from a vinyl-palladium intermediate that terminates with protodepalladation. This spiro-to-fused bicycle conversion tolerates a range of electron-rich and deficient arylboronic acids to give a range of mono- and diaryl substituted annulated fulvenes in moderate to good yields and enantiomeric ratios. Overall, this work connects two classes of molecules with a rich history in physical organic chemistry.

miRNA transcriptomics analysis shows miR-483-5p and miR-503-5p targeted miRNA in extracellular vesicles from severe acute pancreatitis-associated lung injury patients.

AIM: This study sought to identify potential biomarkers and miRNA-mRNA networks within extracellular vesicles (EVs) for detecting severe acute pancreatitis-associated lung injury (SAPALI). METHODS: Blood-derived EVs were isolated, and their miRNA transcriptomic profiles were comprehensively analyzed using miRBase v.21 database along with miRDeep2 tool to predict novel miRNAs. DEGseq R package was deployed for the identification of differentially expressed miRNAs (DEMs). Protein-protein interaction (PPI) networks were assembled using STRING and Cytoscape. A lung injury model was established using Lipopolysaccharide (LPS)-induced BEAS-2B cells, chosen for their respiratory epithelial origin and pertinent association with lung injury. The expression levels of targeted miRNA and associated proteins, TLR4, NF-κB mRNA were quantified via RT-PCR and Western Blot. Levels of IL-6, IL-1ß, TNF-α, and ROS were measured using designated kits. Dual-luciferase reporter assay was conducted to examine the interaction between miRNA and proteins. RESULTS: The comparisons between the SAPALI and the control group revealed 10 DEM, including miR-503-5p and miR-483-5p. The cytoHubba plugin in Cytoscape identified three principal miRNA-mRNA interactions: miR-483-5p with PTK2 and HDAC2; miR-28-5p with MAPK1, TP53BP1, SEMA3A; and miR-503-5p with PPP1CB, SEMA6D, EPHB2, UNC5B. The SAPALI model exhibited elevated miR-503-5p, HDAC2 and inflammatory markers, with a decline UNC5B, miR-483-5p and miR-28-5p. Transfection with miR-503-5p and miR-483-5p inhibitors increased the levels of their supposed binding proteins but not miR-28-5p inhibitor. The Dual-luciferase reporter gene assay identified the interaction of miR-503-5p with UNC5B, and miR-483-5p with HDAC2, but not miR-28-5p with TP53BP1. CONCLUSIONS: Our study maps miRNA-mRNA interactions in SAPALI, identifying miR-503-5p and miR-483-5p as critical regulatory miRNAs.

Does mild flexion of the femoral prosthesis in total knee arthroplasty result in better early postoperative outcomes?

BACKGROUND: The purpose of this study was to measure the femoral prosthesis flexion angle (FPFA) in total knee arthroplasty (TKA) using three-dimensional reconstruction, and to assess the differences in early clinical efficacy between patients with different degrees of flexion. METHODS: We conducted a prospective cohort study. From June 2019 to May 2021, 113 patients admitted for TKA due to osteoarthritis of the knee were selected. The patients' postoperative knee joints were reconstructed in three dimensions according to postoperative three-dimensional computed tomography (CT) scans. The FPFA was measured, and the patients were divided into 4 groups: anterior extension group (FPFA < 0°), mildly flexed group (0° ≤ FPFA < 3°), moderately flexed group (3° ≤ FPFA < 6°) and excessively flexed group (6° ≤ FPFA). The differences in the Knee Society Score (KSS), knee Range of Motion (ROM), and visual analogue scale (VAS) scores were measured and compared between the four groups at each postoperative time point. RESULTS: Postoperative KSS, ROM, and VAS were significantly improved in all groups compared to the preoperative period. At 1 year postoperatively, the ROM was significantly greater in the mildly flexed group (123.46 ± 6.51°) than in the anterior extension group (116.93 ± 8.05°) and the excessively flexed group (118.76 ± 8.20°) (P < 0.05). The KSS was significantly higher in the mildly flexed group (162.68 ± 12.79) than in the other groups at 6 months postoperatively (P < 0.05). The higher KSS (174.17 ± 11.84) in the mildly flexed group was maintained until 1 year postoperatively, with a statistically significant difference (P < 0.05). No significant difference in VAS scores was observed between groups at each time point. CONCLUSIONS: A femoral prosthesis flexion angle of 0-3° significantly improved postoperative knee mobility, and patients could obtain better Knee Society Scores after surgery, which facilitated the postoperative recovery of knee function. TRIAL REGISTRATION: ChiCTR2100051502, 2021/09/24.

rRNA intermediates coordinate the formation of nucleolar vacuoles in C. elegans.

The nucleolus is the most prominent membraneless organelle within the nucleus. How the nucleolar structure is regulated is poorly understood. Here, we identified two types of nucleoli in C. elegans. Type I nucleoli are spherical and do not have visible nucleolar vacuoles (NoVs), and rRNA transcription and processing factors are evenly distributed throughout the nucleolus. Type II nucleoli contain vacuoles, and rRNA transcription and processing factors exclusively accumulate in the periphery rim. The NoV contains nucleoplasmic proteins and is capable of exchanging contents with the nucleoplasm. The high-order structure of the nucleolus is dynamically regulated in C. elegans. Faithful rRNA processing is important to prohibit NoVs. The depletion of 27SA2 rRNA processing factors resulted in NoV formation. The inhibition of RNA polymerase I (RNAPI) transcription and depletion of two conserved nucleolar factors, nucleolin and fibrillarin, prohibits the formation of NoVs. This finding provides a mechanism to coordinate structure maintenance and gene expression.

Enhancing Substrate-Metal Catalyst Affinity via Hydrogen Bonding: Pd(II)-Catalyzed ß-C(sp3)-H Bromination of Free Carboxylic Acids.

The achievement of sufficient substrate-metal catalyst affinity is a fundamental challenge for the development of synthetically useful C-H activation reactions of weakly coordinating native substrates. While hydrogen bonding has been harnessed to bias site selectivity in existing C(sp2)-H activation reactions, the potential for designing catalysts with hydrogen bond donors (HBDs) to enhance catalyst-substrate affinity and, thereby, facilitate otherwise unreactive C(sp3)-H activation remains to be demonstrated. Herein, we report the discovery of a ligand scaffold containing a remote amide motif that can form a favorable meta-macrocyclic hydrogen bonding interaction with the aliphatic acid substrate. The utility of this ligand scaffold is demonstrated through the development of an unprecedented C(sp3)-H bromination of α-tertiary and α-quaternary free carboxylic acids, which proceeds in exceedingly high mono-selectivity. The geometric relationship between the NHAc hydrogen bond donor and the coordinating quinoline ligand is crucial for forming the meta-macrocyclophane-like hydrogen bonding interaction, which provides a guideline for the future design of catalysts employing secondary interactions.

Effect of bone cement sealing of the intramedullary femoral canal on coagulation status after total knee arthroplasty: a retrospective thromboelastography study.

BACKGROUND: The main objective of this study was to investigate whether the use of bone cement in total knee arthroplasty (TKA) has an effect on postoperative coagulation status and bleeding. METHODS: 153 patients who underwent unilateral TKA between September 2019 and February 2023 were collected and divided into Bone and Cement&Bone groups according to whether bone cement was used to seal the bone medullary canal intraoperatively. Routine blood and thromboelastography (TEG) examinations were performed on the day before, the first day and the seventh day after surgery; postoperative bleeding, drainage, transfusion rate and the number of people suffering from deep venous thrombosis (DVT) were recorded. RESULTS: There were no significant differences between the two groups in terms of baseline clinical characteristics before surgery (P > 0.05). In terms of TEG indicators, the coagulation index (CI) of the Bone&Cement group was lower than that of the Bone group on the first postoperative day and on the seventh postoperative day (P < 0.05). The CI of patients in the Bone group on the first postoperative day was lower than that of the preoperative day (P < 0.05); in terms of blood loss, the total blood loss and occult blood loss were lower in the Bone&Cement group than in the Bone group (P < 0.05). In addition, there was no significant difference in postoperative drainage,transfusion rate and the incidence of DVT between the two groups. CONCLUSION: Blocking the intramedullary canal of the femur with bone cement during TKA improves relative postoperative hypocoagulation and reduces postoperative blood loss, although there is no significant effect on transfusion rates, drainage and DVT.

Diagnostic value of mean platelet volume combined with thromboelastography for coagulation state after total knee arthroplasty.

BACKGROUND: The main objective of this study was to predict the status of blood and the occurrence of lower limb deep vein thrombosis (DVT) after total knee arthroplasty(TKA) by means of mean platelet volume (MPV) combined with thromboelastography (TEG). METHODS: We collected 180 patients who underwent unilateral total knee arthroplasty between May 2015 and March 2022, and the patients were divided into DVT group and control group according to whole-leg ultrasonography on the seventh postoperative day. Blood count and TEG were performed on the day before surgery, the first day after surgery and the seventh day respectively. Multifactorial analysis was used to investigate whether the relevant parameters were independent predictors of DVT after TKA. RESULTS: MPV has the strongest correlation with the maximum amplitude (MA), followed by alpha-angle; MPV and alpha-angle on the first postoperative day are independent predictors of DVT. MPV in patients with thrombosis tends to rise and then fall in the perioperative period. The optimal threshold for MPV to predict thrombosis is 10.85 fL and the area under the ROC curve is 0.694, The area under the ROC curve increases to 0.815 using MPV combined with alpha-angle. In addition, MA, α-angle, composite coagulation index (CI) and MPV were all statistically higher in the DVT group than in the control group (p < 0.001). CONCLUSION: MPV is a predictor of DVT after TKA. It can reflect the hypercoagulable state of blood after surgery; Combination of MPV and alpha-angle on the first day after surgery in patients with TKA improves predictive power of DVT.

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Ovid Medline, Embase, and Cochrane Central up to 14 October 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach. RESULTS: The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes). CONCLUSIONS: This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022325948.

Systematic characterization of chromodomain proteins reveals an H3K9me1/2 reader regulating aging in C. elegans.

The chromatin organization modifier domain (chromodomain) is an evolutionally conserved motif across eukaryotic species. The chromodomain mainly functions as a histone methyl-lysine reader to modulate gene expression, chromatin spatial conformation and genome stability. Mutations or aberrant expression of chromodomain proteins can result in cancer and other human diseases. Here, we systematically tag chromodomain proteins with green fluorescent protein (GFP) using CRISPR/Cas9 technology in C. elegans. By combining ChIP-seq analysis and imaging, we delineate a comprehensive expression and functional map of chromodomain proteins. We then conduct a candidate-based RNAi screening and identify factors that regulate the expression and subcellular localization of the chromodomain proteins. Specifically, we reveal an H3K9me1/2 reader, CEC-5, both by in vitro biochemistry and in vivo ChIP assays. MET-2, an H3K9me1/2 writer, is required for CEC-5 association with heterochromatin. Both MET-2 and CEC-5 are required for the normal lifespan of C. elegans. Furthermore, a forward genetic screening identifies a conserved Arginine124 of CEC-5's chromodomain, which is essential for CEC-5's association with chromatin and life span regulation. Thus, our work will serve as a reference to explore chromodomain functions and regulation in C. elegans and allow potential applications in aging-related human diseases.

A ZTF-7/RPS-2 complex mediates the cold-warm response in C. elegans.

Temperature greatly affects numerous biological processes in all organisms. How multicellular organisms respond to and are impacted by hypothermic stress remains elusive. Here, we found that cold-warm stimuli induced depletion of the RNA exosome complex in the nucleoli but enriched it in the nucleoplasm. To further understand the function and mechanism of cold-warm stimuli, we conducted forward genetic screening and identified ZTF-7, which is required for RNA exosome depletion from nucleoli upon transient cold-warm exposure in C. elegans. ZTF-7 is a putative ortholog of human ZNF277 that may contribute to language impairments. Immunoprecipitation followed by mass spectrometry (IP-MS) found that ZTF-7 interacted with RPS-2, which is a ribosomal protein of the small subunit and participates in pre-rRNA processing. A partial depletion of RPS-2 and other proteins of the small ribosomal subunit blocked the cold-warm stimuli-induced reduction of exosome subunits from the nucleoli. These results established a novel mechanism by which C. elegans responds to environmental cold-warm exposure.

[Ontologies Applied in Clinical Decision Support Systems for Diabetes].

A clinical decision support system (CDSS) integrated with electronic health records helps physicians at the grassroots make patient-appropriate and evidence-based treatment decisions and improves the efficiency of diagnosis and treatment. Furthermore, using ontologies to build up the medical knowledge base and patient data for CDSS enhances the automation and transparency of the reasoning process of CDSS and helps generate interpretable and accurate treatment recommendations. Herein, we reviewed the relevant ontologies in the field of diabetes treatment and the progress and challenges concerning ontology-based CDSSs. Firstly, we elaborated on the current status and challenges of diabetes treatment in China, highlighting the urgent need to improve the efficiency and quality of medical services. Then, we presented background information about ontologies and gave an overview of the framework, methodology, and features of using ontologies to construct CDSS. After that, we reviewed the ontologies and instances of ontology-based CDSS in the field of diabetes treatment in China and abroad and summarized their construction methods and features. Last but not the least, we discussed the future prospects of the field, suggesting that integrating evidence-based medicine with ontologies to build a reliable clinical recommendation system should be the current focus of CDSS development.

Biochemical and structural characterization of a sphingomonad diarylpropane lyase for cofactorless deformylation.

Lignin valorization is being intensely pursued via tandem catalytic depolymerization and biological funneling to produce single products. In many lignin depolymerization processes, aromatic dimers and oligomers linked by carbon-carbon bonds remain intact, necessitating the development of enzymes capable of cleaving these compounds to monomers. Recently, the catabolism of erythro-1,2-diguaiacylpropane-1,3-diol (erythro-DGPD), a ring-opened lignin-derived ß-1 dimer, was reported in Novosphingobium aromaticivorans. The first enzyme in this pathway, LdpA (formerly LsdE), is a member of the nuclear transport factor 2 (NTF-2)-like structural superfamily that converts erythro-DGPD to lignostilbene through a heretofore unknown mechanism. In this study, we performed biochemical, structural, and mechanistic characterization of the N. aromaticivorans LdpA and another homolog identified in Sphingobium sp. SYK-6, for which activity was confirmed in vivo. For both enzymes, we first demonstrated that formaldehyde is the C1 reaction product, and we further demonstrated that both enantiomers of erythro-DGPD were transformed simultaneously, suggesting that LdpA, while diastereomerically specific, lacks enantioselectivity. We also show that LdpA is subject to a severe competitive product inhibition by lignostilbene. Three-dimensional structures of LdpA were determined using X-ray crystallography, including substrate-bound complexes, revealing several residues that were shown to be catalytically essential. We used density functional theory to validate a proposed mechanism that proceeds via dehydroxylation and formation of a quinone methide intermediate that serves as an electron sink for the ensuing deformylation. Overall, this study expands the range of chemistry catalyzed by the NTF-2-like protein family to a prevalent lignin dimer through a cofactorless deformylation reaction.

'Stress hyperglycemia ratio and in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes.

OBJECTIVE: To evaluate the impact of stress hyperglycemia on the in-hospital prognosis in non-surgical patients with heart failure and type 2 diabetes. RESEARCH DESIGN AND METHODS: We identified non-surgical hospitalized patients with heart failure and type 2 diabetes from a large electronic medical record-based database of diabetes in China (WECODe) from 2011 to 2019. We estimated stress hyperglycemia using the stress hyperglycemia ratio (SHR) and its equation, say admission blood glucose/[(28.7 × HbA1c)- 46.7]. The primary outcomes included the composite cardiac events (combination of death during hospitalization, requiring cardiopulmonary resuscitation, cardiogenic shock, and the new episode of acute heart failure during hospitalization), major acute kidney injury (AKI stage 2 or 3), and major systemic infection. RESULTS: Of 2875 eligible Chinese adults, SHR showed U-shaped associations with composite cardiac events, major AKI, and major systemic infection. People with SHR in the third tertile (vs those with SHR in the second tertile) presented higher risks of composite cardiac events ([odds ratio, 95% confidence interval] 1.89, 1.26 to 2.87) and major AKI (1.86, 1.01 to 3.54). In patients with impaired kidney function at baseline, both SHR in the first and third tertiles anticipated higher risks of major AKI and major systemic infection. CONCLUSIONS: Both high and low SHR indicates poor prognosis during hospitalization in non-surgical patients with heart failure and type 2 diabetes.