Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs.

Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies."

Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy.

Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.

Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation.

Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation.

METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.

PdMo bimetallene for oxygen reduction catalysis.

The efficient interconversion of chemicals and electricity through electrocatalytic processes is central to many renewable-energy initiatives. The sluggish kinetics of the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER)1-4 has long posed one of the biggest challenges in this field, and electrocatalysts based on expensive platinum-group metals are often required to improve the activity and durability of these reactions. The use of alloying5-7, surface strain8-11 and optimized coordination environments12 has resulted in platinum-based nanocrystals that enable very high ORR activities in acidic media; however, improving the activity of this reaction in alkaline environments remains challenging because of the difficulty in achieving optimized oxygen binding strength on platinum-group metals in the presence of hydroxide. Here we show that PdMo bimetallene-a palladium-molybdenum alloy in the form of a highly curved and sub-nanometre-thick metal nanosheet-is an efficient and stable electrocatalyst for the ORR and the OER in alkaline electrolytes, and shows promising performance as a cathode in Zn-air and Li-air batteries. The thin-sheet structure of PdMo bimetallene enables a large electrochemically active surface area (138.7 square metres per gram of palladium) as well as high atomic utilization, resulting in a mass activity towards the ORR of 16.37 amperes per milligram of palladium at 0.9 volts versus the reversible hydrogen electrode in alkaline electrolytes. This mass activity is 78 times and 327 times higher than those of commercial Pt/C and Pd/C catalysts, respectively, and shows little decay after 30,000 potential cycles. Density functional theory calculations reveal that the alloying effect, the strain effect due to the curved geometry, and the quantum size effect due to the thinness of the sheets tune the electronic structure of the system for optimized oxygen binding. Given the properties and the structure-activity relationships of PdMo metallene, we suggest that other metallene materials could show great promise in energy electrocatalysis.

Ultrahigh efficient emulsification with drag-reducing liquid gating interfacial behavior.

Emulsification is a crucial technique for mixing immiscible liquids into droplets in numerous areas ranging from food to medicine to chemical synthesis. Commercial emulsification methods are promising for high production, but suffer from high energy input. Here, we report a very simple and scalable emulsification method that employs the drag-reducing liquid gating structure to create a smooth liquid-liquid interface for the reduction of resistance and tunable generation of droplets with good uniformity. Theoretical modeling and experimental results demonstrate that our method exhibits ultrahigh efficiency, which can reach up to more than 4 orders of magnitude greater energy-saving compared to commercial methods. For temperature-sensitive biological components, such as enzymes, proteins, and bacteria, it can offer a comfortable environment to avoid exposure to high temperatures during emulsifying, and the interface also enables the suppression of fouling. This unique drag-reducing liquid gating interfacial emulsification mechanism promotes the efficiency of droplet generation and provides fresh insight into the innovation of emulsifications that can be applied in many fields, including the food industry, the daily chemical industry, biomedicine, material fabrication, the petrochemical industry, and beyond.

Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis.

BACKGROUND AND AIMS: Deregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m6A demethylases, in patients with ulcerative colitis (UC). METHODS: We analysed colon tissues of Ftoflox/flox; Villin-cre mice and their Ftoflox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C16-ceramide. RESULTS: FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Ftoflox/flox;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m6A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. CONCLUSIONS: FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m6A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.

eIF3d: A driver of noncanonical cap-dependent translation of specific mRNAs and a trigger of biological/pathological processes.

Eukaryotic initiation factor 3d (eIF3d), a known RNA-binding subunit of the eIF3 complex, is a 66 to 68-kDa protein with an RNA-binding motif and a cap-binding domain. Compared with other eIF3 subunits, eIF3d is relatively understudied. However, recent progress in studying eIF3d has revealed a number of intriguing findings on its role in maintaining eIF3 complex integrity, global protein synthesis, and in biological and pathological processes. It has also been reported that eIF3d has noncanonical functions in regulating translation of a subset of mRNAs by binding to 5'-UTRs or interacting with other proteins independent of the eIF3 complex and additional functions in regulating protein stability. The noncanonical regulation of mRNA translation or protein stability may contribute to the role of eIF3d in biological processes such as metabolic stress adaptation and in disease onset and progression including severe acute respiratory syndrome coronavirus 2 infection, tumorigenesis, and acquired immune deficiency syndrome. In this review, we critically evaluate the recent studies on these aspects of eIF3d and assess prospects in understanding the function of eIF3d in regulating protein synthesis and in biological and pathological processes.

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma.

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3'UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

A radiomics-based interpretable model to predict the pathological grade of pancreatic neuroendocrine tumors.

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Rational Design of a Highly Sensitive Carboxylesterase Probe and Its Application in High-Throughput Screening for Uncovering Carboxylesterase Inhibitors.

Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.

Vonoprazan and amoxicillin dual therapy as the first-line treatment of Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND: Recent clinical trials have evaluated the efficacy of vonoprazan-amoxicillin (VA) dual therapy as the first-line treatment for Helicobacter pylori infection in different regions with inconsistent results reported. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of VA dual therapy compared to the currently recommended therapy for eradicating H. pylori. MATERIALS AND METHODS: A comprehensive search of the PubMed, Cochrane, and Embase databases was performed using the following search terms: ("Helicobacter" OR "H. pylori" OR "Hp") AND ("vonoprazan" OR "potassium-competitive acid blocker" OR "P-CAB") AND ("amoxicillin" OR "penicillin") AND ("dual"). The primary outcome was to evaluate the eradication rate according to intention-to-treat and per-protocol analysis. The secondary outcomes were adverse events and compliance. RESULTS: A total of 15 studies involving 4, 568 patients were included. The pooled eradication rate of VA dual therapy was 85.0% and 90.0% by intention-to-treat and per-protocol analysis, respectively. The adverse events rate and compliance of VA dual therapy were 17.5% and 96%, respectively. The efficacy of VA dual therapy was superior to proton pump inhibitors-based triple therapy (82.0% vs. 71.4%, p < 0.01) but lower than vonoprazan-containing quadruple therapy (83.1% vs. 93.3%, p = 0.02). 7-day VA dual therapy showed lower eradication rates than 10-day (χ2 = 24.09, p < 0.01) and 14-day VA dual therapy (χ2 = 11.87, p < 0.01). The adverse events rate of VA dual therapy was lower than vonoprazan triple therapy (24.6% vs. 30.9%, p = 0.01) and bismuth-containing quadruple therapy (20.5% vs. 47.9%, p < 0.01). No significant difference of compliance was observed between VA dual therapy and each subgroup. CONCLUSION: VA dual therapy, a novel regimen, showed high efficacy as the first-line treatment for H. pylori eradication, which should be optimized before application in different regions.

Microporosity and Catalytic Activity for Hydrodesulfurization of Pharmacosiderite Mo4P3O16 Synthesized at a Moderate Temperature.

Pharmacosiderite Mo4P3O16 (Pharma-MoPO) consists of [Mo4O4] cubane unit and [PO4] tetrahedral to form an open framework with a microporous structure similar to that of LTA-type zeolite. Although attractive applications are expected due to its microporous structure and redox-active components, its physicochemical properties have been poorly investigated due to the specificity of its synthesis, which requires a high hydrothermal synthesis temperature of 360 °C. In this study, we succeeded in synthesizing Pharma-MoPO by hydrothermal synthesis at 230 °C, which can be applied using a commercially available autoclave by changing the metal source. Through the study of the solids and liquids obtained after hydrothermal syntheses, the formation process of Pharma-MoPO under our studied synthesis conditions was proposed. Advanced characterizations provided detailed structural information on Pharma-MoPO, including the location site of a countercation NH4+. Pharma-MoPO could adsorb CO2 with the amount close to the number of cages without removing NH4+. Pharma-MoPO exhibited stable catalytic activity for the hydrodesulfurization of thiophene while maintaining its crystal structure, except for the introduction of sulfide by replacing lattice oxygens. Pharmacosiderite Mo4P3O16 was successfully obtained by hydrothermal synthesis at a moderate temperature, and its microporosity for CO2 adsorption and catalytic properties for hydrodesulfurization were discovered.

A Novel Multi-Functional Fluorescence Probe for the Detection of Al3+/Zn2+/Cd2+ and its Practical Applications.

A novel multi-functional fluorescence probe HMIC based on hydrazide Schiff base has been successfully synthesized and characterized. It can distinguish Al3+/Zn2+/Cd2+ in ethanol, in which fluorescence emission with different colors (blue for Al3+, orange for Zn2+, and green for Cd2+) were presented. The limits of detection of HMIC towards three ions were calculated from the titration curve as 7.70 × 10- 9 M, 4.64 × 10- 9 M, and 1.35 × 10- 8 M, respectively. The structures of HMIC and its complexes were investigated using UV-Vis spectra, Job's plot, infrared spectra, mass spectrometry, 1H-NMR and DFT calculations. Practical application studies have also demonstrated that HMIC can be applied to real samples with a low impact of potential interferents. Cytotoxicity and cellular imaging assays have shown that HMIC has good cellular permeability and potential antitumor effects. Interestingly, HMIC can image Al3+, Zn2+ and Cd2+ in the cells with different fluorescence signals.

The effects of pks+ Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy.

BACKGROUND AND AIM: Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances of getting colorectal adenoma (CRA) or cancer (CRC). We aimed to figure out the effects of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients. METHODS: This was a retrospective observational study that recruited 514 volunteers, including 199 people with normal gallbladders (normal), 152 CL, and 163 CE patients. Discovery cohort was established to explore the difference in gut microbiota through 16S rRNA and metagenomics sequencing. Validation cohort aimed to verify the results through quantitative polymerase chain reaction (qPCR). RESULTS: Significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in the discovery cohort (16S rRNA sequencing, PNormal-CL = 0.013, PNormal-CE = 0.042; metagenomics sequencing, PNormal-CE = 0.026) and validation cohort (PNormal-CL < 0.0001, PNormal-CE < 0.0001). Pks+ E. coli was found enriched in CL and CE patients through qPCR (in discovery cohort: PNormal-CE = 0.018; in validation cohort: PNormal-CL < 0.0001, PNormal-CE < 0.0001). The differences in bile acid metabolism were found both through Tax4Fun analysis of 16S rRNA sequencing (Ko00120, primary bile acid biosynthesis, PNormal-CE = 0.014; Ko00121, secondary bile acid biosynthesis, PNormal-CE = 0.010) and through metagenomics sequencing (map 00121, PNormal-CE = 0.026). The elevation of serum total bile acid of CE patients was also found in validation cohort (PNormal-CE < 0.0001). The level of serum total bile acid was associated with the relative abundance of pks+ E. coli (r = 0.1895, P = 0.0012). CONCLUSIONS: E. coli, especially pks+ species, was enriched in CL and CE patients. Pks+ E. coli and bile acid metabolism were found associated with CRA and CRC in people after cholecystectomy.

Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study.

BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

KIM-1 augments hypoxia-induced tubulointerstitial inflammation through uptake of small extracellular vesicles by tubular epithelial cells.

Tubular epithelial cells (TECs) exposed to hypoxia incite tubulointerstitial inflammation (TII), while the exact mechanism is unclear. In this study, we identified that hypoxia evoked tubule injury as evidenced by tubular hypoxia-inducible factor-1α and kidney injury molecule-1 (KIM-1) expression and that renal small extracellular vesicle (sEV) production was increased with the development of TII after ischemia-reperfusion injury (IRI). Intriguingly, KIM-1-positive tubules were surrounded by macrophages and co-localized with sEVs. In vitro, KIM-1 expression and sEV release were increased in hypoxic TECs and the hypoxia-induced inflammatory response was ameliorated when KIM-1 or Rab27a, a master regulator of sEV secretion, was silenced. Furthermore, KIM-1 was identified to mediate hypoxic TEC-derived sEV (Hypo-sEV) uptake by TECs. Phosphatidylserine (PS), a ligand of KIM-1, was present in Hypo-sEVs as detected by nanoflow cytometry. Correspondingly, the inflammatory response induced by exogenous Hypo-sEVs was attenuated when KIM-1 was knocked down. In vivo, exogenous-applied Hypo-sEVs localized to KIM-1-positive tubules and exacerbated TII in IRI mice. Our study demonstrated that KIM-1 expressed by injured tubules mediated sEV uptake via recognizing PS, which participated in the amplification of tubule inflammation induced by hypoxia, leading to the development of TII in ischemic acute kidney injury.

Comprehensively evaluating the relationships between marital status and other family factors with cardiovascular disease and long-term overall mortality in the elderly: a study of 48 510 Chinese individuals.

BACKGROUND: Marital status is associated with cardiovascular disease (CVD) incidence and overall mortality, yet limited research on this topic in elderly individuals is available. Our aim was to comprehensively assess the impact of marital status and other family factors on CVD incidence and long-term mortality among elderly people. METHODS: Data from the Chinese Longitudinal Healthy Longevity Survey (2002/2005/2008-2018) for participants aged ≥60 years were analysed. A cross-sectional study initially examined the correlation between spouses, offspring, living arrangements, and CVD using logistic regression. Subsequently, a retrospective cohort study investigated the long-term associations of these factors with overall mortality via Kaplan-Meier and Cox regression analyses. RESULTS: The study involved 48 510 subjects (average age: 87 years). The cross-sectional analysis revealed a correlation between living with a spouse and an increased incidence of heart disease (adjusted OR 1.27, 95% CI 1.04-1.55) and cerebrovascular disease/stroke (adjusted OR 1.26, 95% CI 1.11-1.42). According to the retrospective cohort analysis, living with a spouse significantly reduced overall mortality (adjusted HR 0.84, 95% CI 0.80-0.87), irrespective of marital relationship quality. Conversely, living with offspring (adjusted HR 1.12, 95% CI 1.08-1.16), having more children (adjusted Pnonlinearity = 0.427) or cohabitants (adjusted Pnonlinearity < 0.0001) were associated with increased overall mortality. CONCLUSION: In the elderly population, being married and living with a spouse were not significantly associated with a decrease in CVD incidence but were associated with a reduction in long-term overall mortality. Living with offspring, having more children, or having a larger family size did not replicate the protective effect but indicated greater overall mortality.

Effects of acute and chronic stair-climbing exercise on metabolic health: A systematic review.

Stair climbing exercise (SE) provides a feasible approach to elevate physical activity, but the effects on metabolic health are unclear. We systematically reviewed the currently available evidence on the effects of SE on fasting and postprandial glycaemia and lipidaemia. Studies were included if they investigated the effects of acute or chronic (at least 2 weeks) SE on fasting and/or postprandial glycaemic (insulin and glucose) and lipidaemic (triacylglycerols and non-esterified fatty acids) responses in healthy, prediabetic or type 2 diabetic adult populations. PubMed, Web of Science and Scopus were searched for eligible studies until July 2022. A total of 25 studies (14 acute and 11 chronic) were eligible for review. Acute bout(s) of SE can reduce postprandial glycaemia in individuals with prediabetes and type 2 diabetes (8 of 9 studies), but not in normoglycemic individuals. The effects of acute SE on postprandial lipidaemic responses and SE training on both fasting and postprandial glycaemia/lipidaemia were unclear. Acute SE may reduce postprandial glucose concentrations in people with impaired glycaemic control, but high-quality studies are needed. More studies are needed to determine the effect of chronic SE training on postprandial glucose and lipid responses, and the acute effects of SE on lipid responses.