Bacteroides uniformis degrades ß-glucan to promote Lactobacillus johnsonii improving indole-3-lactic acid levels in alleviating colitis.

BACKGROUND: Intake of dietary fiber is associated with a reduced risk of inflammatory bowel disease. ß-Glucan (BG), a bioactive dietary fiber, has potential health-promoting effects on intestinal functions; however, the underlying mechanism remains unclear. Here, we explore the role of BG in ameliorating colitis by modulating key bacteria and metabolites, confirmed by multiple validation experiments and loss-of-function studies, and reveal a novel bacterial cross-feeding interaction. RESULTS: BG intervention ameliorates colitis and reverses Lactobacillus reduction in colitic mice, and Lactobacillus abundance was significantly negatively correlated with the severity of colitis. It was confirmed by further studies that Lactobacillus johnsonii was the most significantly enriched Lactobacillus spp. Multi-omics analysis revealed that L. johnsonii produced abundant indole-3-lactic acid (ILA) leading to the activation of aryl hydrocarbon receptor (AhR) responsible for the mitigation of colitis. Interestingly, L. johnsonii cannot utilize BG but requires a cross-feeding with Bacteroides uniformis, which degrades BG and produces nicotinamide (NAM) to promote the growth of L. johnsonii. A proof-of-concept study confirmed that BG increases L. johnsonii and B. uniformis abundance and ILA levels in healthy individuals. CONCLUSIONS: These findings demonstrate the mechanism by which BG ameliorates colitis via L. johnsonii-ILA-AhR axis and reveal the important cross-feeding interaction between L. johnsonii and B. uniformis. Video Abstract.

Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.

BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Exposure to Polypropylene Microplastics Causes Cardiomyocyte Apoptosis Through Oxidative Stress and Activation of the MAPK-Nrf2 Signaling Pathway.

Microplastics are a growing concern as pollutants that impact both public health and the environment. However, the toxic effects of polypropylene microplastics (PP-MPs) are not well understood. This study aimed to investigate the effects of PP-MPs on cardiotoxicity and its underlying mechanisms. The cardiotoxicity of exposure to different amounts of PP-MPs were investigated in both ICR mice and H9C2 cells. Our results demonstrated that sub-chronic exposure to 5 and 50 mg/L PP-MPs led to myocardial structural damage, apoptosis, and fibrosis in mice cardiomyocytes. Flow cytometry analysis revealed that PP-MPs could decrease mitochondrial membrane potential and induce apoptosis in H9C2 cells. Western blotting revealed decreased expression of Bcl-2, poly(ADP-ribose) polymerase (PARP) and caspase 3 and increased expression of Bax, cleaved-PARP, and cleaved-caspase 3 in PP-MPs-treated cardiac tissue and H9C2 cells. These results confirmed the apoptotic effects induced by PP-MPs. Moreover, PP-MPs treatment triggered oxidative stress, as evidenced by the increased levels of malondialdehyde; reduction in glutathione peroxidase, superoxide dismutase, and catalase activities in mice cardiac tissues; and increased reactive oxygen species levels in H9C2 cells. Finally, western blotting demonstrated that exposure to PP-MPs significantly reduced the expression levels of Nrf2 and p-ERK proteins associated with MAPK-Nrf2 pathway in both cardiac tissue and H9C2 cells. Overall, our findings indicate that PP-MPs can induce cardiomyocyte apoptosis through MAPK-Nrf2 signaling pathway, which is triggered by oxidative stress. This study provides a foundation for determining the effects of PP-MPs on cardiotoxicity and their underlying mechanisms.

Increased peripheral leukocyte aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis: A study based on clinical evidence.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.

Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice.

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal depalmitoylation enzyme that mediates protein posttranslational modifications. Loss-of-function mutation of PPT1 causes a failure of the lysosomal degradation of palmitoylated proteins and results in a congenital disease characterized by progressive neuronal degeneration referred to as infantile neuronal ceroid lipofuscinosis (INCL). A mouse knock-in model of PPT1 (PPT1-KI) was established by introducing the R151X mutation into exon 5 of the PPT1 gene, which exhibited INCL-like pathological lesions. We previously reported that hippocampal γ oscillations were impaired in PPT1 mice. Hippocampal γ oscillations can be enhanced by selective activation of the dopamine D4 receptor (DR4), a dopamine D2-like receptor. In this study, we investigated the changes in DR expression and the effects of dopamine and various DR agonists on neural network activity, cognition and motor function in PPT1KI mice. Cognition and motor defects were evaluated via Y-maze, novel object recognition and rotarod tests. Extracellular field potentials were elicited in hippocampal slices, and neuronal network oscillations in the gamma frequency band (γ oscillations) were induced by perfusion with kainic acid (200 nM). PPT1KI mice displayed progressive impairments in γ oscillations and hippocampus-related memory, as well as abnormal expression profiles of dopamine receptors with preserved expression of DR1 and 3, increased membrane expression of DR4 and decreased DR2 levels. The immunocytochemistry analysis revealed the colocalization of PPT1 with DR4 or DR2 in the soma and large dendrites of both WT and PPT1KI mice. Immunoprecipitation confirmed the interaction between PPT1 and DR4 or DR2. The impaired γ oscillations and cognitive functions were largely restored by the application of exogenous dopamine, the selective DR2 agonist quinpirole or the DR4 agonist A412997. Furthermore, the administration of A412997 (0.5 mg/kg, i.p.) significantly upregulated the activity of CaMKII in the hippocampus of 5-month-old PPT1KI mice. Collectively, these results suggest that the activation of D2-like dopamine receptors improves cognition and network activity in PPT1KI mice and that specific DR subunits may be potential targets for the intervention of neurodegenerative disorders, such as INCL.

Luteipulveratus flavus sp. nov. isolated from two lichen species.

Two novel strains, YIM 133132T and YIM 133296, were isolated from lichen samples collected from Yunnan Province, Southwest PR China. YIM 133132T and YIM 133296 are aerobic, Gram-staining-positive, non-motile actinomycetes. They are also catalase-positive and oxidase-negative, and YIM 133132T formed flat yellowish colonies that were relatively dry on YIM38 agar medium. Flat yellowish colonies of YIM 133296 were also observed on YIM38 agar medium. YIM 133132T grew at 25-35 °C (optimum 25-30 °C), pH 6.0-9.0 (optimum pH 7.0) and in the presence of 0-8% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains YIM 133132T and YIM 133296 represented members of the genus Luteipulveratus and exhibited high sequence similarity (96.93%) with Luteipulveratus halotolerans C296001T. The genomic DNA G+C content of both strains was 71.8%. The DNA-DNA hybridisation (dDDH) values between YIM 133132T and YIM 133296 were 85.1%, and the DNA-DNA hybridisation value between YIM 133132T and YIM 133296 and L. halotolerans C296001T was 23.4%. On the basis of the draft genome sequences, the average nucleotide identity (ANI) between strains YIM 133132T and YIM 133296 and L. halotolerans C296001T was 80.8%. The major menaquinones that were identified were MK-8(H4), MK-9 and MK-8(H2). The polar lipids were diphosphatidylglycerol and phosphatidylinositol. On the basis of the morphological, physiological, biochemical, genomic, phylogenetic and chemotaxonomic characteristics, strains YIM 133132T and YIM 133296 can be clearly distinguished from L. halotolerans C296001T, and the two strains represent a novel species for which the name L. flavus sp. nov. is proposed. The type strain is YIM 133132T (CGMCC= 1.61357T and KCTC= 49824T).

Metarhiziumpuerense (Hypocreales, Clavicipitaceae): a new species from Yunnan, south-western China.

Background: As a genus within the Clavicipitaceae, Metarhizium exhibits rich morphological and ecological diversity, with a wide distribution and a variety of hosts. Currently, sixty-eight species of Metarhizium have been described. New information: A new species of Metarhizium, M.puerense (Hong Yu bis), was described in Pu'er City, Yunnan Province, south-western China. Based on morphological characteristics and multilocus phylogenetic analyses, Metarhiziumpuerense was confirmed to be phylogenetically related to M.album, but was clearly separated and formed a distinct branch. In contrast, the host of Metarhiziumalbum was plants and leafhoppers and that lepidopteran larvae were the host of M.puerense. The diagnostic features of M.puerense were solitary to multiple stromata and smooth-walled, cylindrical with rounded apices conidia.

Blood Pressure and Cardiovascular Risk in Women With Breast Cancer: The Pathways Heart Study.

Background: Hypertension is an important contributor to cardiovascular disease (CVD) in breast cancer (BC) survivors; however, research on blood pressure (BP) and CVD outcomes in BC survivors is limited. Objectives: The purpose of this study was to better characterize the association between BP and CVD in a large, longitudinal cohort of BC patients. Methods: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California were matched 1:5 to women without BC. Patient data were obtained from electronic health records. Multivariable Cox regression and penalized spline models were used to explore the linear and nonlinear relationship of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CVD outcomes. Results: BC cases (n = 12,713) and controls (n = 55,886) had median follow-up of 9.6 years (IQR: 5.0-11.9 years). Women with BC had a mean age of 60.6 years; 64.8% were non-Hispanic White. For ischemic heart disease (IHD), every 10 mmHg increase in SBP and DBP was associated with 1.23 (95% CI: 1.14-1.33) and 1.10 (95% CI: 0.98-1.24) risk, respectively, in women with BC. For stroke, every 10 mmHg increase in SBP and DBP was associated with a 1.45 (95% CI: 1.34-1.58) and 1.91 (95% CI: 1.68-2.18) risk, respectively. A U-shaped relationship was observed between heart failure/cardiomyopathy and BP. The associations between BP and risk of IHD, stroke, and any primary CVD were not statistically different comparing women with BC to controls, but risks varied by BC status for heart failure/cardiomyopathy (P for interaction = 0.01). Conclusions: Women with and without BC showed similar risks for IHD, stroke, and any primary CVD suggesting similar BP targets should be pursued regardless of BC survivorship status.

Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis.

BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects. CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.

Establishment of an Animal Model of Oral Squamous Cell Carcinoma Invading the Mandible.

OBJECTIVE: To establish an animal model of oral squamous cell carcinoma invading the mandible through multi-sample experiments that verified the stability, repeatability, tumorigenicity and mandible destruction rate of the model. METHODS: Oral squamous cell carcinoma cell suspension was injected into the outer side of the mandible through the anterior edge of the masseter muscle of naked mice to observe the tumourforming process. Then, the anatomical, histological and imaging examinations were carried out to determine whether the tumour had invaded the mandible. By comparing the tumour growth of multiple groups of various squamous cell carcinoma cells (CAL27, HN6 and HN30 cells), the changes in body weight and characteristics of tumour formation were compared, and the experience was summarised to further verify the stability, repeatability, tumour formation rate and arch damage rate of the model. RESULTS: The subsequent specimens of tumour-bearing nude mice were validated once the model had been established. In vitro, tumour tissue wrapped around the mandible's tumour-bearing side, and the local texture was tough with no resistance to acupuncture. Haematoxylin and eosin staining revealed that squamous cells were infiltrating the mandible in both the horizontal and sagittal planes. Microcomputed tomography results showed that the mandible on the tumour-bearing side displayed obvious erosion damage. Cell lines with various passage rates clearly had diverse tumour-bearing life cycles. CONCLUSION: This study successfully established an animal model of oral squamous cell carcinoma invasion of the mandible. The model has excellent biological stability, repeatability, tumorigenesis rate and mandible destruction rate.

Novel point-of-care rapid detection of monkeypox virus.

Monkeypox, a viral zoonotic disease caused by MPXV, has emerged as a significant global health concern since the first outbreak outside Africa in 2003. As of the current data, there have been 30 189 confirmed cases of monkeypox in 88 countries, with 29 844 cases reported in 81 countries. Given the absence of prior documented instances of the disease, swift and accurate testing is imperative to contain the spread of monkeypox. In this study, we developed a LAMP detection reagent for monkeypox and evaluated its performance in terms of sensitivity, specificity, repeatability, stability, linear range, and linearity, utilizing a commercial magnetic bead-based nucleic acid extraction system. This has led to the establishment of an integrated on-site detection platform for the monkeypox virus, utilizing a closed cartridge. The sensitivity was found to be 100 copies per µL, with no cross-reactivity observed with three other viruses, indicating robust performance. The parameters of repeatability, stability, linear range, and linearity were also assessed. For 28 simulated samples, the detection results obtained from the integrated system were consistent with those from conventional laboratory methods, specifically qPCR and LAMP detection following nucleic acid extraction. The entire process can be completed in approximately one hour, making it highly suitable for immediate rapid testing.

Serial Shock Severity Assessment Within 72 Hours After Diagnosis: A Cardiogenic Shock Working Group Report.

BACKGROUND: The Cardiogenic Shock Working Group-modified Society for Cardiovascular Angiography and Interventions (CSWG-SCAI) staging was developed to risk stratify cardiogenic shock (CS) severity. Data showing progressive changes in SCAI stages and outcomes are limited. OBJECTIVES: We investigated serial changes in CSWG-SCAI stages and outcomes of patients presenting with cardiogenic shock complicating acute myocardial infarction (MI-CS) and heart failure-related CS (HF-CS). METHODS: The multicenter CSWG registry was queried. CSWG-SCAI stages were computed at CS diagnosis and 24, 48, and 72 hours. RESULTS: A total of 3,268 patients (57% HF-CS; 27% MI-CS) were included. At CS diagnosis, CSWG-SCAI stage breakdown was 593 (18.1%) stage B, 528 (16.2%) stage C, 1,659 (50.8%) stage D, and 488 (14.9%) noncardiac arrest stage E. At 24 hours, >50% of stages B and C patients worsened, but 86% of stage D patients stayed at stage D. Among stage E patients, 54% improved to stage D and 36% stayed at stage E by 24 hours. Minimal SCAI stage changes occurred beyond 24 hours. SCAI stage trajectories were similar between MI-CS and HF-CS groups. Within 24 hours, unadjusted mortality rates of patients with any SCAI stage worsening or improving were 44.6% and 34.2%, respectively. Patients who presented in or progressed to stage E by 24 hours had the worst prognosis. Survivors had lower lactate than nonsurvivors. CONCLUSIONS: Most patients with CS changed SCAI stages within 24 hours from CS diagnosis. Stage B patients were at high risk of worsening shock severity by 24 hours, associated with excess mortality. Early CS recognition and serial assessment may improve risk stratification.

Molecular mechanism of regulating tat protein expression of pingganjiedu TCM in the treatment of AIDS based on network pharmacology.

AIDS is a serious disease with impaired immune function caused by human immunodeficiency virus (HIV) infection. The treatment of AIDS has always been the focus of global scientific research, and Tat protein is a key regulatory protein in the process of HIV infection. Its high expression is closely related to virus replication, disease progression, etc. The aim of this study is to explore the molecular mechanism of regulating Tat protein expression by using network pharmacology based traditional Chinese medicine for calming the liver and detoxifying. 129 AIDS patients were enrolled in the study and randomly divided into HAART combined with PGJDP treatment and HAART alone treatment groups. The virological response rate, immunological response status (CD4 + T cell level, CD4/CD8) and incidence of abnormal liver function were observed before and 48 weeks after treatment. Using the TCMSP database to obtain the chemical components and targets of the main traditional Chinese medicine components in PGJDP, clinical results indicate that the combination of HAART and PGJDP treatment can improve the virological response rate (P > 0.05); Increase the number of CD4 + T lymphocytes (P > 0.05); Significantly increased CD4/CD8 ratio (P < 0.01); Simultaneously, it significantly reduced the incidence of liver dysfunction (P < 0.01). After screening and analysis, the Chinese herbal medicine for calming liver and detoxifying has the potential to significantly regulate the expression of Tat protein. These Chinese herbal compounds can reduce the expression of Tat protein by affecting key pathways and regulating the expression of related genes, which has potential therapeutic effects on the treatment of AIDS.

Posterior-only approach cervical hemivertebrectomy and short fusion with pedicle screws in young children with cervical scoliosis: case report and technical note.

PURPOSE: Cervical hemivertebrae (C3-6) causing significant osseous torticollis, head tilt and facial asymmetry are rare and complicated. Cervical hemivertebrectomy (CHVE) by a posterior-only approach was never reported because it is highly risky and its efficacy remains controversial. This study is to evaluate the feasibility and preliminary clinical outcomes of posterior-only approach for CHVE and torticollis correction in young children. METHODS: Four young children aged 5-9 years old with significant torticollis caused by cervical hemivertebrae underwent deformity correction consisting of cervical pedicle screw (CPS) placement with O-arm-based intraoperative navigation, CHVE using ultrasonic bone scalpel and short-segmental posterior instrumentation and fusion. Details of this novel technique were presented. The preliminary short-term clinical and radiographic outcomes were assessed. RESULTS: On average, the operative time was 312.5 ± 49.9 min, and the surgical blood loss was 375.0 ± 150.0 ml. The structural cervical scoliosis was corrected from 31.5 ± 7.3° to 11.0 ± 4.1°, and the average correction rate was 64.9%. Head tilt was favorably corrected from 11.0 ± 4.2° to 3.5 ± 2.6°. The shoulder balance improved from 6.3 ± 1.3° to 1.5 ± 1.9°. One case with C6 CHVE had convex side radiating nerve root pain but no sign of muscle power weakness. Full recovery was achieved one month after surgery. No other complication occurred. CONCLUSIONS: CHVE by a posterior-only approach was a feasible alternative option for the treatment of congenital cervical scoliosis. It could resect the CHV effectively and achieve satisfactory torticollis correction without additional anterior access surgery. Successful CPS placement in this child population was essentially important to enable reliable osteotomy closure and firm posterior instrumentation.

Antiviral Activity of Selective Estrogen Receptor Modulators against Severe Fever with Thrombocytopenia Syndrome Virus In Vitro and In Vivo.

Severe fever with thrombocytopenia syndrome virus (SFTSV), also known as the Dabie Banda virus, is an emerging tick-borne Bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS). Currently, symptomatic treatment and antiviral therapy with ribavirin and favipiravir are used in clinical management. However, their therapeutical efficacy is hardly satisfactory in patients with high viral load. In this study, we explored the antiviral effects of selective estrogen receptor modulators (SERMs) on SFTSV infection and the antiviral mechanisms of a representative SERM, bazedoxifene acetate (BZA). Our data show that SERMs potently inhibited SFTSV-induced cytopathic effect (CPE), the proliferation of infectious viral particles, and viral RNA replication and that BZA effectively protected mice from lethal viral challenge. The mode of action analysis reveals that BZA exerts antiviral effects during the post-entry stage of SFTSV infection. The transcriptome analysis reveals that GRASLND and CYP1A1 were upregulated, while TMEM45B and TXNIP were downregulated. Our findings suggest that SERMs have the potential to be used in the treatment of SFTSV infection.

Antiviral activity of vitamin D derivatives against severe fever with thrombocytopenia syndrome virus in vitro and in vivo.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus that causes the severe fever thrombocytopenia syndrome, which manifests as fever and haemorrhage, accompanied by severe neurological complications. To date, no specific antiviral drugs have been approved for this indication. Herein, we investigated whether vitamin D derivatives inhibit SFTSV both in vitro and in vivo. An in vitro study demonstrated that vitamin D derivatives significantly suppressed viral RNA replication, plaque formation, and protein expression in a dose-dependent manner. Subsequently, in vivo studies revealed that doxercalciferol and alfacalcidol were associated with increased survival and reduced viral RNA load in the blood. Time-of-addition assay suggested that vitamin D derivatives primarily acted during the post-entry phase of SFTSV infection. However, cytopathic effect protective activity was not observed in RIG-I immunodeficient cell line Huh7.5, and the administration of vitamin D derivatives did not improve the survival rates or reduce the blood viral loads in adult A129 mice. Further transcriptome exploration into the antiviral mechanism revealed that alfacalcidol stimulates host innate immunity to exert antiviral effects. To expand the application of vitamin D derivatives, in vitro and in vivo drug combination assays were performed, which highlighted the synergistic effects of vitamin D derivatives and T-705 on SFTSV. The combination of alfacalcidol and T-705 significantly enhanced the therapeutic effects in mice. This study highlights the potential of vitamin D derivatives against SFTSV and suggests that they may have synergistic effects with other compounds used in the treatment of SFTSV infection.

The underlying mechanisms by which boron mitigates copper toxicity in Citrus sinensis leaves revealed by integrated analysis of transcriptome, metabolome and physiology.

Both copper (Cu) excess and boron (B) deficiency are often observed in some citrus orchard soils. The molecular mechanisms by which B alleviates excessive Cu in citrus are poorly understood. Seedlings of sweet orange (Citrus sinensis (L.) Osbeck cv. Xuegan) were treated with 0.5 (Cu0.5) or 350 (Cu350 or Cu excess) µM CuCl2 and 2.5 (B2.5) or 25 (B25) µM HBO3 for 24 wk. Thereafter, this study examined the effects of Cu and B treatments on gene expression levels revealed by RNA-Seq, metabolite profiles revealed by a widely targeted metabolome, and related physiological parameters in leaves. Cu350 upregulated 564 genes and 170 metabolites, and downregulated 598 genes and 58 metabolites in leaves of 2.5 µM B-treated seedlings (LB2.5), but it only upregulated 281 genes and 100 metabolites, and downregulated 136 genes and 40 metabolites in leaves of 25 µM B-treated seedlings (LB25). Cu350 decreased the concentrations of sucrose and total soluble sugars and increased the concentrations of starch, glucose, fructose and total nonstructural carbohydrates in LB2.5, but it only increased the glucose concentration in LB25. Further analysis demonstrated that B addition reduced the oxidative damage and alterations in primary and secondary metabolisms caused by Cu350, and alleviated the impairment of Cu350 to photosynthesis and cell wall metabolism, thus improving leaf growth. LB2.5 exhibited some adaptive responses to Cu350 to meet the increasing need for the dissipation of excessive excitation energy (EEE) and the detoxification of reactive oxygen species (reactive aldehydes) and Cu. Cu350 increased photorespiration, xanthophyll cycle-dependent thermal dissipation, nonstructural carbohydrate accumulation, and secondary metabolite biosynthesis and abundances; and upregulated tryptophan metabolism and related metabolite abundances, some antioxidant-related gene expression, and some antioxidant abundances. Additionally, this study identified some metabolic pathways, metabolites and genes that might lead to Cu tolerance in leaves.

Establishment and validation of a nomogram for predicting the risk of hip fracture in patients with stroke: A multicenter retrospective study.

PURPOSE: There are currently no models for predicting hip fractures after stroke. This study wanted to investigate the risk factors leading to hip fracture in stroke patients and to establish a risk prediction model to visualize this risk. PATIENTS AND METHODS: We reviewed 439 stroke patients with or without hip fractures admitted to the Affiliated Hospital of Xuzhou Medical University from June 2014 to June 2017 as the training set, and collected 83 patients of the same type from the First Affiliated Hospital of Harbin Medical University and the Affiliated Hospital of Xuzhou Medical University from June 2020 to June 2023 as the testing set. Patients were divided into fracture group and non-fracture group based on the presence of hip fractures. Multivariate logistic regression analysis was used to screen for meaningful factors. Nomogram predicting the risk of hip fracture occurrence were created based on the multifactor analysis, and performance was evaluated using receiver operating characteristic curve (ROC), calibration curves, and decision curve analysis (DCA). A web calculator was created to facilitate a more convenient interactive experience for clinicians. RESULTS: In training set, there were 35 cases (7.9 %) of hip fractures after stroke, while in testing set, this data was 13 cases (15.6 %). In training set, univariate analysis showed significant differences between the two groups in the number of falls, smoking, hypertension, glucocorticoids, number of strokes, Mini-Mental State Examination (MMSE), visual acuity level, National Institute of Health stroke scale (NIHSS), Berg Balance Scale (BBS), and Stop Walking When Talking (SWWT) (P<0.05). Multivariate analysis showed that number of falls [OR=17.104, 95 % CI (3.727-78.489), P = 0.000], NIHSS [OR=1.565, 95 % CI (1.193-2.052), P = 0.001], SWWT [OR=12.080, 95 % CI (2.398-60.851), P = 0.003] were independent risk factors positively associated with new fractures. BMD [OR = 0.155, 95 % CI (0.044-0.546), P = 0.012] and BBS [OR = 0.840, 95 % CI (0.739-0.954), P = 0.007] were negatively associated with new fractures. The area under the curve (AUC) of nomogram were 0.939 (95 % CI: 0.748-0.943) and 0.980 (95 % CI: 0.886-1.000) in training and testing sets, respectively, and the calibration curves showed a high agreement between predicted and actual status with an area under the decision curve of 0.034 and 0.109, respectively. CONCLUSIONS: The number of falls, fracture history, low BBS score, high NIHSS score, and positive SWWT are risk factors for hip fracture after stroke. Based on this, a nomogram with high accuracy was developed and a web calculator (https://stroke.shinyapps.io/DynNomapp/) was created.

Fecal microbiota from patients with Parkinson's disease intensifies inflammation and neurodegeneration in A53T mice.

AIMS: We evaluated the potential of Parkinson's disease (PD) fecal microbiota transplantation to initiate or exacerbate PD pathologies and investigated the underlying mechanisms. METHODS: We transplanted the fecal microbiota from PD patients into mice by oral gavage and assessed the motor and intestinal functions, as well as the inflammatory and pathological changes in the colon and brain. Furthermore, 16S rRNA gene sequencing combined with metabolomics analysis was conducted to assess the impacts of fecal delivery on the fecal microbiota and metabolism in recipient mice. RESULTS: The fecal microbiota from PD patients increased intestinal inflammation, deteriorated intestinal barrier function, intensified microglia and astrocyte activation, abnormal deposition of α-Synuclein, and dopaminergic neuronal loss in the brains of A53T mice. A mechanistic study revealed that the fecal microbiota of PD patients stimulated the TLR4/NF-κB/NLRP3 pathway in both the brain and colon. Additionally, multiomics analysis found that transplantation of fecal microbiota from PD patients not only altered the composition of the gut microbiota but also influenced the fecal metabolic profile of the recipient mice. CONCLUSION: The fecal microbiota from PD patients intensifies inflammation and neurodegeneration in A53T mice. Our findings demonstrate that imbalance and dysfunction in the gut microbiome play significant roles in the development and advancement of PD.

Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain.

Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.