Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS-STING signalling in mice.

Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-ß and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-ß stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer.

[Developmental toxicity of Cry1Ab protein in the embryonic stem-cell model].

OBJECTIVE: To evaluate the developmental toxicity of Cry1Ab protein by studying its effects on cell proliferation and differentiation ability using a developmental toxicity assessment model based on embryonic stem-cell. METHODS: Cry1Ab protein was tested in seven dose groups (31.25, 62.50, 125.00, 250.00, 320.00, 1 000.00, and 2 000.00 µg/L) on mouse embryonic stem cells D3 (ES-D3) and 3T3 mouse fibroblast cells, with 5-fluorouracil (5-FU) used as the positive control and phosphate buffer saline (PBS) as the solvent control. Cell viability was detected by CCK-8 assay to calculate the 50% inhibitory concentration (IC50) of the test substance for different cells. Additionally, Cry1Ab protein was tested in five dose groups (125.00, 250.00, 320.00, 1 000.00, and 2 000.00 µg/L) on ES-D3 cells, with PBS as the solvent control and 5-FU used for model validation. After cell treatment, cardiac differentiation was induced using the embryonic bodies (EBs) culture method. The growth of EBs was observed under a microscope, and their diameters on the third and fifth days were measured. The proportion of EBs differentiating into beating cardiomyocytes was recorded, and the 50% inhibition concentration of differentiation (ID50) was calculated. Based on a developmental toxicity discrimination function, the developmental toxicity of the test substances was classified. Furthermore, at the end of the culture period, mRNA expression levels of cardiac differentiation-related markers (Oct3/4, GATA-4, Nkx2.5, and ß-MHC) were quantitatively detected using real-time quantitative polymerase chain reaction (qPCR) in the collected EBs samples. RESULTS: The IC50 of 5-FU was determined as 46.37 µg/L in 3T3 cells and 32.67 µg/L in ES-D3 cells, while the ID50 in ES-D3 cells was 21.28 µg/L. According to the discrimination function results, 5-FU was classified as a strong embryotoxic substance. There were no statistically significant differences in cell viability between different concentrations of Cry1Ab protein treatment groups and the control group in both 3T3 cells and ES-D3 cells (P>0.05). Moreover, there were no statistically significant differences in the diameter of EBs on the third and fifth days, as well as their morphology, between the Cry1Ab protein treatment groups and the control group (P>0.05). The cardiac differentiation rate showed no statistically significant differences between different concentrations of Cry1Ab protein treatment groups and the control group (P>0.05). 5-FU significantly reduced the mRNA expression levels of ß-MHC, Nkx2.5, and GATA-4 (P < 0.05), showing a dose-dependent trend (P < 0.05), while the mRNA expression levels of the pluripotency-associated marker Oct3/4 exhibited an increasing trend (P < 0.05). However, there were no statistically significant differences in the mRNA expression levels of mature cardiac marker ß-MHC, early cardiac differentiation marker Nkx2.5 and GATA-4, and pluripotency-associated marker Oct3/4 between the Cry1Ab protein treatment groups and the control group (P>0.05). CONCLUSION: No developmental toxicity of Cry1Ab protein at concentrations ranging from 31.25 to 2 000.00 µg/L was observed in this experimental model.

Total flavonoids of Rhizoma drynariae promote angiogenesis and osteogenesis in bone defects.

Bone defects are difficult to heal, which conveys a heavy burden to patients' lives and their economy. The total flavonoids of Rhizoma drynariae (TFRD) can promote the osteogenesis of distraction osteogenesis. However, the dose effect is not clear, the treatment period is short, and the quality of bone formation is poor. In our study, we observed the long-term effects and dose effects of TFRD on bone defects, verified the main ingredients of TFRD in combination with network pharmacology for the first time, explored its potential mechanism, and verified these findings. We found that TFRD management for 12 weeks regulated osteogenesis and angiogenesis in rats with 4-mm tibial bone defects through the PI3K/AKT/HIF-1α/VEGF signaling pathway, especially at high doses (135 mg kg-1  d-1 ). The vascularization effect of TFRD in promoting human umbilical vein endothelial cells was inhibited by PI3K inhibitors. These results provide a reference for the clinical application of TFRD.

Garlic Powder Supplementation Improves Growth, Nonspecific Immunity, Antioxidant Capacity, and Intestinal Flora of Chinese Mitten Crabs (Eriocheir sinensis).

This study was conducted to survey the effects of garlic powder on growth performance, nonspecific immunity, antioxidant capacity, and intestinal flora structure of Chinese mitten crabs. Altogether, 216 crabs which originally weigh 20.71 ± 0.13 g were randomly allocated into three treatment groups with 6 replicates of 12 crabs per replicate. The control group (CN) was fed a basal diet, while the other two groups were fed the basal diet supplemented with 1000 mg/kg (GP1000) and 2000 mg/kg (GP2000) garlic powder, respectively. This trial lasted 8 weeks. The results showed that the supplementation of garlic powder improved the final body weight, weight gain rate, and specific growth rate of the crabs (P < 0.05). Meanwhile, in serum, better nonspecific immune was confirmed by the enhancement of phenoloxidase and lysozyme levels, with the improvement of phosphatase activities in GP1000 and GP2000 (P < 0.05). On the other hand, the levels of total antioxidant capacity, glutathione peroxidases, and total superoxide dismutase in serum and hepatopancreas were increased (P < 0.05) while malondialdehyde content declined (P < 0.05) as the garlic powder was added to the basal diet. And, catalase in serum also shows an increase (P < 0.05). In both GP1000 and GP2000, genes related to antioxidant and immunity, for instance, Toll-like receptor 1, glutathione peroxidase, catalase, myeloid differentiation factor 88, TuBe, Dif, relish, crustins, antilipopolysaccharide factor, lysozyme, and prophenoloxidase mRNA expression levels, were increased (P < 0.05). The abundance of Rhizobium and Rhodobacter was reduced by adding garlic powder (P < 0.05). This study indicated that dietary addition of garlic powder promoted growth, enhanced nonspecific immunity and antioxidant capacity, activated Toll pathway, IMD pathway, and proPO system, increased antimicrobial peptide expression, while simultaneously improving the intestinal flora of Chinese mitten crabs.

Using Eukaryotic Expression Systems to Generate Human α1,3-Fucosyltransferases That Effectively Create Selectin-Binding Glycans on Stem Cells.

Recruitment of circulating cells toward target sites is primarily dependent on selectin/ligand adhesive interactions. Glycosyltransferases are involved in the creation of selectin ligands on proteins and lipids. α1,3-Fucosylation is imperative for the creation of selectin ligands, and a number of fucosyltransferases (FTs) can modify terminal lactosamines on cells to create these ligands. One FT, fucosyltransferase VI (FTVI), adds a fucose in an α1,3 configuration to N-acetylglucosamine to generate sialyl Lewis X (sLex) epitopes on proteins of live cells and enhances their ability to bind E-selectin. Although a number of recombinant human FTVIs have been purified, apart from limited commercial enzymes, they were not characterized for their activity on live cells. Here we focused on establishing a robust method for producing FTVI that is active on living cells (hematopoietic cells and mesenchymal stromal cells). To this end, we used two expression systems, Bombyx mori (silkworm) and Pichia pastoris (yeast), to produce significant amounts of N-terminally tagged FTVI and demonstrated that these enzymes have superior activity when compared to currently available commercial enzymes that are produced from various expression systems. Overall, we outline a scheme for obtaining large amounts of highly active FTVI that can be used for the application of FTVI in enhancing the engraftment of cells lacking the sLex epitopes.

The protective effect of cycloastragenol on aging mouse circadian rhythmic disorder induced by d-galactose.

Aging process in mammals is associated with a decline in amplitude and a long period of circadian behaviors which are regulated by a central circadian regulator in the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. It is unclear whether enhancing clock function can retard aging. Using fibroblasts expressing per2::lucSV and senescent cells, we revealed cycloastragenol (CAG), a natural aglycone derivative from astragaloside IV, as a clock amplitude enhancing small molecule. CAG could activate telomerase to antiaging, but no reports focused on its effects on circadian rhythm disorders in aging mice. Here we analyze the potential effects of CAG on d-galactose-induced aging mice on the circadian behavior and expression of clock genes. For this purpose, CAG (20 mg/kg orally), was administered daily to d-galactose (150 mg/kg, subcutaneous) mice model of aging for 6 weeks. An actogram analysis of free-running activity of these mice showed that CAG significantly enhances the locomotor activity. We further found that CAG increase expressions of per2 and bmal1 genes in liver and kidney of aging mouse. Furthermore, CAG enhanced clock protein BMAL1 and PER2 levels in aging mouse liver and SCN. Our results indicated that the CAG could restore the behavior of circadian rhythm in aging mice induced by d-galactose. These data of present study suggested that CAG could be used as a novel therapeutic strategy for the treatment of age-related circadian rhythm disruption.

Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis.

OBJECTIVES: MTHFR C677T and A1298C have been associated with the risk of preeclampsia (PE), but with conflicting results. We performed this meta-analysis to derive a more precise estimation of the association between MTHFR polymorphisms and PE. STUDY DESIGN: An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. 54 case controlled studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. RESULT: These studies evaluated 7398 cases and 11230 controls for MTHFR C677T. The overall results suggested that MTHFR C677T was associated with the risk of PE. (T vs. C: OR = 1.157, 95% CI: 1.057-1.266, p = 0.002; TT + CT vs. CC: OR = 1.165, 95% CI : 1.049-1.293, P = 0.004; TT vs. CT + CC: OR = 1.371, 95% CI: 1.153-1.63, p < 0.001). We also evaluated 1103 cases and 988 controls for MTHFR A1298C but could not demonstrate an increased risk of PE for this polymorphism (p = 0.667). A symmetric funnel plot, the Egger's test (p = 0.819) suggested a lack of publication bias. CONCLUSION: This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for PE, especially in the case of Asians and Caucasians.

Switchable CO2-Responsive Janus Nanoparticle for Lipase Catalysis in Pickering Emulsion.

The use of convertible immobilized enzyme carriers is crucial for biphasic catalytic reactions conducted in Pickering emulsions. However, the intense mechanical forces during the conversion process lead to enzyme leakage, affecting the stability of the immobilized enzymes. In this study, a CO2-responsive switchable Janus (CrSJ) nanoparticle (NP) was developed using silica NP, with one side featuring aldehyde groups and the other side adsorbing N,N-dimethyldodecylamine. A switchable Pickering emulsion catalytic system for biphasic interface reactions was prepared by covalently immobilizing lipase onto the CrSJ NPs. The CO2-responsive nature of the CrSJ NPs allowed for rapid conversion of the Pickering emulsion, and covalent immobilization substantially reduced lipase leakage while enhancing the stability of the immobilization during the conversion process. Impressively, after repeated transformations, the Pickering emulsion still maintains its original structure. Following 10 consecutive cycles of esterification and hydrolysis reactions, the immobilized enzyme's activity remains at 77.7 and 79.5% of its initial activity, respectively. The Km of the CrSJ catalytic system showed no significant change compared to the free enzyme, while its Vmax values were 1.2 and 1.6 times that of the free enzyme in esterification and hydrolysis reactions, respectively.

Decreased YB-1 expression denervates brown adipose tissue and contributes to age-related metabolic dysfunction.

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y-box binding protein 1 (YB-1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB-1 in the BAT accelerated diet-induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB-1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet-induced obesity and insulin resistance. Interestingly, YB-1 had no direct effect on adipose UCP1 expression. Instead, YB-1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB-1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat-sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age-related metabolic disorders.

Meta-Analysis of Internet Gaming Disorder Prevalence: Assessing the Impacts of DSM-5 and ICD-11 Diagnostic Criteria.

With the inclusion of Internet gaming disorder (IGD) in both the DSM-5 and ICD-11, understanding the prevalence and diagnostic discrepancies is crucial for developing appropriate interventions. This study presents a meta-analysis of the prevalence of IGD based on two diagnostic criteria. We systematically searched the PubMed and Web of Science databases. A total of 22 studies were included in the final analysis. The analysis incorporated studies employing the DSM-5 and ICD-11 criteria and focused on the impact of various factors, including study location, sample characteristics, sample size, and quality score, on the reported prevalence rates using a random-effects model. The pooled prevalence of IGD is 6.7% (95% CI: 5.7-7.7%). The subgroup analysis indicated significant differences in the prevalence rates of IGD (DSM-5 criteria) and GD (ICD-11 criteria) (Q b = 38.46, p < 0.01). There were also significant differences in IGD prevalence rates between different scales (Q b = 54.23, p < 0.001). Our findings indicate that different diagnostic criteria and different assessment scales have a significant impact on the prevalence of IGD. This underscores the importance of adopting standardized methodologies to guide public health interventions. However, given the limited research based on ICD-11 diagnostic criteria, further investigation is necessary to determine the variations in prevalence rates of IGD under different diagnostic standards.

Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.

Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2SPD, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.

Dietary n-3 fatty acids intake and all-cause and cardiovascular mortality in patients with pre-diabetes and diabetes.

BACKGROUND: While the association between n-3 polyunsaturated fatty acids (PUFA) and cardiovascular events has been thoroughly examined, there is still a scarcity of research regarding their impact on the long-term prognosis in diabetic patients. METHOD: Herein, a total of 16,539 eligible individuals were enrolled from the National Health and Nutrition Examination Survey (NHANES) 2003-2018, and categorized into T1, T2, and T3 based on the tertiles of n-3 PUFA. The Cox proportional risk regression models, Kaplan-Meier curve, and subgroup analysis were conducted to evaluate the association between n-3 PUFA and mortality. Restricted cubic spline (RCS) curves graphically demonstrated the dose-response relationship. Additionally, weighted quantile sum (WQS) models were adopted to measure the mixed and individual effects of n-3 PUFA on mortality. RESULTS: Following a median follow-up period of 8.42 years, 3,010 individuals died, with 989 deaths attributed to cardiovascular diseases. Significantly lower risk of all-cause [T2: 0.81 (0.71, 0.92), T3: 0.77 (0.64, 0.94)] and cardiovascular [T2: 0.75 (0.61, 0.93)] mortality was observed after adjusting for multivariable compared to the reference (T1). Meanwhile, the RCS curve revealed a negative non-linear association between the n-3 PUFA and mortality. None of the interactions in any subgroup analysis were statistically significant except for BMI (p for interaction = 0.049). Finally, the WQS analysis demonstrated alpha-linolenic acid (ALA) and docosapentaenoic acid (DPA) as the main contributors to the n-3 PUFA benefits against mortality. CONCLUSIONS: Increased dietary intake of n-3 PUFA, particularly ALA and DPA, was associated with a reduced risk of all-cause and cardiovascular mortality among Americans with prediabetes and diabetes.

An anti-infection and biodegradable TFRD-loaded porous scaffold promotes bone regeneration in segmental bone defects: experimental studies.

BACKGROUND: Addressing segmental bone defects remains a complex task in orthopedics, and recent advancements have led to the development of novel drugs to enhance the bone regeneration. However, long-term oral administration can lead to malnutrition and poor patient compliance. Scaffolds loaded with medication are extensively employed to facilitate the restoration of bone defects. METHODS: Inspired by the local application of total flavonoids of Rhizoma Drynariae (TFRD) in the treatment of fracture, a novel 3D-printed HA/CMCS/PDA/TFRD scaffold with anti-infection, biodegradable and induced angiogenesis was designed, and to explore its preclinical value in segmental bone defect of tibia. RESULTS: The scaffold exhibited good degradation and drug release performance. In vitro, the scaffold extract promoted osteogenesis by enhancing bone-related gene/protein expression and mineral deposition in BMSCs. It also stimulated endothelial cell migration and promoted angiogenesis through the upregulation of specific genes and proteins associated with cell migration and tube formation. This may be attributed to the activation of the PI3k/AKT/HIF-1α pathway, facilitating the processes of osteogenesis and angiogenesis. Furthermore, the HA/CMCS/PDA/TFRD scaffold was demonstrated to alleviate infection, enhance angiogenesis, promote bone regeneration, and increase the maximum failure force of new formed bone in a rat model of segmental bone defects. CONCLUSION: Porous scaffolds loaded with TFRD can reduce infection, be biodegradable, and induce angiogenesis, presenting a novel approach for addressing tibial segmental bone defects.

Association Between the Neutrophil-Lymphocyte Ratio and Prognosis of Patients Admitted to the Intensive Care Unit With Chronic Heart Failure: A Retrospective Cohort Study.

The present study aimed to explore the association between the neutrophil-to-lymphocyte ratio (NLR) and prognosis of critically ill chronic heart failure patients. The records of 5298 patients who met the inclusion criteria were extracted from the Medical Information Mart for Intensive Care IV database. The primary outcome was 30-days all-cause mortality and the secondary outcome was 90-days all-cause mortality. Multivariable logistic regression analysis was performed to examine the relationship between NLR and 30-days mortality. Subgroup analysis was carried out to identify whether the association between NLR and 30-days mortality differed across various subgroups. For 30-days mortality, after adjusting for multiple confounders, the odds ratio (OR) (95% confidence interval [CI]) for the second (NLR 4.0-8.4) and the third (NLR ≥8.4) tertiles were 1.52 (1.13-2.03) and 2.53 (1.92-3.34), respectively, compared with the first tertile (NLR <4.0). As for 90-days mortality, the OR for the second (NLR 4.0-8.4) was 1.34 (1.07-1.67) and 2.23 (1.81-2.76) for the third (NLR ≥8.4) tertiles compared with the reference (NLR<4.0). The interactions between the sepsis subgroup and 30-days mortality were significant. Our study concluded that the NLR was an independent predictor of 30- and 90-days mortality for critically ill patients with chronic heart failure.

Relationship between serum 25-hydroxyvitamin D concentrations and blood pressure among US adults without a previous diagnosis of hypertension: evidence from NHANES 2005-2018.

Background: There are various cross-sectional studies that concluded that vitamin D is associated with blood pressure, but randomized controlled studies have not yielded consistent conclusions. Considering many limitations indeed, our study aimed to examine whether concentrations of 25(OH)D are inversely associated with blood pressure in people without a previous diagnosis of hypertension. Method: We analyzed data from the 2005-2018 National Health and Nutrition Examination Survey. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by applying multivariable logistic regression models. The dose-response relationship was assessed by means of restricted cubic spline regression, and stratification analyses were employed to test the consistency between the subgroups. Results: Of 17,467 participants aged ≥ 20 years without a previous diagnosis of hypertension, 4,769 had higher blood pressure. Compared with individuals whose 25(OH)D levels were in the bottom quartile (<44.3 nnol/L), adjusting for multiple confounders, the ORs for higher blood pressure were 0.90(95%CI 0.78, 1.05), 0.85(95%CI 0.72, 0.99), and 0.86(95%CI 0.72, 1.02), respectively (P for trend = 0.096). Furthermore, as a continuous variable, 25(OH)D concentrations were non-linearly associated with an increased risk of hypertension (P < 0.001). The interaction between the sleeplessness subgroup and higher blood pressure was significant (P = 0.042). Conclusion: In adults without a previous diagnosis of hypertension in the United States, concentrations of 25(OH)D were inversely associated with higher blood pressure when it was <84 nmol/L.

Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.

Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA+ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C-C Motif Chemokine Receptor 10 (CCR10)-dependent manner. Transplanting GCA+ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low-density lipoprotein receptor-related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aß and potentiating neuropathological changes. Importantly, GCA-neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA+ immune cells instigating cognitive and memory decline, suggesting that GCA+ immune cells can be a potential target for innovative therapeutic strategies in AD.

Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.

Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.

Combined SERS Microfluidic Chip with Gold Nanocone Array for Effective Early Lung Cancer Prognosis in Mice Model.

Introduction: As the most common malignant tumor in the world, the prognosis of patients with advanced lung cancer remains poor even after treatment. There are many prognostic marker assays available, but there is still more room for the development of high-throughput and sensitive detection of circulating tumor DNA (ctDNA). Surface-enhanced Raman spectroscopy (SERS), a spectroscopic detection method that has received wide attention in recent years, can achieve exponential amplification of Raman signals by using different metallic nanomaterials. Integrating SERS with signal amplification strategy into the microfluidic chip and applying it to ctDNA detection is expected to be an effective tool for the prognosis of lung cancer treatment effect in the future. Methods: To construct a high-throughput SERS microfluidic chip integrated with enzyme-assisted signal amplification (EASA) and catalytic hairpin self-assembly (CHA) signal amplification strategies, using hpDNA-functionalized Au nanocone arrays (AuNCAs) as capture substrates and cisplatin-treated lung cancer mice to simulate the detection environment for sensitive detection of ctDNA in serum of lung cancer patients after treatment. Results: The SERS microfluidic chip constructed by this scheme, with two reaction zones, can simultaneously and sensitively detect the concentrations of four prognostic ctDNAs in the serum of three lung cancer patients with a limit of detection (LOD) as low as the aM level. The results of the ELISA assay are consistent with this scheme, and its accuracy is guaranteed. Conclusion: This high-throughput SERS microfluidic chip has high sensitivity and specificity in the detection of ctDNA. This could be a potential tool for prognostic assessment of lung cancer treatment efficacy in future clinical applications.

Structural dynamics of the CROPs domain control stability and toxicity of Paeniclostridium sordellii lethal toxin.

Paeniclostridium sordellii lethal toxin (TcsL) is a potent exotoxin that causes lethal toxic shock syndrome associated with fulminant bacterial infections. TcsL belongs to the large clostridial toxin (LCT) family. Here, we report that TcsL with varied lengths of combined repetitive oligopeptides (CROPs) deleted show increased autoproteolysis as well as higher cytotoxicity. We next present cryo-EM structures of full-length TcsL, at neutral (pH 7.4) and acidic (pH 5.0) conditions. The TcsL at neutral pH exhibits in the open conformation, which resembles reported TcdB structures. Low pH induces the conformational change of partial TcsL to the closed form. Two intracellular interfaces are observed in the closed conformation, which possibly locks the cysteine protease domain and hinders the binding of the host receptor. Our findings provide insights into the structure and function of TcsL and reveal mechanisms for CROPs-mediated modulation of autoproteolysis and cytotoxicity, which could be common across the LCT family.

Analysis of Clinical Features and Risk Factors in Pregnant Women With Miliary Pulmonary Tuberculosis After In Vitro Fertilization Embryo Transfer.

Purpose: Miliary pulmonary tuberculosis (TB) among pregnant women after in vitro fertilization embryo transfer (IVF-ET) causes poor outcomes but is rarely reported. This study analyzed the clinical characteristics and risk factors of these patients to provide hints for further studies. Method: The demographic characteristics, clinical manifestations, radiologic features, treatment, and outcomes of six patients diagnosed from May 2012 to August 2021 in Xiangya Hospital and 69 patients that were reported in English or Chinese literature from January 1980 to August 2021 were retrospectively analyzed. Continuous variables were compared between groups by t-test or Mann-Whitney U test, and categorical variables were compared between groups by chi-square test or Fisher exact test. Univariate and multiple logistic regression analyses were used to determine the predictors of respiratory failure. Results: A total of 75 patients were included. The average age of patients was about 30 years. All patients had tubal obstruction; 5 of them were diagnosed with pelvic TB before. Thirteen cases had a history of pulmonary or extrapulmonary TB, six out of them without any antituberculosis treatment history. All patients were in their first or second trimester during the onset of symptoms. The average interval between onset of symptoms and radiologic examination was about 21 days. The most common abnormalities on chest computed tomography scan were multiple nodules, pulmonary infiltrate, and consolidation. Merely 10 patients obtained bacteriological diagnosis by Mycobacterium tuberculosis culture or polymerase chain reaction test. The other patients were clinically diagnosed. All the patients received antituberculosis treatment. Although 44% of patients had fatal complications, all cases were cured or improved after antituberculosis treatment. Unfortunately, only eight fetuses survived (10.6%). The most frequent and severe complication was type I respiratory failure (20%). Patients with expectoration, dyspnea, coarse breath sounds, ground-glass opacity, and pulmonary infiltrate or consolidation were more likely to have respiratory failure (P < 0.05). Ground-glass opacity (OR = 48.545, 95% CI = 2.366-995.974, P = 0.012) and pulmonary infiltrate or consolidation (OR = 19.943, 95% CI = 2.159-184.213, P = 0.008) were independent predictors for respiratory failure. Conclusion: Tube infertility with underscreened or untreated TB is a risk factor for miliary TB during pregnancy after IVF-ET. Ground-glass opacity and pulmonary infiltrate or consolidation are predictors of respiratory failure. We demonstrate risk factors for incidence and complications to supply clues for future intervention and improve patient prognosis.