Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Retinal vascular density as a potential biomarker of diabetic cerebral small vessel disease.

AIM: The retina and brain share similar anatomical and physiological features. Thus, retinal imaging by optical coherence tomography angiography (OCTA) might be a potential tool for the early diagnosis of diabetic cerebral small vessel disease (CSVD). In this study, we aimed to evaluate retinal vascular density (VD) in diabetic CSVD by OCTA imaging and explore the associations between retinal VD and cerebral magnetic resonance imaging (MRI) markers and cognitive function. METHODS: In total, 131 patients were enrolled, including CSVD (n = 43) and non-CSVD groups (n = 88). The VD and foveal avascular zone of the retinal capillary plexus were measured with OCTA. A brain MRI was performed. RESULTS: MRI imaging showed that in the diabetic CSVD group, white matter hyperintensities (WMHs), particularly deep WMHs (58.82%), are the most common MRI marker, followed by cerebral microbleeds in the subtentorial and cortical areas (34.78%). The CSVD group showed increases in the prevalence of cognitive dysfunction (p = .034) and depression (p = .033) and decreases in visuospatial/executive ability and delayed recall ability. In the CSVD group, VDs of the macular superficial vascular plexus (32.93 ± 7.15% vs. 36.97 ± 6.59%, p = .002), intermediate capillary plexus (20.87 ± 4.30% vs. 23.08 ± 4.30%, p = .005) and deep capillary plexus (23.54 ± 5.00% vs. 26.05 ± 4.20%, p = .003) were lower than those of the non-CSVD group. Multiple linear regression analysis showed that VD of the macular superficial vascular plexus was independently associated with cerebral microbleeds. Meanwhile, VD of the macular intermediate capillary plexus was associated with white matter lacunar infarcts after adjustment. CONCLUSIONS: Diabetic CSVDs are characterized by MRI markers, including deep WMHs and cerebral microbleeds, and showed impaired cognition with decreased visuospatial/executive ability and delayed recall ability. OCTA imaging revealed a significant decrease in retinal microvascular perfusion in diabetic CSVD, which was related to MRI markers and cognitive function. OCTA might be a valuable potential measurement for the early diagnosis of CSVD.

The Gut Microbiome and Acute Leukemia: Implications for Early Diagnostic and New Therapies.

Acute leukemia (AL), one of the hematological malignancies, shows high heterogeneity. Tremendous progresses are achieved in treating AL with novel targeted drugs and allogeneic hematopoietic stem cell transplantation, there are numerous issues including pathogenesis, early diagnosis, and therapeutic efficacy of AL to be solved. In recent years, an increasing number of studies regarding microbiome have shed more lights on the role of gut microbiota in promoting AL progression. Mechanisms related to the role of gut microbiota in enhancing AL genesis are summarized in the present work, especially on critical pathways like leaky gut, bacterial dysbiosis, microorganism-related molecular patterns, and bacterial metabolites, resulting in AL development. Additionally, the potential of gut microbiota as the biomarker for early AL diagnosis is discussed. It also outlooks therapies targeting gut microbiota for preventing AL development.

Genomic gain/methylation modification/hsa-miR-132-3p increases RRS1 overexpression in liver hepatocellular carcinoma.

This study aimed to determine the upstream regulatory factors affecting ribosome biogenesis regulator 1 homolog (RRS1) expression and the development and prognosis of liver hepatocellular carcinoma (LIHC). The expression profiles of RRS1 were evaluated in pan-cancer tissues and liver tumor cell lines. The associations of RRS1 with pan-cancer survival, immune infiltrations, immune checkpoints, and drug sensitivity were identified. We explored the potential upstream regulatory mechanisms of RRS1 expression. Hsa-miR-132-3p knockdown, CCK-8 assays, transwell, and wound healing assays were performed to validate the regulatory effect of hsa-miR-132-3p on RRS1 expression and the development of LIHC. Our findings demonstrated that RRS1 was significantly elevated in 27 types of cancers. RRS1 predicts a poor outcome of LIHC, lung adenocarcinoma, head and neck cancer, and kidney papillary cell carcinoma. RRS1 expression showed a significant association with immune cell infiltrates and the expression of immune checkpoints-related genes in LIHC tissues. Increased RRS1 expression may have a negative effect on these anticancer drugs of LIHC. Low methylation of the RRS1 promoter and its genomic gain may elevate RRS1 expression and predict poor prognosis for LIHC. Increased hsa-miR-132-3p expression may elevate RRS1 expression and result in poor prognosis for LIHC. Hsa-miR-132-3p inhibition can decrease RRS1 expression and the development of liver tumor cell lines. Low methylation of the RRS1 promoter, RRS1 genomic gain, and hsa-miR-132-3p upregulation in LIHC may promote RRS1 upregulation and thus lead to the development and poor prognosis for LIHC. RRS1 is a promising therapeutic target for LIHC.

Iron-inhibited autophagy via transcription factor ZFP27 in Parkinson's disease.

Parkinson's disease (PD) is a challenge because of the ageing of the population and the disease's complicated pathogenesis. Accumulating evidence showed that iron and autophagy were involved in PD. Nevertheless, the molecular mechanism and role of iron and autophagy in PD are not yet elucidated. In the present study, it was shown that PD mice had significant motor dysfunction, increased iron content, less dopamine neurons and more α-synuclein accumulation in the substantia nigra. Meanwhile, PD mice treated with deferoxamine exhibited less iron content, relieved the dyskinesia and had a significant increase in dopamine neurons and a significant decrease in α-synuclein. Autophagy induced by LC3 was inhibited in PD models with iron treatment. Following verification showed that iron aggregation restrained insulin-like growth factor 2 (IGF2) and transcription factor zinc finger protein 27 (ZFP27) in PD models. In addition, LC3-induced autophagy flux was reduced with ZFP27 knockdown. Furthermore, ZFP27 affected autophagy by regulating LC3 promoter activity. These data suggest that iron deposition inhibits IGF2 and ZFP27 to reduce LC3-induced autophagy, and ultimately decrease dopamine neurons, accelerating PD progression. Our findings provide a novel insight that ZFP27-mediated iron-related autophagy and IGF2 may activate the downstream kinase gene to trigger autophagy in the PD model.

Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer.

Ephrin type-A receptor 2 (EphA2) is a member of the tyrosine receptor kinases, a family of membrane proteins recognized as potential anticancer targets. EphA2 highly expressed in a variety of human cancers, playing roles in proliferation, migration, and invasion. However, whether and how EphA2 regulates basal-like breast cancer (BLBC) cell stemness and chemoresistance has not been revealed. Here, KLF5 was proven to be a direct transcription factor for EphA2 in BLBC cells, and its expression was positively correlated in clinical samples from breast cancer patients. The inflammatory factor TNF-α could promote BLBC cell stemness partially by activating the KLF5-EphA2 axis. Moreover, phosphorylation of EphA2 at S897 (EphA2 pS897) induced by TNF-α and PTX/DDP contributes to chemoresistance of BLBC. Furthermore, the EphA2 inhibitor ALW-II-41-27 could effectively reduce EphA2 pS897 and tumor cell stemness in vitro and significantly enhance the sensitivity of xenografts to the chemotherapeutic drugs PTX and DDP in vivo. Clinically, tumor samples from breast patients with less response to neoadjuvant chemotherapy showed a high level of EphA2 pS897 expression. In conclusion, KLF5-EphA2 promotes stemness and drug resistance in BLBC and could be a potential target for the treatment of BLBC.

Association of Body Fat Distribution and Risk of Breast Cancer in Pre- and Postmenopausal Women.

INTRODUCTION: Obesity is a risk factor for both the development of and mortality from breast cancer in postmenopausal but not in premenopausal women. However, which part of the fat mass is associated with risk remains unclear, and whether the difference in the risk for breast cancer is associated with discrepancy in the distribution of fat with menstrual status requires further study. METHODS: A dataset from the UK Biobank, which included 245,009 female participants and 5,402 females who developed breast cancer during a mean follow-up of 6.6 years, was analyzed. Body fat mass was measured according to bioelectrical impedance at baseline by trained technicians. Age- and multivariable-adjusted hazard ratios and corresponding 95% confidence intervals for associations between body fat distribution and the risk for breast cancer were estimated using Cox proportional-hazards regression. Height, age, education level, ethnicity, index of multiple deprivation, alcohol intake, smoking, physical activity, fruit consumption, age at menarche, age at first birth, number of births, hormone replacement therapy, family history of breast cancer, hysterectomy, and ovariotomy were adjusted for potential confounders. RESULTS: Fat distribution differed between pre- and postmenopausal women. After menopause, there was an increase in fat mass in different body segments (arms, legs, and trunk). After age- and multivariable adjustment, fat mass in different segments, BMI, and waist circumference were significantly associated with the risk for breast cancer among postmenopausal but not premenopausal women. CONCLUSION: Postmenopausal women exhibited more fat in different body segments, which are associated with increased risk for breast cancer, compared to premenopausal women. Fat mass control throughout the body may be beneficial in mitigating the risk for breast cancer and was not limited to abdominal fat alone among postmenopausal women.

Association of the KISS1, LIN28B, VDR and ERα gene polymorphisms with early and fast puberty in Chinese girls.

OBJECTIVES: To explore the association of KISS1, LIN28B, vitamin D receptor (VDR), and estrogen receptor α (ERα) gene polymorphisms and the risk of early with fast puberty (EFP) risk, and with hormone levels in EFP cases, in Chinese girls. METHODS: The analysis was based on the data of 141 girls with EFP and 152 girls without EFP. Clinical features were documented, and all SNP genotyping was conducted using SNaPshot method. Statistical analysis was performed to assess the association of the SNPs with EFP risk, and with hormone levels in EFP cases. RESULTS: There was a significant association between rs7759938-C polymorphism in the LIN28B gene and the risk for EFP in the recessive (TT + CT vs. CC) model (p = 0.040). Remarkably, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene were significantly associated with peak LH (luteinizing hormone) levels (p = 0.008, 0.045) and peak LH/FSH (follicle-stimulating hormone) ratio (p = 0.007, 0.006). Additionally, on 7 of the 8 variant loci the alleles associated with increased levels of both peak LH levels and peak LH/FSH ratio in EFP cases were also associated with increased CPP risk. CONCLUSIONS: Our findings indicate that rs7759938-C polymorphism in the LIN28B gene might have a protective effect on EFP susceptibility. The most striking findings of this study is that, rs5780218-delA polymorphism in the KISS1 gene and rs2234693-C polymorphism in the ERα gene influenced levels of GnRH-stimulated peak LH and LH/FSH ratio, and in general CPP risk genes might also contributes to the abnormality of hormonal levels in EFP.

Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I.

Herpes simplex virus-1 (HSV-1) is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis (HSE) with a high mortality rate. Most patients present with changes in neurological and behavioral status, and survivors suffer long-term neurological sequelae. To date, the pathogenesis leading to brain damage is still not well understood. HSV-1 induced encephalitis in the central nervous system (CNS) in animals are usually very diffuse and progressing rapidly, and mostly fatal, making the analysis difficult. Here, we established a mouse model of HSE via intracerebral inoculation of modified version of neural-attenuated strains of HSV-1 (deletion of ICP34.5 and inserting a strong promoter into the latency-associated transcript region), in which the LMR-αΔpA strain initiated moderate productive infection, leading to strong host immune and inflammatory response characterized by persistent microglia activation. This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage, amyloidosis, Alzheimer's disease, and neurodegeneration, eventually leading to neuronal loss and behavioral changes characterized by hypokinesia. Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled, mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.

RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy.

Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low-dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR-induced ATR-CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11-RAD50-NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair-prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2-AKT-NF-κB pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126-mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.

A modified mouse model of perioperative neurocognitive disorders exacerbated by sleep fragmentation.

Aging is one of the greatest risk factors for postoperative cognitive dysfunction (POCD), also known as perioperative neurocognitive disorder (PND). Animal models of PND are usually induced in mice over 18 months of age, which imposes expensive economic and time costs for PND-related studies. Sleep disorders, including sleep fragmentation, are reported to aggravate memory impairment in neurocognitive-related diseases such as Alzheimer's disease (AD). Therefore, the aim of the present study was to explore whether a PND model could be constructed in younger mice with the help of fragmented sleep. We found that fragmented sleep followed by laparotomy under isoflurane anesthesia could stably induce PND in 15-month-old mice. To determine whether the neurocognitive decline in this model could be salvaged by clinical treatments, we administered repetitive transcranial magnetic stimulation (rTMS) to the model mice before anesthesia and surgery. We found that 10 days of high-frequency rTMS (HF-rTMS) could improve spatial learning and memory deficits in this modified PND model. We are the first to successfully construct a PND model in younger mice,which is more economical, that can be used as an alternative model for future PND studies.

Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders.

Perioperative neurocognitive disorders (PND) is a common postoperative complication associated with regional or general anesthesia and surgery. Growing evidence in both patient and animal models of PND suggested that neuroinflammation plays a critical role in the development and progression of this problem, therefore, mounting efforts have been made to develop novel therapeutic approaches for PND by targeting specific factors or steps alongside the neuroinflammation. Multiple studies have shown that perioperative anti-neuroinflammatory strategies via administering pharmacologic agents or performing nonpharmacologic approaches exert benefits in the prevention and management of PND, although more clinical evidence is urgently needed to testify or confirm these results. Furthermore, long-term effects and outcomes with respect to cognitive functions and side effects are needed to be observed. In this review, we discuss recent preclinical and clinical studies published within a decade as potential preventive and therapeutic approaches targeting neuroinflammation for PND.

In Situ Measurement of Cyclic Plastic Zone and Internal Strain Response of Q&P Steel near Fatigue Crack Tip Region Based on Micro-DIC.

The shape and internal dynamic response characteristics of the plastic zone near the fatigue crack tip region, especially the cyclic plastic zone (CPZ), are the main factors affecting the fatigue crack initiation and propagation behaviors of ductile metal materials. The existing methods for characterizing the CPZ have some problems, which include the complexity of the process, the difficulty of achieving in situ measurement, and the inability to characterize the dynamic response in the CPZ during the crack propagation process. Therefore, a novel method is proposed for the in situ measurement of the CPZ near the crack tip region based on image stitching and matching algorithms, a load-strain loop curve characteristic judgement algorithm, and the microscopic digital image correlation (DIC) method. A microscopic camera and a macroscopic camera are used to simultaneously capture the micro crack tip speckle images and the global crack image of the two sides of the Compact Tension (CT) specimen for calculating in situ crack length and crack tip strain fields. The proposed method was performed and verified by a fatigue crack growth (FCG) test and micro-hardness experiments with Quenching and Partitioning 980 (Q&P980) steel, and the results show that the method is feasible because the maximum error is less than 5%. A "butterfly wings" shape of the CPZ and a strain concentration phenomenon in the CPZ of the Q&P980 were observed. Moreover, as the fatigue crack propagates, the area of the CPZ and the degree of the strain concentration increase gradually. This method, which can obtain the in situ and tracking measurements of the crack tip CPZ, will help to increase our understanding of CPZ characteristics, the FCG mechanism, and the behavior of Q&P steel and the plastic metal materials similar to Q&P steel.

Gene Polymorphisms Associated with Central Precocious Puberty and Hormone Levels in Chinese Girls.

Central precocious puberty (CPP) is associated with adverse health outcomes in females; however, CPP pathogenesis remains unclear. In this study, we investigated the association of 20 single nucleotide polymorphisms (SNPs) in eight genes with CPP risk and hormone levels. A case-control study on 247 and 243 girls with and without CPP, respectively, was conducted at Kunming Children's Hospital, China, from September 2019 to August 2020. The genotype of the SNPs and their haplotypes were identified. Additionally, the effects of the polymorphisms on hormone levels were investigated. Three variants (rs10159082, rs7538038, and rs5780218) in KISS1 and two variants (rs7895833 and rs3758391) in SIRT1 were related to an increased CPP risk (odds ratio (OR) = 1.524, 1.507, 1.409, 1.348, and 1.737; 95% confidence interval (CI) = 1.176-1.974, 1.152-1.970, 1.089-1.824, 1.023-1.777, and 1.242-2.430, respectively). Rs3740051in SIRT1 and rs1544410 in VDR reduced CPP risk (OR = 0.689, 0.464; 95% CI, 0.511-0.928, 0.232-0.925, respectively). Rs1544410, rs7975232, and rs731236 in VDR were negatively correlated with peak follicle-stimulating hormone (FSH; ß = -2.181; P=0.045), basal FSH (ß = -0.391; P=0.010), and insulin-like growth factor (ß = -50.360; P=0.041) levels, respectively. KISS1, SIRT1, and VDR variants were associated with CPP susceptibility, and VDR SNPs influenced hormonal levels in Chinese females with CPP. In particular, VDR polymorphism rs1544410 was associated with both CPP risk and GnRH-stimulated peak FSH levels. Further functional research and large-scale genetic studies of these loci and genes are required to confirm our findings.

Identification of individuals at risk for postoperative cognitive dysfunction (POCD).

Postoperative cognitive dysfunction (POCD) is common, occurring in around 10-54% of individuals within first few weeks after surgery. Although the majority of POCD is less commonly persistent later than 3 months following surgery, the condition increases length of stay (LOS), mortality and long-term cognitive decline, raising the need for a broad screening to identify individuals at risk for POCD during the perioperative period. In this narrative review, we summarize preoperative, intraoperative and postoperative risk factors for POCD reported in last 5 years and discuss neuropsychological tools and potential biomarkers and time points for assessment that might be suitable for clinical use. We aim to provide crucial information for developing a strategy of routine screening for POCD, which may assist with better identification of at-risk individuals for early interventions. Very importantly, the utilization of a standardized strategy may also allow higher consistency and comparability across different studies.

In Situ Measurement of the Strain Field at the Fatigue Crack Tip Based on Sub-Image Stitching and Matching DIC.

Studying the in situ measurement and evolution of the strain field at the crack tip during fatigue crack growth (FCG) is of great significance for understanding the fracture characteristics of materials and predicting fatigue life. Herein, a new method is proposed for the in-situ measurement of the strain field at the fatigue crack tip based on microscopic digital image correlation (DIC). The method proposed solves the problem of the existing in situ strain field measurement method being unable to dynamically track the crack tip and take the crack tip image due to the limitation of the field of view of the microscopic camera. A macroscopic camera is used to capture the global crack images on one side of the compact tension (CT) specimen. Meanwhile, a microscopic camera is used to track and capture the crack propagation speckle image on the other side of the CT specimen. The proposed method was verified by experiments with Quenching and Partitioning 980 (Q&P980) steel, and the results showed that the method has high accuracy, with the average measurement error being less than 5% and the maximum error being less than 10%. A butterfly shape of the measured strain field and the strain concentration near the crack tip were observed. The success of this method will help to obtain better insight into and understanding of the fracture behavior of metal materials as well as precise prediction of the fatigue life of metal materials.

Efficient and Durable Sodium, Chloride-doped Iron Oxide-Hydroxide Nanohybrid-Promoted Capacitive Deionization of Saline Water via Synergetic Pseudocapacitive Process.

Recently, the rational design and development of efficient faradaic deionization electrodes with high theoretical capacitance, natural abundance, and attractive conductivity have shown great promise for outstanding capacitive deionization (CDI)-based desalination applications. Herein, the construction of novel FeOOH hybrid heterostructures with Na and Cl dopants (e.g., Na-FeOOH and Cl-FeOOH) via a robust hydrothermal strategy is reported, and an asymmetric CDI cell (Na-FeOOH//Cl-FeOOH) comprising Na-FeOOH and Cl-FeOOH working as the cathode and anode, respectively, is assembled. The multiple coupling effects of the specific structural features (e.g., enriched porosity, hierarchical pore alignment, and highly open crystalline framework), enhanced electrochemical conductivity, and optimized ion-transfer property endow the FeOOH hybrid electrode with improved electrochemical performance. Impressively, the Na-FeOOH//Cl-FeOOH cell demonstrates a superior salt adsorption capacity (SACNaCl ) of 35.12 mg g-1 in a 500 mg L-1 NaCl solution, a faster removal rate, and remarkable cycling stability. Moreover, the pseudocapacitive removal mechanism from the synergetic contribution of the Na-FeOOH cathode and Cl-FeOOH anode account for the significant desalination promotion of the Na-FeOOH//Cl-FeOOH cell.

Bioinformatics Analysis of the Characteristics and Correlation of m6A Methylation in Breast Cancer Progression.

Growing cutting-edge study has demonstrated the RNA m6A methylation's critical role in regulating tumorigenesis and progression all over the world, while it is still a mystery whether RNA m6A methylation has a positive impact on breast cancer treatment. In this article, we utilize bioinformatics to analyze three data sets including TCGA-BRCA, GSE96058, and GSE25066 and discover that breast cancer samples could be divided into 4 subtypes, which are quiescent, m6A methylation, protein-binding, and mixed, clarified by the expression level of m6A-related genes. R-survival analysis results also prove that the survival rate of breast cancer samples of the four subtypes significantly varies and remarkable differences in the number of exons' skip among the four subtypes can be seen according to the analysis of breast cancer gene expression characteristics. The degree of TP53 mutation and copy number loss is most obvious in the protein-binding subtype when it comes to tumor driver genes. Among the DNA damage repair genes, there is a sharp increase in the copy number of RAD54B of the protein-binding subtype, but fewer mutations in other DNA damage repair-related genes and copy number deletion is everywhere. Results of m6A methylation influencing on the proportion of infiltrated immune cells also indicate significant differences of the four m6A subgroups in macrophages M0 and mast cells resting which are closely correlated to patient prognosis. In addition, findings of the highest tumor stemness index and the lowest in the m6A methylated type in breast cancer samples can prove the critical role of the high expression of m6A reader protein in the progression of breast cancer.

Secondary cross infection with dengue virus serotype 2/3 aggravates vascular leakage in BALB/c mice.

Dengue virus (DV) has occasionally emerged at epidemic levels in Yunnan, China. Vaccine development is limited by antibody-dependent enhancement and a lack of good animal models. Thus, the study investigated cross infection based on maternal immunity in BALB/c mice and assessed the risk of cross infection by DV2-D13113 and DV3-YNWS2 epidemic virus strains. DV replicated within the organs of the BALB/c infant mice, even causing death. Particularly, DV3-infected infant mice were at higher risk of severe disease if their mothers were infected with DV2. Although BALB/c adults and pups survived DV2/DV3 infection and produced anti-DV antibodies after 5-8 days, extensive subcutaneous vascular leakage was observed after secondary DV infection. Furthermore, vascular permeability in the lung and kidney significantly increased in offspring born to heterotypic virus-infected mothers. Thus, vascular leakage indicates severe DV infection. The results indicate that maternal immunity increases the severity of subsequent heterotypic infection. Additionally, secondary cross infection by D13113 and YNWS2 represents a risk of serious disease. This study has implications for studies of DV cross infection and vaccine development.

Effects of Konjaku Flour on the Gut Microbiota of Obese Patients.

Objective: Gut microbiota have been thought to play a role in the emergence of obesity and metabolic disorders, thus dietary fiber may be an effective strategy for the management of obesity by modulating the gut microbiota. The aim of the present study was to investigate the effects of konjaku flour (KF) supplementation on treating obesity and regulating intestinal microbiota in obese adults. Methods: In a 5-week, randomized, double-blind, place-controlled trial, sixty-nine obese volunteers aged 25 to 35 with body mass index ≥28 kg/m2 were randomly assigned to receive KF or placebo (lotus root starch). Obesity index, blood parameters, and gut microbiota were analyzed. Results: KF remarkably reduced the body mass index (BMI), fat mass, percentage body fat (PBF), serum triglyceride (TG), glycated hemoglobin A1c (HbA1c), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels in the patients (p <0.05 or p <0.01). Meanwhile, high-throughput sequencing and bioinformatics analysis showed that the konjac flour treatment notably increased the α-diversity and changed the ß-diversity of intestinal microflora in patients (p <0.01). Moreover, konjac flour could also evidently increase the abundance of some of the beneficial microorganisms related to obesity of patients, such as Lachnospiraceae, Roseburia, Solobacterium, R. inulinivorans, Clostridium perfringens, and Intestinimonas butyriciproducens, and reduce the abundance of the harmful microorganisms, such as Lactococcus, Bacteroides fragilis, Lactococcus garvieae, B. coprophilus, B. ovatus, and B. thetaiotaomicron (p <0.01). Specifically, C. perfringens was significantly negatively correlated with serum total cholesterol (TC) (p <0.01). Conclusion: These results suggested that KF can achieve positive effects on treating obesity, which manifest on reducing BMI, fat mass, blood glucose, and blood lipid, improving hepatic function, and also regulating intestinal microfloral structure. Therefore, changes in gut microbiota may explain in part the effects of KF.