TMK-based cell-surface auxin signalling activates cell-wall acidification.

The phytohormone auxin controls many processes in plants, at least in part through its regulation of cell expansion1. The acid growth hypothesis has been proposed to explain auxin-stimulated cell expansion for five decades, but the mechanism that underlies auxin-induced cell-wall acidification is poorly characterized. Auxin induces the phosphorylation and activation of the plasma membrane H+-ATPase that pumps protons into the apoplast2, yet how auxin activates its phosphorylation remains unclear. Here we show that the transmembrane kinase (TMK) auxin-signalling proteins interact with plasma membrane H+-ATPases, inducing their phosphorylation, and thereby promoting cell-wall acidification and hypocotyl cell elongation in Arabidopsis. Auxin induced interactions between TMKs and H+-ATPases in the plasma membrane within seconds, as well as TMK-dependent phosphorylation of the penultimate threonine residue on the H+-ATPases. Our genetic, biochemical and molecular evidence demonstrates that TMKs directly phosphorylate plasma membrane H+-ATPase and are required for auxin-induced H+-ATPase activation, apoplastic acidification and cell expansion. Thus, our findings reveal a crucial connection between auxin and plasma membrane H+-ATPase activation in regulating apoplastic pH changes and cell expansion through TMK-based cell surface auxin signalling.

SPA, a Stigma-style-transmitting tract Physical microenvironment Assay for investigating mechano-signaling in pollen tubes.

Accurate sensing and responding to physical microenvironment are crucial for cell function and survival, but the underlying molecular mechanisms remain elusive. Pollen tube (PT) provides a perfect single-cell model for studying mechanobiology since it's naturally subjected to complex mechanical instructions from the pistil during invasive growth. Recent reports have revealed discrepant PT behaviors between in vivo and flat, two-dimensional in vitro cultures. Here, we established the Stigma-style-transmitting tract (TT) Physical microenvironment Assay (SPA) to recapitulate pressure changes in the pistil. This biomimetic assay has enabled us to swiftly identify highly redundant genes, GEF8/9/11/12/13, as new regulators for maintaining PTs integrity during style-to-TT emergence. In contrast to normal growth on solid medium, SPA successfully phenocopied gef8/9/11/12/13 PT in vivo growth-arrest deficiency. Our results suggest the existence of distinct signaling pathways regulating in vivo and in vitro PT integrity maintenance, underscoring the necessity of faithfully mimicking the physical microenvironment for studying plant cell biology.

An electrostatic cluster guides Aß40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aß peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aß40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aß40 fibril structures. One population has an ordered N-terminal fold comprised of two ß-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

MhCLC-c1, a Cl channel c homolog from Malus hupehensis, alleviates NaCl-induced cell death by inhibiting intracellular Cl- accumulation.

BACKGROUND: Overaccumulation of chloride (Cl) when plants suffer NaCl causes cell damage and death, and is regulated by Cl- channel protein (CLC). Apple roots are very sensitive to Cl-, but information associated with CLC is limited in apple crop that widely cultivated in the world. RESULTS: We identified 9 CLCs from the apple genome and divided them into two subclasses. Among them, MdCLC-c1 promoter contained the largest number of cis-acting elements associated with NaCl stress, and only the MdCLC-c1, MdCLC-d, and MdCLC-g were predicted that may be Cl- antiporters or channels. Expression analysis of MdCLCs homologs in the roots of Malus hupehensis showed that most of the MhCLCs expression were response to NaCl stress, especially MhCLC-c1 expression was upregulated continuously and rapidly expressed during NaCl treatment. Therefore, we isolated MhCLC-c1 and observed it was a plasma membrane-localized protein. The MhCLC-c1 suppression significantly increased sensitivity, reactive oxygen species content, and cell death of apple calli; while MhCLC-c1 overexpression decreased sensitivity, reactive oxygen species content, and cell death of apple calli and Arabidopsis by inhibiting intracellular Cl- accumulation under NaCl stress. CONCLUSIONS: The study selected and isolated a CLC-c gene MhCLC-c1 from Malus hupehensis based on identification of CLCs gene family in apple, and their homologs MhCLCs expression patterns during NaCl treatments, revealing that MhCLC-c1 alleviates NaCl-induced cell death by inhibiting intracellular Cl- accumulation. Our findings confer the comprehensive and in-depth upstanding of the mechanism that plants resist salt stress, and might also confer genetic improvement of salt tolerance in horticultural crops and the development and utilization of saline-alkali land.

Canonical Rab5 GTPases are essential for pollen tube growth through style in Arabidopsis.

Pollen tubes have dynamic tubular vacuoles. Functional loss of AP-3, a regulator of one vacuolar trafficking route, reduces pollen tube growth. However, the role of canonical Rab5 GTPases that are responsible for two other vacuolar trafficking routes in Arabidopsis pollen tubes is obscure. By using genomic editing, confocal microscopy, pollen tube growth assays, and transmission electron microscopy, we demonstrate that functional loss of canonical Rab5s in Arabidopsis, RHA1 and ARA7, causes the failure of pollen tubes to grow through style and thus impairs male transmission. Functional loss of canonical Rab5s compromises vacuolar trafficking of tonoplast proteins, vacuolar biogenesis, and turgor regulation. However, rha1;ara7 pollen tubes are comparable to those of wild-type in growing through narrow passages by microfluidic assays. We demonstrate that functional loss of canonical Rab5s compromises endocytic and secretory trafficking at the plasma membrane (PM), whereas the targeting of PM-associated ATPases is largely unaffected. Despite that, rha1;ara7 pollen tubes contain a reduced cytosolic pH and disrupted actin microfilaments, correlating with the mis-targeting of vacuolar ATPases (VHA). These results imply a key role of vacuoles in maintaining cytoplasmic proton homeostasis and in pollen tube penetrative growth through style.

The association between the maternal pre-pregnancy platelet count and fecundability in mainland China: a population-based cohort study.

BACKGROUND: Currently, awareness about platelet count (PC) and its consequences for perinatal outcome have increased, but there is little reliable evidence on fecundability. METHODS: Based on the National Free Pre-conception Check-up Projects supported by the Chinese government, 5,524,886 couples met the inclusion criteria were included in this cohort study. Cox regression models were adopted to estimate fecundability ratios (FRs) and their 95% confidence intervals for pre-pregnancy PC quintiles. Restricted cubic splines were used to flexibly model and visualize the relationship of PC with FRs. Microsoft SQL server and R software were used for data management and analysis. RESULTS: The median of pre-pregnancy PC among women was 221.00×109/L. The first (<177.00 ×109/L) and second quintile (177.00-207.99 ×109/L) of PC showed slightly increased fecundability (Q1: adjusted FR 1.05, 95% CI 1.04-1.06; Q2: adjusted FR 1.04, 95% CI 1.03-1.05), while higher quintals (Q4: 236.00-271.99 ×109/L; Q5: ≥272.00 ×109/L) were related to reduction of fecundability, when compared with the third quintile of PC (208.00-235.99 ×109/L) (Q4: adjusted FR 0.96, 95% CI 0.95-0.97; Q5: adjusted FR 0.88, 95% CI 0.87-0.89). In the first quintiles (<177.00×109/L), only 20.93% women had PC below 129.94×109/L. An inverse-U shape association was consistently observed among women such that the lower PC of normal range (<118.03×109/L) and higher PC (>223.06×109/L) were associated with the risk of reduced female fecundability (P for non-linearity < 0.01). CONCLUSION: PC is associated with female fecundability. Further classification of PC levels may deepen our understanding of the early warnings and significance of female fecundability.

Highly sensitive liquid chromatographic method combined with online ion suppression to remove interfering anions and mass spectrometry for impurity profiling of paromomycin sulfate.

A previously developed high-performance liquid chromatography method combined with pulsed amperometric detection allowed to separate many impurities of paromomycin. However, due to the presence of ion pairing agents and sodium hydroxide in the mobile phase, direct coupling to mass spectrometry for the identification of the chemical structures of the impurities was not an option. Indeed, ion suppression was encountered by trifluoroacetic acid and pentafluoroproponic acid in the mobile phase. A cation self-regenerating suppressor, which was originally designed for increasing analyte conductivity of ammonia and amines analysis in ion chromatography, was coupled between the liquid chromatography and ion trap-time of flight-mass spectrometry and almost all trifluoroacetic acid and pentafluoroproponic acid in the mobile phase was removed. The limit of detection of paromomycin in this integrated system improved significantly to 20 ng/ml (0.4 ng). The chemical structures of 19 impurities were elucidated and seven impurities were reported for the first time.

Human cerebral vascular amyloid contains both antiparallel and parallel in-register Aß40 fibrils.

The accumulation of fibrillar amyloid-ß (Aß) peptides alongside or within the cerebral vasculature is the hallmark of cerebral amyloid angiopathy (CAA). This condition commonly co-occurs with Alzheimer's disease (AD) and leads to cerebral microbleeds, intracranial hemorrhages, and stroke. CAA also occurs sporadically in an age-dependent fashion and can be accelerated by the presence of familial Aß mutant peptides. Recent studies using Fourier transform infrared (FTIR) spectroscopy of vascular Aß fibrils derived from rodents containing the double E22Q/D23N mutations indicated the presence of a novel antiparallel ß-sheet structure. To address whether this structure is associated solely with the familial mutations or is a common feature of CAA, we propagated Aß fibrils from human brain vascular tissue of patients diagnosed with nonfamilial CAA. Aß fibrils were isolated from cerebral blood vessels using laser capture microdissection in which specific amyloid deposits were removed from thin slices of the brain tissue. Transmission electron microscopy revealed that these deposits were organized into a tight meshwork of fibrils, which FTIR measurements showed could serve as seeds to propagate the growth of Aß40 fibrils for structural studies. Solid-state NMR measurements of the fibrils propagated from vascular amyloid showed they contained a mixture of parallel, in-register, and antiparallel ß-sheet structures. The presence of fibrils with antiparallel structure derived from vascular amyloid is distinct from the typical parallel, in-register ß-sheet structure that appears in fibrils derived from parenchymal amyloid in AD. These observations reveal that different microenvironments influence the structures of Aß fibrils in the human brain.

Elevated expression of urokinase plasminogen activator in rodent models and patients with cerebral amyloid angiopathy.

AIMS: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA). MATERIALS AND METHODS: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-ß (Aß) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA). RESULTS: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aß deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aß deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA.

Efficient Capture and Separation of Cancer Cells Using Hyaluronic Acid-Modified Magnetic Beads in a Microfluidic Chip.

The efficient isolation and specific discrimination of circulating tumor cells (CTCs) is expected to provide valuable information for understanding tumor metastasis and play an important role in the treatment of cancer patients. In this study, we developed a novel and rapid method for efficient capture and specific identification of cancer cells using hyaluronic acid (HA)-modified SiO2-coated magnetic beads in a microfluidic chip. First, polyacrylamide-surfaced SiO2-coated magnetic beads (SiO2@MBs) were covalently conjugated with HA, and the created HA-modified SiO2@MBs (HA-SiO2@MBs) display binding specificity to HeLa cells (a human cervical carcinoma cell line) overexpressing CD44 receptors. After incubating the HA-SiO2@MBs with cancer cells for 1 h, the mixture of MBs and cells was drawn into a designed microfluidic channel with two inlets and outlets. Through the formation of lamellar flow, cells specifically bound with the HA-SiO2@MBs can be separated under an external magnetic field with a capture efficiency of up to 92.0%. The developed method is simple, fast, and promising for CTC separation and cancer diagnostics applications.

The prevalence and influencing factors of anaemia among pre-pregnant women in mainland China: a large population-based, cross-sectional study.

Anaemia is a global public health problem affecting women worldwide, and reproductive-age women are at increased risk. We conducted a population-based cross-sectional study analysing the prevalence of overall anaemia and anaemia according to severity in Chinese pre-pregnant women to update current knowledge on anaemia epidemiology. Based on the National Free Preconception Check-up Projects supported by the Chinese government, 5 679 782 women participating in this project in 2017 were included in the present study. The cyanmethemoglobin method was applied to assess Hb concentrations. Univariate and multivariate logistic regressions were applied for associated factors. The prevalence of anaemia among Chinese pre-pregnant women was 21·64 % (mild: 14·10 %, moderate: 7·17 % and severe : 0·37 %). The prevalence of overall and severe anaemia was the highest in Tibet and the lowest in Beijing among thirty-one provinces. Women's age, region, ethnic origin, educational level, occupation and pregnancy history were all correlated with anaemia. Women with B blood type (adjusted OR (aOR) = 0·89), higher BMI (overweight: aOR = 0·84; obesity: aOR = 0·70) and alcohol consumption (aOR = 0·69) were less likely to have anaemia, while those with rhesus negative blood type (aOR = 1·10), history of anaemia (aOR = 2·60), older age at menarche (aOR = 1·19), heavy menstrual blood loss (aOR = 1·39), longer menstrual period (aOR = 1·09) and shorter menstrual cycle (aOR = 1·08) were more likely to suffer from anaemia. Meat or egg eaters were not significantly associated with severe anaemia. Anaemia is of moderate public health significance among Chinese pre-pregnant women. Interventions should be considered to prevent anaemia to the greatest extent possible to avoid potential harm in this population.

Identifying DNA-binding proteins based on multi-features and LASSO feature selection.

DNA-binding proteins perform an indispensable function in the maintenance and processing of genetic information and are inefficiently identified by traditional experimental methods due to their huge quantities. On the contrary, machine learning methods as an emerging technique demonstrate satisfactory speed and accuracy when used to study these molecules. This work focuses on extracting four different features from primary and secondary sequence features: Reduced sequence and index-vectors (RS), Pseudo-amino acid components (PseAACS), Position-specific scoring matrix-Auto Cross Covariance Transform (PSSM-ACCT), and Position-specific scoring matrix-Discrete Wavelet Transform (PSSM-DWT). Using the LASSO dimension reduction method, we experiment on the combination of feature submodels to obtain the optimized number of top rank features. These features are respectively input into the training Ensemble subspace discriminant, Ensemble bagged tree and KNN to predict the DNA-binding proteins. Three different datasets, PDB594, PDB1075, and PDB186, are adopted to evaluate the performance of the as-proposed approach in this work. The PDB1075 and PDB594 datasets are adopted for the five-fold cross-validation, and the PDB186 is used for the independent experiment. In the five-fold cross-validation, both the PDB1075 and PDB594 show extremely high accuracy, reaching 86.98% and 88.9% by Ensemble subspace discriminant, respectively. The accuracy of independent experiment by multi-classifiers voting is 83.33%, which suggests that the methodology proposed in this work is capable of predicting DNA-binding proteins effectively.

Association Between Tumor Necrosis Factor-α (G-308A) Polymorphism and Chronic Periodontitis, Aggressive Periodontitis, and Peri-implantitis: A Meta-analysis.

OBJECTIVE: Chronic periodontitis (CP), aggressive periodontitis (AP), and peri-implantitis (PI) are chronic inflammatory diseases. Tumor necrosis factor-α (TNF-a) is an effective immune inflammatory mediator. Several studies have been conducted to explore the association between the TNF-α (G-308A) polymorphism and susceptibility to CP, AP, and PI. Our objective was to examine whether the TNF-α (G-308A) polymorphism is related to these diseases. METHODS: We conducted a meta-analysis to investigate the association between the TNF-α (G-308A) polymorphism and CP, AP, and PI. The PubMed, Embase, CNKI, and Web of Science electronic databases were searched for studies published from inception to August 11, 2020; the reference lists of included studies were also searched. The included studies were assessed in the following genetic models: dominant model, recessive model, allelic model, heterozygous model, and homozygous model. RESULTS: Forty articles (50 comparisons) with 2243 CP, 824 AP, 615 PI, 795 healthy peri-implant, and 3575 healthy controls were considered for the TNF-α (G-308A) polymorphism in this meta-analysis. Variant A of TNF-α (G-308A) was associated with increased AP risk in the general population, especially in Asians, and this polymorphism was significantly associated with elevated risk of CP in Asians and Caucasians. There was no association between the A allele and PI risk. None of the contrasts of the genetic model yielded a significant finding in Latin Americans. Different genotyping methods may affect the association between the TNF-α (G-308A) polymorphism and these diseases. CONCLUSION: These findings supported that variant A of the TNF-α (G-308A) polymorphism may contribute to CP and AP susceptibility, particularly in Asians and Caucasians. More efforts and further studies with larger sample sizes will be required to validate the risk of CP, AP, and PI.

Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease of the aged and a prominent comorbidity of Alzheimer's disease (AD). CAA can promote a variety of vascular-related pathologies including neuroinflammation, cerebral infarction, and hemorrhages, which can all contribute to vascular cognitive impairment and dementia (VCID). Our understanding of the pathogenesis of CAA remains limited and further investigation of this condition requires better preclinical animal models that more accurately reflect the human disease. Recently, we generated a novel transgenic rat model for CAA (rTg-DI) that develops robust and progressive microvascular CAA, consistent microhemorrhages and behavioral deficits. METHODS: In the current study, we investigated perivascular pathological processes that accompany the onset and progressive accumulation of microvascular CAA in this model. Cohorts of rTg-DI rats were aged to 3 months with the onset of CAA and to 12 months with advanced stage disease and then quantitatively analyzed for progression of CAA, perivascular glial activation, inflammatory markers, and perivascular stress. RESULTS: The rTg-DI rats developed early-onset and robust accumulation of microvascular amyloid. As the disease progressed, rTg-DI rats exhibited increased numbers of astrocytes and activated microglia which were accompanied by expression of a distinct subset of inflammatory markers, perivascular pericyte degeneration, astrocytic caspase 3 activation, and disruption of neuronal axonal integrity. CONCLUSIONS: Taken together, these results demonstrate that rTg-DI rats faithfully mimic numerous aspects of human microvascular CAA and provide new experimental insight into the pathogenesis of neuroinflammation and perivascular stress associated with the onset and progression of this condition, suggesting new potential therapeutic targets for this condition. The rTg-DI rats provide an improved preclinical platform for developing new biomarkers and testing therapeutic strategies for microvascular CAA.

Association between polycystic ovary syndrome and the vaginal microbiome: A case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Some evidence suggests that dysbiosis of the gut microbiota could be associated with PCOS clinical parameters, but little is known for the association between vaginal microbiome and PCOS. OBJECTIVE: To determine differences in the vaginal microbiome between women with PCOS and healthy control women. RESEARCH DESIGN AND METHODS: In this case-control study, the women with newly diagnosed PCOS (n = 39) and healthy controls (n = 40) were included from the hospital and maternal and child health centre, respectively. The vaginal swabs were collected, and microbiome structures were identified by 16S rRNA gene sequencing. The screening values for potential bacteria biomarker for PCOS were assessed by receiver operating characteristic (ROC) curve method. RESULTS: There was significant difference in vaginal bacterial structures between PCOS and healthy control women. The vaginal bacterial species in the PCOS group were more diverse than the control group (Simpson index for PCOS group vs. control group: median 0.49 vs. 0.80, P = .008; Shannon index: median 1.07 vs. 0.44, P = .003; Chao1 index: median 85.12 vs. 66.13, P < .001). The relative abundance of Lactobacillus crispatus in the PCOS group was significantly lower than controls (P = .001), and the relative abundance of Mycoplasma and Prevotella was higher than controls (P < .001, P = .002, respectively). The Mycoplasma genus could be a potential biomarker for PCOS screening, as ROC analysis showed that the area under the curve (AUC) for the relative abundance of Mycoplasma was 0.958 (95% CI: 0.901-0.999). Subgroup analyses also showed these associations would not change among the women with the same BMI level and vagina cleanliness grading. CONCLUSIONS: In the vaginal microbiome, the Mycoplasma genus was associated with PCOS. Further research is required to explore causal correlations between PCOS and the vaginal microbiome.

The coarse-grained plaque: a divergent Aß plaque-type in early-onset Alzheimer's disease.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aß deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aß-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aß-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrPC), Aß isoform composition (Aß40, Aß42, AßN3pE, pSer8Aß), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aß40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aß40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aß plaque-type associated with EOAD. Differences in Aß processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aß deposits. Disentangling specific Aß deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

The association between vaginal microbiota and female infertility: a systematic review and meta-analysis.

PURPOSE: This study aimed to explore the association between vaginal microbiota and infertility. METHODS: We searched a range of electronic databases for appropriate articles, including PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang, from inception to 8th September 2019. Identified articles were then screened using strict inclusion and exclusion criteria. By referring to Tamarelle's method, we divided vaginal microbiota into two categories: low-Lactobacillus vaginal microbiota (LL-VMB) and high-Lactobacillus vaginal microbiota (HL-VMB). Patients were defined as HL-VMB if they had a Nugent score of 0-3, a negative Amesel/Spiegel's test, or if the vaginal community status was dominated by either L. crispatus, L. iners, L. gasseri and L. jensenii via 16S rRNA sequencing. Otherwise, cases were regarded as LL-VMB. Statistical analyses were performed with STATA 13.0 statistical software. Effect estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Fifteen articles were included in our final analysis. The HL-VMB was negatively related to infertility; a fixed model showed that the pooled OR was 0.83 (95% CI 0.77-0.90). There was no significant publication bias, as determined by Begg's test (P = 0.488) and Egger's test (P = 0.652). Using a random effect model, the pooled OR for intermediate bacterial vaginitis (BV) and infertility was 1.39 (95% CI 1.10-1.76) and the pooled OR for positive BV was 1.72 (95% CI 1.10-2.69). Subgroup and sensitivity analyses further demonstrated that the associations identified were stable. However, the acquired evidence was not sufficient to make inferences with regards to the mechanisms underlying these relationships. CONCLUSION: This systematic review and meta-analysis identified a negative correlation between HL-VMB and female infertility. However, due to a variety of limitations, the evidence acquired does not allow us to identify the specific mechanisms underlying this association. Further high-quality studies are needed to verify the causal relationship and explore the molecular mechanisms involved.

Reduced Levels of Cerebrospinal Fluid/Plasma Aß40 as an Early Biomarker for Cerebral Amyloid Angiopathy in RTg-DI Rats.

The accumulation of fibrillar amyloid ß-protein (Aß) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer's disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aß40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aß40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aß40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aß40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aß40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention.

A Microfluidic Chip Integrated with Hyaluronic Acid-Functionalized Electrospun Chitosan Nanofibers for Specific Capture and Nondestructive Release of CD44-Overexpressing Circulating Tumor Cells.

Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for early-stage cancer diagnosis, estimation of cancer development, and individualized cancer therapy. Herein, we report the development of hyaluronic acid (HA)-functionalized electrospun chitosan nanofiber (CNF)-integrated microfludic platform for highly specific capture and nondestructive release of CTCs. First, electrospun CNFs were formed and modified with zwitterion of carboxyl betaine acrylamide (CBAA) via Michael addition reaction and then targeting ligand HA through a disulfide bond. We show that the formed nanofibers still maintain the smooth fibrous morphology after sequential surface modifications, have a good hemocompatibility, and exhibit an excellent antifouling property due to the CBAA modification. After being embedded within a microfluidic chip, the fibrous mat can capture cancer cells (A549, a human lung cancer cell line) with an efficiency of 91% at a flow rate of 1.0 mL/h. Additionally, intact release of cancer cells is able to be achieved after treatment with glutathione for 40 min to have a release efficiency of 90%. Clinical applications show that 9 of 10 nonsmall-cell lung cancer patients and 5 of 5 breast cancer patients are diagnosed to have CTCs (1 to 18 CTCs per mL of blood). Our results suggest that the developed microfluidic system integrated with functionalized CNF mats may be employed for effective CTCs capture for clinical diagnosis of cancer.