A low-sugar diet enhances Drosophila body size in males and females via sex-specific mechanisms.

In Drosophila, changes to dietary protein elicit different body size responses between the sexes. Whether these differential body size effects extend to other macronutrients remains unclear. Here, we show that lowering dietary sugar (0S diet) enhanced body size in male and female larvae. Despite an equivalent phenotypic effect between the sexes, we detected sex-specific changes to signalling pathways, transcription and whole-body glycogen and protein. In males, the low-sugar diet augmented insulin/insulin-like growth factor signalling pathway (IIS) activity by increasing insulin sensitivity, where increased IIS was required for male metabolic and body size responses in 0S. In females reared on low sugar, IIS activity and insulin sensitivity were unaffected, and IIS function did not fully account for metabolic and body size responses. Instead, we identified a female-biased requirement for the Target of rapamycin pathway in regulating metabolic and body size responses. Together, our data suggest the mechanisms underlying the low-sugar-induced increase in body size are not fully shared between the sexes, highlighting the importance of including males and females in larval studies even when similar phenotypic outcomes are observed.

Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex.

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease which is the major cause of vision loss. X-linked RP patients account for 5%-15% of all inherited RP cases and mutations in RP2 (Retinitis pigmentosa 2) were responsible for about 20% X-linked RP families. A majority of RP2 pathogenic mutations displayed a vulnerable protein stability and degraded rapidly through ubiquitin-proteasome system (UPS). Though the RP2 protein could be readily recovered by proteasome inhibitors, e.g., MG132, their applications for RP2-related RP therapy were limited by their nonspecific characterization. In the present study, we aimed to identify UPS-related factors, such as E3 ligases, which are specifically involved in degradation of RP2 pathogenic mutants. We identified several E3 ligases, such as HUWE1, and the co-chaperon BAG6 specifically interacting with RP2 pathogenic mutants. Knockdown of HUWE1 and BAG6 could partially rescue the reduced protein levels of RP2 mutants. BAG6 is required for recruitment of HUWE1 to ubiquitinate RP2 mutants at the K268 site. The HUWE1 inhibitor BI8622 could restore the levels of RP2 mutant and then the binding to its partner ARL3 in retina cell lines. This study revealed the details of UPS-related degradation of RP2 mutants and possibly provided a potential treatment for RP2-related RP.

Recognition Method of Knob Gear in Substation Based on YOLOv4 and Darknet53-DUC-DSNT.

When unattended substations are popular, the knob is a vital monitoring object for unattended substations. However, in the actual scene of the substation, the recognition method of a knob gear has low accuracy. The main reasons are as follows. Firstly, the SNR of knob images is low due to the influence of lighting conditions, which are challenging to extract image features. Secondly, the image deviates from the front view affected by the shooting angle; that knob has a certain deformation, which causes the feature judgment to be disturbed. Finally, the feature distribution of each kind of knob is inconsistent, which interferes with image extraction features and leads to weak spatial generalization ability. For the above problems, we propose a three-stage knob gear recognition method based on YOLOv4 and Darknet53-DUC-DSNT models for the first time and apply key point detection of deep learning to knob gear recognition for the first time. Firstly, YOLOv4 is used as the knob area detector to find knobs from a picture of a cabinet panel. Then, Darknet53, which can extract features, is used as the backbone network for keypoint detection of knobs, combined with DUC structure to recover detailed information and DSNT structure to enhance feature extraction and improve spatial generalization ability. Finally, we obtained the knob gear by calculating the angle between the line of the rotating center point and the pointing point and horizontal direction. The experimental results show that this method effectively solves the above problems and improves the performance of knob gear detection.

The misdiagnosis of prolonged disorders of consciousness by a clinical consensus compared with repeated coma-recovery scale-revised assessment.

BACKGROUND: Previous studies have shown that a single Coma-Recovery Scale-Revision (CRS-R) assessment can identify high rates of misdiagnosis by clinical consensus. The aim of this study was to investigate the proportion of misdiagnosis by clinical consensus compared to repeated behavior-scale assessments in patients with prolonged disorders of consciousness (DOC). METHODS: Patients with prolonged DOC during hospitalization were screened by clinicians, and the clinicians formed a clinical-consensus diagnosis. Trained professionals used the CRS-R to evaluate the consciousness levels of the enrolled patients repeatedly (≥5 times) within a week. Based on the repeated evaluation results, the enrolled patients with prolonged DOC were divided into unresponsive wakefulness syndrome (UWS), minimally conscious state (MCS), and emergence from MCS (EMCS). Finally, the relationship between the results of the CRS-R and the clinical consensus were analyzed. RESULTS: In this study, 137 patients with a clinical-consensus diagnosis of prolonged DOC were enrolled. It was found that 24.7% of patients with clinical UWS were actually in MCS after a single CRS-R behavior evaluation, while the repeated CRS-R evaluation results showed that the proportion of misdiagnosis of MCS was 38.2%. A total of 16.7% of EMCS patients were misdiagnosed with clinical MCS, and 1.1% of EMCS patients were misdiagnosed with clinical UWS. CONCLUSIONS: The rate of the misdiagnosis by clinical consensus is still relatively high. Therefore, clinicians should be aware of the importance of the bedside CRS-R behavior assessment and should apply the CRS-R tool in daily procedures. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04139239 ; Registered 24 October 2019 - Retrospectively registered.

Development of Fluorescence-Linked Immunosorbent Assay for Icariin.

We have been looking for a faster and simpler method for traditional Chinese medicine and natural product assay. In this study, we developed a fluorescent immunoassay approach to detect icariin (ICA) using a fluorescently labelled monoclonal antibody. The ICA-specific antibody was purified by the caprylic acid-ammonium sulphate method and then labelled with rhodamine B isothiocyanate (RBITC). Subsequently, an indirect competitive fluorescence-linked immunosorbent assay (icFLISA) was developed to detect ICA using RBITC-labelled anti-ICA MAbs. The RBITC-labelled monoclonal antibody was highly specific for ICA. The fluorescence assay demonstrated an effective ICA measurement range of 1.28 ng/mL to 20 µg/mL (R2 = 0.9946) with relative standard deviations below 10% for both intra-assay and inter-assay repeatability and precision. This icFLISA for ICA is simple, rapid, and sensitive, with a 20-fold greater linear range and a 10-fold lower limit of detection than with the previously developed indirect competitive enzyme-linked immunosorbent assay (ELISA). Thus, this study establishes a useful method for detecting ICA, enabling in vivo visualization research. In the future, FLISA can be also used to assay the concentrations of ICA in biological samples, as well as to investigate the pharmacokinetics of ICA in different tissues to explore the targets of ICA in vivo.

GEMimp: An accurate and robust imputation method for microbiome data using graph embedding neural network.

Microbiome research has increasingly underscored the profound link between microbial compositions and human health, with numerous studies establishing a strong correlation between microbiome characteristics and various diseases. However, the analysis of microbiome data is frequently compromised by inherent sparsity issues, characterized by a substantial presence of observed zeros. These zeros not only skew the abundance distribution of microbial species but also undermine the reliability of scientific conclusions drawn from such data. Addressing this challenge, we introduce GEMimp, an innovative imputation method designed to infuse robustness into microbiome data analysis. GEMimp leverages the node2vec algorithm, which incorporates both Breadth-First Search (BFS) and Depth-First Search (DFS) strategies in its random walks sampling process. This approach enables GEMimp to learn nuanced, low-dimensional representations of each taxonomic unit, facilitating the reconstruction of their similarity networks with unprecedented accuracy. Our comparative analysis pits GEMimp against state-of-the-art imputation methods including SAVER, MAGIC and mbImpute. The results unequivocally demonstrate that GEMimp outperforms its counterparts by achieving the highest Pearson correlation coefficient when compared to the original raw dataset. Furthermore, GEMimp shows notable proficiency in identifying significant taxa, enhancing the detection of disease-related taxa and effectively mitigating the impact of sparsity on both simulated and real-world datasets, such as those pertaining to Type 2 Diabetes (T2D) and Colorectal Cancer (CRC). These findings collectively highlight the strong effectiveness of GEMimp, allowing for better analysis on microbial data. With alleviation of sparsity issues, it could be greatly facilitated in downstream analyses and even in the field of microbiology.

Association between lipoprotein-associated phospholipase A2 and 25-hydroxy-vitamin D on early stage diabetic kidney disease in patients with type-2 diabetes mellitus.

Objective: This study aimed to analyse the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and 25-hydroxy-vitamin D (25[OH]D) and early diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) and evaluate the potential roles of these two biomarkers in the clinical diagnosis of DKD. Methods: A total of 422 inpatients with T2DM were retrospectively enrolled between January 2018 and March 2022 at the First Affiliated Hospital of Nanjing Medical University. The baseline clinical parameters of each patient were determined, and their demographic characteristics were extracted from the hospital information system. The patients were separated into groups according to serum Lp-PLA2 and 25(OH)D levels and binary logistic regression analysis was used to determine independent predictors of early DKD incidence. Results: Levels of Lp-PLA2 significantly increased and those of 25(OH)D significantly decreased with DKD progression (both P < 0.001). Lp-PLA2 concentrations were positively correlated with albuminuria levels (r = 0.37, P < 0.001), whereas 25(OH)D levels were negatively correlation (r = -0.34, P < 0.001). The incidence of DKD was higher in the Lp-PLA2 elevated and 25(OH)D deficient groups (all P < 0.001). Body mass index, systemic immune-inflammatory index, serum uric acid, C-peptide, and triglyceride-glucose indices were positively associated with Lp-PLA2 levels (all P < 0.001) and negatively associated with 25(OH)D (all P < 0.05). Furthermore, Lp-PLA2 was an independent risk factor (OR = 1.003, P = 0.015), and 25(OH)D was an independent protective factor (OR = 0.937, P = 0.008) for early DKD occurrence in binary logistic regression analysis. The area under the curve for the combination of Lp-PLA2 and 25(OH)D for diagnosing DKD was 0.867, with a sensitivity of 70.4 % and a specificity of 89.5 %. Conclusions: Increased serum Lp-PLA2 and decreased 25(OH)D levels are risk factors for early DKD in patients with T2DM. The combined detection of Lp-PLA2 and 25(OH)D may enhance the diagnostic efficacy of DKD.

Methodology exploration and reproducibility evaluation of TAI and TSI for quantitative ultrasound assessment of hepatic steatosis.

Background and aim: New quantitative ultrasound techniques can be used to quantify hepatic steatosis, including tissue attenuation imaging (TAI), tissue scatter -distribution imaging (TSI), and the hepatorenal index (HRI). However, the measurement norms and the effects of fasting on these measurements remain unclear. The present study performed a methodological exploration and investigated the reliability of these measurements. Methods: In total, 103 participants were prospectively recruited for ultrasonography and magnetic resonance imaging (MRI) scans. For the TAI and TSI data, the upper (2 cm), middle (4 cm) and lower (6 cm) areas determined according to the depth of the region of interest from the liver capsule, were sampled three times. Correlation analyses were performed to compare the measurements of TAI, TSI, and HRI with the controlled attenuation parameter (CAP) or MRI-proton density fat fraction (MRI-PDFF). Intra- and inter-operator repeatability was assessed using intraclass correlation coefficients. The effects of fasting on these measurements were then compared. Results: The TAI and TSI measurements obtained from the upper and middle depths exhibited stronger correlations with the CAP measurements than those obtained from the lower depth. Specifically, the mean TAI had a significant positive correlation with MRI-PDFF (r = 0.753, P < 0.0001). TAI and TSI measurements exhibited excellent intra- (0.933 and 0.925, respectively) and inter- (0.896 and 0.766, respectively) examiner reliability. However, the correlation between HRI and CAP measurements was only 0.281, with no significant correlation with MRI-PDFF, and intra- and inter-examiner reproducibility of 0.458 and 0.343, respectively. Fasting did not affect these measurements. Conclusions: TAI and TSI measurements demonstrated good intra- and interobserver reliability and correlated well with CAP and MRI-PDFF measurements. However, in practice-based clinical applications, the sampling depth should be controlled within 2-4 cm of the hepatic capsule; no fasting is required before the examination.

PPARs in atherosclerosis: The spatial and temporal features from mechanism to druggable targets.

BACKGROUND: Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, and other factors. It is closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages of atherosclerosis and for cell types at different tissue sites. AIM OF REVIEW: Considering the spatial and temporal characteristics of the pathological evolution of atherosclerosis, the roles and pharmacological and clinical studies of PPARs were summarized systematically and updated under different pathological stages and in different vascular cells of atherosclerosis. Moreover, selective PPAR modulators and PPAR-pan agonists can exert their synergistic effects meanwhile reducing the side effects, thereby providing novel insight into future drug development for precise spatial-temporal therapeutic strategy of anti-atherosclerosis targeting PPARs. KEY SCIENTIFIC: Concepts of Review: Based on the spatial and temporal characteristics of atherosclerosis, we have proposed the importance of stage- and cell type-dependent precision therapy. Initially, PPARs improve endothelial cells' dysfunction by inhibiting inflammation and oxidative stress and then regulate macrophages' lipid metabolism and polarization to improve fatty streak. Finally, PPARs reduce fibrous cap formation by suppressing the proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, research on the cell type-specific mechanisms of PPARs can provide the foundation for space-time drug treatment. Moreover, pharmacological studies have demonstrated that several drugs or compounds can exert their effects by the activation of PPARs. Selective PPAR modulators (that specifically activate gene subsets of PPARs) can exert tissue and cell-specific effects. Furthermore, the dual- or pan-PPAR agonist could perform a better role in balancing efficacy and side effects. Therefore, research on cells/tissue-specific activation of PPARs and PPAR-pan agonists can provide the basis for precision therapy and drug development of PPARs.

Association between preoperative denosumab and the risk of local recurrence in patients with giant cell tumor of bone: A meta-analysis and systematic review.

Objectives: This meta-analysis aimed at determining the association between preoperative denosumab and the risk of local recurrence in patients with giant cell tumors of the bone. Methods and Materials: Web of Science, EMBASE, Cochrane Library, and PubMed were comprehensively searched on April 20th, 2022. Data from the included articles were analyzed using meta-analysis. The bias of all included studies was evaluated according to ROBINS-I. Also, subgroup and sensitivity analyses were performed. Results: Eight studies with 1270 cases (195 in the denosumab group and 1075 in the control group) were eventually included. Patients receiving denosumab before curettage had a higher risk of local recurrence than those who underwent curettage alone (odds ratio: 2.29, 95% confidence intervals: 1.44-3.64, P = 0.0005). The denosumab group showed a significantly higher risk of local recurrence in most subgroup analyses, except for those with preoperative denosumab duration ≤six months/doses (P = 0.66) and sample size ranging from 100 to 180 (P = 0.69). Conclusion: Denosumab before curettage may increase the risk of local recurrence in patients with giant cell tumor of the bone. Preoperative denosumab should be used with caution after weighing an increased risk of local recurrence against the clinical benefits and a duration time of less than six months before surgery is recommended.

CEACAM6 serves as a biomarker for leptomeningeal metastasis in lung adenocarcinoma.

BACKGROUND AND AIMS: Diagnosis of leptomeningeal metastasis (LM) is challenging. In our previous study, CEACAM6 mRNA was found to be highly expressed in the circulating tumor cells of cerebrospinal fluid (CSF) from patients with lung adenocarcinoma with LM (LUAD-LM). The aim of this study was to identify whether CEACAM6 could be used as a biomarker for LUAD-LM. MATERIALS AND METHODS: The level of CEACAM6 was determined by enzyme-linked immunosorbent assay (ELISA) in CSF from 40 LUAD-LM and 44 normal controls, and additional serum samples from 138 LUAD patients, including 12 LUAD-LM patients, and 30 healthy controls. Carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1) and neuron-specific enolase (NSE) levels in the CSF and sera were detected by chemiluminescent immunoassay. Receiver operating characteristic curve was plotted to evaluate the diagnostic performance for LUAD-LM. RESULTS: CSF CEACAM6 level was higher in LUAD-LM than that in normal controls. In serum, LUAD patients had a higher level of CAECAM6 than healthy controls, and LM patients had the highest level among them. Serum CEACAM6 had a higher AUC than CEA in differentiating LM from non-LM in LUAD patients (0.95 vs. 0.64, p < 0.001). CONCLUSION: CEACAM6 may serve as a potential biomarker in diagnosing LUAD-LM.

Multifunctional Regioisomeric Passivation Strategy for Fabricating Self-Driving, High Detectivity All-Inorganic Perovskite Photodetectors.

The fluorination of the aromatic multifunctional Lewis base passivation strategy has been demonstrated recently as an effective approach to markedly enhance the performance of perovskite photovoltaic devices. However, the regulation mechanisms of the passivation efficiency by varying the functional group position of fluorine (F) in the regioisomers have received little attention and inadequate research. Herein, a pair of bifluorine-substituted aminobenzoic acid regioisomers [3-amino-2,6-difluorobenzoic acid (13-FABA) and 4-amino-3,5-difluorobenzoic acid (14-FABA)] were employed to investigate the passivation effects of Lewis bases dependent on behaviors of the ortho/meta-substituted position of fluorine. The density functional theory calculation on electron cloud density, interaction energy, and the basicity of Lewis bases combined with experimental evidence reveal that the ortho-effect induced by fluorine substitution weakens the passivating effect of 13-FABA Lewis base and induces its molecular propensity to form internal salts, accelerating the degradation and deterioration of the device performance. Conversely, 14-FABA with meta-connected fluorine atoms exhibit superior efficacy in suppressing defects and enhancing hydrophobicity. Eventually, the 14-FABA-modified photodetectors (PDs) achieved a high detectivity of 1.69 × 1013 Jones, the comparatively lower dark current density of 2.2 × 10-10 A/cm2 among all-inorganic perovskite PD systems. Our work has not only clarified the fundamental mechanisms of the F-substituted position effects of Lewis base on suppressing defects but also provided a promising passivation strategy for perovskite films via designing the regioisomeric atoms in a multifunctional Lewis base molecule.

Construction of Novel Prognostic Nomogram for Mucinous and Signet Ring Cell Colorectal Cancer Patients with a Survival Longer Than 5 Years.

Purpose: Mucinous adenocarcinoma (MA) and signet ring cell carcinoma (SRCC) are aggressive colorectal cancer histological subtypes with dismal prognosis. This study investigated prognostic factors and constructed novel nomograms for MA and SRCC patients who survived for over 5 years to optimize the follow-up regime, especially for early-onset patients. Patients and Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database registered between 2004 and 2018 were extracted. MA and SRCC patients were divided into two groups with survival time of 5 years as a cut-off point. Prognostic factors for overall survival (OS) and cancer-specific survival (CSS) were determined by Cox regression models, and survival curves were plotted by the Kaplan-Meier method. Results: We identified 8286 MA patients (45.73%) and 551 SRCC patients (20.32%) who survived for over 5 years. Multivariable Cox analyses identified age, tumor location, N stage, metastasis, CEA level, surgery, and lymph nodes dissection as independent risk factors for MACSS. SRCC was more aggressive and only N2 stage (P = 0.011) and metastasis (P = 0.043) were inversely associated with SRCCSS. Furthermore, we observed that small tumor size, well differentiation, and chemotherapy no longer provided survival benefit to ≥5-year survivors. Therefore, we constructed novel nomograms appropriate for MA patients who survived for over 5 years. The consistency indexes for predicting 10-year OS and CSS were respectively 0.717, 0.712 in the training cohort and 0.727, 0.735 in the validation cohort. Conclusion: Our well-calibrated nomograms represent the first clinical prognostic models developed especially for MA patients with a survival longer than 5 years. For both MA and SRCC patients, TNM stage was a stable prognostic factor, while the prognostic values of tumor size, differentiation grade, and chemotherapy changed over time. We are hopeful that our prognostic models will help define personalized follow-up managements to further prolong patient survival.

Olfactory Stimulation and the Diagnosis of Patients With Disorders of Consciousness: A Double-Blind, Randomized Clinical Trial.

OBJECTIVES: The aim of this study was to determine whether behavioral responses elicited by olfactory stimulation are a predictor of conscious behavioral response and prognosis of patients with disorders of consciousness (DOC). METHODS: Twenty-three DOC patients (8 unresponsive wakefulness syndrome [UWS]; 15 minimally conscious state [MCS]) were recruited for this study in which 1-Octen-3-ol (familiar neutral odor) and pyridine were used to test odor behavioral responses, and water was used as an odorless stimulus. One rater presented the three odors in front of each patient's nose randomly, and another one videotaped all behavioral responses (e.g., pouting, wrinkling nose, slightly shaking head, frowning, etc.). Two independent raters, blind to the stimuli and the patient's diagnosis, gave the behavioral results according to the recorded videos. One-, 3-, and 6-month follow-up evaluations were conducted to obtain a good prognostic value. RESULTS: All MCS patients showed behavioral responses to the 1-Octen-3-ol stimulus; nine MCS and one UWS showed olfactory emotional responses to the pyridine, and two MCS showed olfactory emotional responses to the water stimulus. The incidence of behavioral response was significantly higher using 1-Octen-3-ol than it was for water by McNemar test (p < 0.001), significantly higher using pyridine than it was for water (p < 0.01). The χ2 test results indicated that there were significant differences between MCS and UWS to 1-Octen-3-ol (p < 0.001). For MCS patients, the incidence of behavioral response was no different between using 1-Octen-3-ol and pyridine (p > 0.05). There was no significant relationship between the olfactory behavioral response and the improvement of consciousness based on the χ2 test analysis (p > 0.05). CONCLUSION: Olfactory stimuli, especially for the familiar neutral odor, might be effective for eliciting a conscious behavioral response and estimating the clinical diagnosis of DOC patients. CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/ct2/show/NCT03732092], [identifier NCT03732092].

Cell-Free DNA Variables including Gene Mutations in CA15-3 Normal Breast Cancer Reflect Prognosis.

BACKGROUND: Cell-free DNA (cfDNA) has attracted considerable attention in precision medicine. However, few data are available regarding to the prognostic value of cfDNA variables in CA15-3 normal breast cancer (BC) patients. Here, we aimed at investigating the prognostic value of cfDNA variables including gene mutations in CA15-3 normal BC patients. METHODS: A total of 68 BC patients with normal CA15-3 levels were enrolled. cfDNA concentration and integrity were assessed based on qPCR. cfDNA gene mutations were conducted by using next gene sequencing (NGS). The association between cfDNA variables and the prognosis of patients was analyzed. RESULTS: cfDNA concentration was related to tumor stage (P = 0.002), metastases (P = 0.001), and distant metastases (P < 0.001). The elevated copy number variants (CNV) were found in distant metastasis patients compared with patients without distant metastases (P = 0.008). Nineteen mutant genes were validated in enrolled CA15-3 normal BC patients. Thirty-two patients (47.0%) had single nucleotide variants (SNV), and 13 (19.1%) patients had TP53 mutations (TP53 mut). SNV (P = 0.033) was related to tumor stage, and TP53 mut was related to metastases (P = 0.016) and distant metastases (P = 0.006). In multivariate logistic analysis, cfDNA concentration was associated with metastases (OR = 3.404, 95% CI: 1.074-10.788, P = 0.037) and distant metastases (OR = 13.750, 95% CI: 1.473-128.358, P = 0.021). Cases with high cfDNA levels (>15.6 ng/ml), SNV, and TP53 mut showed worse DFS compared with patients with low cfDNA levels (P < 0.001), without SNV (P = 0.002) and with TP53 wildtype (P < 0.001), respectively. In the multivariate Cox proportional hazard model, cfDNA concentration was an independent predictor of poor survival (HR = 5.786, 95% CI: 1.101-30.407, P = 0.038). CONCLUSIONS: Assessment of cfDNA concentration, CNV, SNV, and TP53 mut could be useful in predicting prognosis for CA15-3 normal BC patients. The cfDNA concentration was an independent predictor prognostic factor in CA15-3 normal BC patients.

Single-cell RNA sequencing reveals the characteristics of cerebrospinal fluid tumour environment in breast cancer and lung cancer leptomeningeal metastases.

Leptomeningeal metastases (LM) occur in patients with breast cancer (BC) and lung cancer (LC) showing exceptionally poor prognosis. The cerebrospinal fluid (CSF) tumour microenvironment (TME) of LM patients is not well defined at a single-cell level. Based on the 10× genomics single-cell RNA sequencing (scRNA-seq) data from GEO database including five patient-derived CSF samples of BC-LM and LC-LM, and four patient-derived CSF samples of idiopathic intracranial hypertension (IIH) as controls, we analysed single-cell transcriptome characteristics of CSF TME in LM patients compared to controls simultaneously and comprehensively. In addition, we performed 10× genomics scRNA-seq on CSF cells derived from a BC-LM patient to help generate a solid conclusion. The CSF macrophages in LM patients showing M2-subtype signature and the emergence of regulatory T cells in LM confirmed the direction of tumour immunity toward immunosuppression. Then, the characteristics of CSF circulating tumour cells (CTCs) of breast cancer LM (BC-LM) patients were classified into five molecular subtypes by PAM50 model. The communication between macrophages and five subtype-specific CSF-CTCs showed largest number of ligand-receptor interactions. The five subtypes-specific CSF-CTCs showed great heterogeneities which were manifested in cell proliferation and cancer-testis antigens expression. Gene regulatory networks (GRNs) analysis revealed that transcription factor SREBF2 was universally activated in the five subtypes-specific CSF-CTCs. Our results will provide inspiration on new directions of the mechanism research, diagnosis and therapy of LM.

Genetic manipulation of insulin/insulin-like growth factor signaling pathway activity has sex-biased effects on Drosophila body size.

In Drosophila raised in nutrient-rich conditions, female body size is approximately 30% larger than male body size due to an increased rate of growth and differential weight loss during the larval period. While the mechanisms that control this sex difference in body size remain incompletely understood, recent studies suggest that the insulin/insulin-like growth factor signaling pathway (IIS) plays a role in the sex-specific regulation of processes that influence body size during development. In larvae, IIS activity differs between the sexes, and there is evidence of sex-specific regulation of IIS ligands. Yet, we lack knowledge of how changes to IIS activity impact body size in each sex, as the majority of studies on IIS and body size use single- or mixed-sex groups of larvae and/or adult flies. The goal of our current study was to clarify the body size requirement for IIS activity in each sex. To achieve this goal, we used established genetic approaches to enhance, or inhibit, IIS activity, and quantified pupal size in males and females. Overall, genotypes that inhibited IIS activity caused a female-biased decrease in body size, whereas genotypes that augmented IIS activity caused a male-specific increase in body size. These data extend our current understanding of body size regulation by showing that most changes to IIS pathway activity have sex-biased effects, and highlights the importance of analyzing body size data according to sex.

Association of Rotavirus Vaccines With Reduction in Rotavirus Gastroenteritis in Children Younger Than 5 Years: A Systematic Review and Meta-analysis of Randomized Clinical Trials and Observational Studies.

Importance: Rotavirus vaccines have been introduced worldwide, and the clinical association of different rotavirus vaccines with reduction in rotavirus gastroenteritis (RVGE) after introduction are noteworthy. Objective: To evaluate the comparative benefit, risk, and immunogenicity of different rotavirus vaccines by synthesizing randomized clinical trials (RCTs) and observational studies. Data Sources: Relevant studies published in 4 databases: Embase, PubMed, the Cochrane Library, and Web of Science were searched until July 1, 2020, using search terms including "rotavirus" and "vaccin*." Study Selection: Randomized clinical trials and cohort and case-control studies involving more than 100 children younger than 5 years that reported the effectiveness, safety, or immunogenicity of rotavirus vaccines were included. Data Extraction and Synthesis: A random-effects model was used to calculate relative risks (RRs), odds ratios (ORs), risk differences, and 95% CIs. Adjusted indirect treatment comparison was performed to assess the differences in the protection of Rotarix and RotaTeq. Main Outcomes and Measures: The primary outcomes were RVGE, severe RVGE, and RVGE hospitalization. Safety-associated outcomes involved serious adverse events, intussusception, and mortality. Results: A meta-analysis of 20 RCTs and 38 case-control studies revealed that Rotarix (RV1) significantly reduced RVGE (RR, 0.316 [95% CI, 0.224-0.345]) and RVGE hospitalization risk (OR, 0.347 [95% CI, 0.279-0.432]) among children fully vaccinated; RotaTeq (RV5) had similar outcomes (RVGE: RR, 0.350 [95% CI, 0.275-0.445]; RVGE hospitalization risk: OR, 0.272 [95% CI, 0.197-0.376]). Rotavirus vaccines also demonstrated higher protection against severe RVGE. Additionally, no significant differences in the protection of RV1 and RV5 against rotavirus disease were noted in adjusted indirect comparisons. Moderate associations were found between reduced RVGE risk and Rotavac (RR, 0.664 [95% CI, 0.548-0.804]), Rotasiil (RR, 0.705 [95% CI, 0.605-0.821]), and Lanzhou lamb rotavirus vaccine (RR, 0.407 [95% CI, 0.332-0.499]). All rotavirus vaccines demonstrated no risk of serious adverse events. A positive correlation was also found between immunogenicity and vaccine protection (eg, association of RVGE with RV1: coefficient, -1.599; adjusted R2, 99.7%). Conclusions and Relevance: The high protection and low risk of serious adverse events for rotavirus vaccines in children who were fully vaccinated emphasized the importance of worldwide introduction of rotavirus vaccination. Similar protection provided by Rotarix and RotaTeq relieves the pressure of vaccines selection for health care authorities.

Serum miR-27a is a biomarker for the prognosis of non-small cell lung cancer patients receiving chemotherapy.

BACKGROUND: Lung cancer has a high incidence and a 5-year survival rate of less than 15%. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Chemotherapy and immunotherapy are the most frequently used alternative treatments for patients with advanced-stage NSCLC in whom surgery failed. Previous studies have suggested that miR-27a is involved in cancer development and progression. The purpose of this study was to investigate the clinical value of miR-27a in the prognosis of NSCLC patients after chemotherapy. METHODS: Flow cytometry was used to detect the apoptosis rate of SPC-A1 cells treated with optical cisplatin at different times. Simultaneously, the expression of miR-27a in supernatants and cells was detected. Fifty-two newly diagnosed NSCLC patients were recruited. All patients received gemcitabine and cisplatin as first-line chemotherapy and docetaxel as second-line chemotherapy. At the end of every chemotherapy cycle, a therapeutic evaluation was performed according to the RECIST criteria. The expression of serum miR-27a was detected in each cycle. RESULTS: After treatment with 2.5 µg/mL cisplatin, the apoptosis rates of SPC-A1 cells were significantly greater than those of the paired untreated control groups at 12, 24, 48 and 72 h. The expression of miR-27a in supernatants and cells was also consistent with the apoptosis rate and changed a time-dependent manner. The chi-square test showed that an increase in miR-27a after chemotherapy was more common in patients who achieved partial response (PR) than in those who achieved no response (NR) (61.5% vs. 30.8%, P=0.026). Kaplan-Meier survival analysis indicated that patients with decreased miR-27a levels had poorer outcomes than those with increased miR-27a levels (P<0.05). Furthermore, dynamic changes in serum miR-27a with a gradual increasing trend during chemotherapy predicted a good prognosis. CONCLUSIONS: Collectively, our results suggest that miR-27a is involved in the apoptosis of lung cancer cells and that serum miR-27a levels are related to the prognosis of NSCLC patients. The expression levels of miR-27a in the serum may be an independent predictor for the prognosis of NSCLC.