Search

Recent studies have demonstrated that hyperglycemia may result in a poor prognosis following aneurysmal subarachnoid hemorrhage (aSAH). However, the association between hyperglycemia and the clinical outcome of aSAH has not been clearly established thus far. Therefore, we performed a systematic review and meta-analysis to investigate the association between hyperglycemia and the development of aSAH. We completed a literature search in four databases (PubMed, EMBASE, Cochrane Library, and Web of Science) up to November 1, 2021, including all eligible studies investigating the prognostic value of hyperglycemia in patients with aSAH. We performed a quality assessment of included studies using the Newcastle-Ottawa Quality Assessment Scale. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association of hyperglycemia in aneurysmal subarachnoid hemorrhage. A total of 35 studies with 11,519 patients were finally included in the meta-analysis. Nineteen studies reported the association between hyperglycemia and poor outcome, 12 studies reported the association between hyperglycemia and all-cause mortality, 7 studies reported the association between hyperglycemia and cerebral vasospasm, and 9 studies reported the association between hyperglycemia and cerebral infarction. The pooled data of these studies suggested that hyperglycemia was significantly associated with poor functional outcomes (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.17-1.42; P 0.00001; I

Objectives Due to its high morbidity, high mortality, and high disability, stroke has been the first cause of death and the major cause of adult disability in China. Natural borneol has been widely utilized in Traditional Chinese Medicine to promote drug absorption. Formononetin is a natural isoflavonoid with potent neuroprotective activity but poor brain delivery. Methods This study aimed to screen the optimum proportion that natural borneol promotes formononetin entry into the brain, evaluate the anti-cerebral ischaemia efficacy of formononetin/natural borneol combination in middle cerebral artery occlusion/reperfusion model rats, and clarify the possible mechanism for natural borneol’s promoting formononetin delivery in the brain. Key findings Our studies exhibited that natural borneol remarkably promoted formononetin entry into the brain when combined with formononetin in a 1 : 1 molar ratio and notably improved neuro-behavioural scores and reduced the infarct of middle cerebral artery occlusion/reperfusion model rats. This study further discovered that the enhanced anti-cerebral ischaemia effect resulted from natural borneol increasing the permeability of the blood-brain barrier to elevate formononetin concentration in the brain rather than the pharmacodynamic synergy or addition between formononetin and natural borneol. Conclusions The study provides a good strategy to screen drug combinations for the treatment of brain disease by combining natural borneol with other drugs.

Objective The most used drug for the treatment of rheumatoid arthritis (RA) remains methotrexate (MTX). Unfortunately, up to 50% of patients do not achieve a clinically adequate outcome. Here we study whether the gut microbiota patterns can aid in the prediction of MTX efficacy for RA. Method To dissect gut microbiome profiles of RA patients (n = 145), 16S rRNA gene sequencing was performed. Dirichlet multinomial mixture (DMM) clustering was used to identify enterotypes at genus level. The relationships between enterotypes and clinical measures (such as lymphocyte subsets and cytokines detected by flow cytometry) were explored. Then, enterotype stability was evaluated by the stratification of the RA patient cohort (n = 66) in Shanghai, China, using the same method. Finally, the enterotype-based gut microbial human index classifier was applied to another independent RA patient cohort (n = 27) to identify the factors associated with MTX clinical response. Results Our analysis revealed that the RA patients always displayed two different dysbiotic microbiota patterns: RA E1 comprised predominantly Prevotella and RA E2 comprised predominantly Bacteroides. Among all of the lymphocyte subsets and cytokines, only the number of CD8+ T cells showed a significant difference between RA E1 and RA E2. These results were validated in the RA patient cohort in Shanghai, China. Significant associations of RA E1 with clinical response to subsequent MTX treatment were confirmed by another independent RA patient cohort. Conclusion Together, the enterotype-based gut microbial human index (EGMI) classifier was useful to precisely and effectively identify enterotypes of individual RA patients, which could effectively evaluate MTX clinical responses.

The Square Kilometre Array (SKA) is the largest radio interferometer under construction in the world. The high accuracy, wide-field and large size imaging significantly challenge the construction of the Science Data Processor (SDP) of SKA. We propose a hybrid imaging method based on improved W-Stacking and snapshots. The w range is reduced by fitting the snapshot $uv$ plane, thus effectively enhancing the performance of the improved W-Stacking algorithm. We present a detailed implementation of WS-Snapshot. With full-scale SKA1-LOW simulations, we present the imaging performance and imaging quality results for different parameter cases. The results show that the WS-Snapshot method enables more efficient distributed processing and significantly reduces the computational time overhead within an acceptable accuracy range, which would be crucial for subsequent SKA science studies., 10 pages, 10 figures, 6 tables, accepted by MNRAS

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are central to the stress response. Chemogenetic activation of PVN CRH neurons decreases LH pulse frequency but the mechanism is unknown. In the present study, optogenetic stimulation of PVN CRH neurons suppressed LH pulse frequency in estradiol (E2)-replaced ovariectomised (OVX) CRH-cre mice and this effect was augmented or attenuated by intra-PVN GABAA or GABAB receptor antagonism respectively. PVN CRH neurons signal to local GABA neurons which may provide a possible indirect mechanism by which PVN CRH neurons suppress LH pulse frequency. Optogenetic stimulation of potential PVN GABAergic projection terminals in the hypothalamic arcuate nucleus (ARC) in OVX E2-replaced Vgat-cre-tdTomato mice via an optic fibre implanted in the ARC suppressed LH pulse frequency. To further determine whether PVN CRH neurons signal through PVN GABA neurons to suppress LH pulsatility, we combined recombinase mice with intersectional vectors to selectively target these neurons. CRH-cre::Vgat-FlpO mice expressing the stimulatory opsin, ChRmine in non-GABAergic CRH neurons alone or in combination with the inhibitory opsin NpHR3.3 in non-CRH expressing GABA neurons in the PVN were used. Optogenetic stimulation of non-GABAergic CRH neurons suppressed pulsatile LH secretion, however LH pulse frequency was not affected when CRH neurons were stimulated and PVN GABA neurons were simultaneously inhibited. Together, these studies demonstrate that suppression of LH pulse frequency in response to PVN CRH neuronal activation is mediated by GABAergic signalling intrinsic to the PVN and may incorporate PVN GABAergic projection to the hypothalamic GnRH pulse generator.

Background The interferon-gamma (IFN-γ) signaling pathway is activated in Systemic lupus erythematosus (SLE). This study aims to assess the causal association between IFN-γ, IFN-γR1, and IFN-γR2 and SLE within a bidirectional Mendelian-randomization design.Methods Genetic instruments of exposure to IFN-γ, IFN-γR1, and IFN-γR2 were derived from the large genome-wide association study (GWAS), including 3,301 sample size. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 7,219 cases and 15,991 controls with European ancestry. Bi-directional two-sample MR was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results.Results The IVW showed IFN-γ had a positive causal association with the risk of SLE [OR 1.24 (95% CI 0.85, 2.26), P = 0.018]. IFN-γR2 was found to have a negative correlation with the onset of SLE [OR 0.85 (95% CI 0.73, 0.99), P = 0.034]. However, no genetic association was detected between IFN-γR1 and SLE [OR 0.97 (95% CI 0.79, 1.19), P = 0.768]. Evidence from bidirectional MR did not support reverse causality. Weighted median regression also showed directionally similar estimates.Conclusion Higher levels of IFN-γ or lower levels of IFN-γR2 are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.

Atmospheric circulations bring moisture from above the ocean to the high mountains of the western Tibet Plateau (TP), thus wind variability is of great importance to the water cycle centered on the western TP. This study therefore examines the leading modes of the wind fields over the western TP. We use the multivariate empirical orthogonal function (MV-EOF) analysis method to detect the dominant wind patterns above the western TP. This method extracts the leading modes of combined meridional and zonal wind variability at 200-hPa in the region of 22° N–50° N, 50° E–92° E. We find the first leading mode of the combined zonal and meridional wind field in the annual mean and in most seasons (spring, summer and autumn) over the western TP shows high similarity to the Western Tibetan Vortex (WTV), a large-scale atmospheric vortex-like pattern recently recognized over the western TP. In winter, the WTV, however, is closer to the second leading mode. We estimate the sensitivity of our results by changing the domain of the MV-EOF analysis region surrounding the western. We find the influence of the WTV is less sensitive to analysis location around the western TP. In short, the WTV generally represents the first leading mode of the wind field in most seasons over the western TP. This study augments our knowledge on wind variability over the western TP.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by disturbed cellular and humoral immune responses. Dysregulations of immune system and immunosuppressive medications predispose SLE patients to infection. This study aims to investigate the alterations and absolute concentrations of lymphocyte subpopulations in SLE patients with different infection and their responses of low-dose IL-2 therapy. A total of 333 patients with SLE without recent infection, 162 patients suffering infection, and age and sex-matched 132 healthy controls (HCs) were recruited. Of them, 54 SLE patients (including 41 non-infected group and 13 infected group) received a 5-day course of low-dose IL-2 administration at a dose of 0.5 million IU per day. Lymphocyte subpopulations were analyzed by flow cytometry. Patients with SLE had lower levels of lymphocyte subpopulations in peripheral blood such as T, B, NK, CD4 + T, CD8+ T, Th1, Th2, Th17, and Treg cells, and the reduction in these cells was more obvious in patients with infection (p p <.01). Low-dose IL-2 effectively expanded T (p p p p p p p

Graves' disease (GD) is one of the most common autoimmune conditions, but the mechanisms underlying the associated induction of autoimmunity are not known. We explored the role of peripheral lymphocyte subpopulations in disease pathogenesis.In total, 32 patients and 40 age- and sex-matched healthy controls were recruited in this study. Peripheral levels of T, B, NK, CD4The absolute numbers of circulating Th17 cells (0.45 ± 1.16, p 0.05) between GD patients and healthy controls were not significantly different. However, the percentage of Th17 cells was significantly increased (0.25 ± 0.11, p 0.05). The absolute numbers and percentages of circulating Tregs in GD patients were significantly decreased compared with those in healthy participants (11.61 ± 2.75, p 0.05). There was a significant difference in Treg absolute numbers between the untreated and drug-treated groups. Furthermore, we found that the Treg percentage in untreated patients (mean=4.78) was not significantly different from that in the drug-treated group (mean=4.81). In addition, circulating Treg absolute numbers in GD patients with exophthalmos were significantly lower than those in GD patients without exophthalmos (9.96 ± 4.16, p 0.05). A similar trend was observed in GD patients with weight loss (11.97 ± 3.28, p 0.05).GD pathogenesis was associated with a lower Treg population and an increased Th17/Treg ratio (T helper cell 17/ regulatory T cells). Th17 cells in this study were not related to the disease. Furthermore, anti-thyroid drug therapy improved immune-mediated system disorders. Finally, we found lower absolute numbers of circulating Tregs in GD patients with certain positive signs, such as exophthalmos and/or weight loss. Thus, immune changes are correlated with partial clinical manifestations.

SARS-CoV-2 has evolved into a panel of variants of concern (VOCs) and constituted a sustained threat to global health. The wildtype (WT) SARS-CoV-2 isolates fail to infect mice, while the Beta variant, one of the VOCs, has acquired the capability to infect standard laboratory mice, raising a spreading risk of SARS-CoV-2 from humans to mice. However, the infectivity and pathogenicity of other VOCs in mice remain not fully understood. In this study, we systematically investigated the infectivity and pathogenicity of three VOCs, Alpha, Beta, and Delta, in mice in comparison with two well-understood SARS-CoV-2 mouse-adapted strains, MASCp6 and MASCp36, sharing key mutations in the receptor-binding domain (RBD) with Alpha or Beta, respectively. Our results showed that the Beta variant had the strongest infectivity and pathogenicity among the three VOCs, while the Delta variant only caused limited replication and mild pathogenic changes in the mouse lung, which is much weaker than what the Alpha variant did. Meanwhile, Alpha showed comparable infectivity in lungs in comparison with MASCp6, and Beta only showed slightly lower infectivity in lungs when compared with MASCp36. These results indicated that all three VOCs have acquired the capability to infect mice, highlighting the ongoing spillover risk of SARS-CoV-2 from humans to mice during the continued evolution of SARS-CoV-2, and that the key amino acid mutations in the RBD of mouse-adapted strains may be referenced as an early-warning indicator for predicting the spillover risk of newly emerging SARS-CoV-2 variants.

The development of construction requires large amounts of resources which resulted in scarcity in good quality natural resources. Cement, being the main and widely used binder in the construction industry, are sourced from non-renewable source which causes negative impact to the environment. This study was conducted to evaluate the effect of SS on the fresh and hardened properties of mortar under conditions of different replacement ratio (2.5% and 12.5%) and water to cement ratio (w/c) (0.4, 0.45, 0.5). Flow table test, compressive strength test, flexural test and water absorption test have been conducted in this study. Results showed that flow table value of fresh mortar increased with the increase of w/c for both SS replacement ratio. Fresh property of mortar with lower SS replacement ratio was more sensitive to the variation of w/c. The increased w/c ratio has negative effect on the compressive strength and flexural strength of mortar specimens. Water absorption capacity of SS mortar increases with the increasing on w/c for both SS replacement ratio and the mortar specimens with higher SS replacement ratio has higher water absorption capacity at the same w/c level.

The coupling test of marine atmospheric environment and tensile-compressive fatigue load for 2A12 aluminum alloy was carried out in outdoor environment of Hainan station by coupling test equipment of mechanical load. The coupling effect of marine atmospheric environment corrosion and tensile-compressive fatigue load on the environmental damage behavior of 2A12 aluminum alloy was discussed from the aspects of corrosion morphology, tensile properties and fracture morphology. The results show that the corrosion characteristics of 2A12 aluminum alloy in coupling test and static exposure test are consistent. The corrosion depths of the static exposure test for 6 months and the coupling test for 35 days are 71 μm and 121 μm, respectively. The results of tensile properties show that the decrease rate of tensile properties of 2A12 aluminum alloy are accelerated by the coupling effect. And the accelerated ratio of the coupling test was more than 10 times that of the static exposure test. The fracture morphology shows that the coupling fracture crack of 2A12 aluminum alloy starts from the corrosion surface, and the crack source and propagation zone are quasi-cleavage fatigue crack propagation characteristics. The coupling test results are closer to the actual situation of equipment, which has important reference value for the design and material selection of bearing structure.

Accurate in situ analysis of beryllium (Be) is still a technical bottleneck in the fields of geoscience and materials science.

Supplementary Figure 1 from Visualization of Hypoxia in Microscopic Tumors by Immunofluorescent Microscopy

The suspected link of Zika virus (ZIKV) to birth defects led the World Health Organization to declare ZIKV a Public Health Emergency of International Concern. ZIKV has been identified to have two dominant phylogenetic lineages, African and Asian.

Supplementary Figure 2 from Visualization of Hypoxia in Microscopic Tumors by Immunofluorescent Microscopy

Supplementary Legends 1-2 from Visualization of Hypoxia in Microscopic Tumors by Immunofluorescent Microscopy

Tumor hypoxia is commonly observed in primary solid malignancies but the hypoxic status of subclinical micrometastatic disease is largely unknown. The distribution of hypoxia in microscopic tumors was studied in animal models of disseminated peritoneal disease and intradermal (i.d.) growing tumors. Tumors derived from human colorectal adenocarcinoma cell lines HT29 and HCT-8 ranged in size from a few hundred microns to several millimeters in diameter. Hypoxia was detected by immunofluorescent visualization of pimonidazole and the hypoxia-regulated protein carbonic anhydrase 9. Tumor blood perfusion, cellular proliferation, and vascularity were visualized using Hoechst 33342, bromodeoxyuridine, and CD31 staining, respectively. In general, tumors of

Chilling injury owing to low temperatures severely affects the growth and development of maize (Zea mays.L) seedlings during the early and late spring seasons. The existing maize germplasm is deficient in the resources required to improve maize’s ability to tolerate cold injury. Therefore, it is crucial to introduce and identify excellent gene/QTLs that confer cold tolerance to maize for sustainable crop production. Wild relatives of maize, such as Z. perennis and Tripsacum dactyloides, are strongly tolerant to cold and can be used to improve the cold tolerance of maize. In a previous study, a genetic bridge among maize that utilized Z. perennis and T. dactyloides was created and used to obtain a highly cold-tolerant maize introgression line (MIL)-IB030 by backcross breeding. In this study, two candidate genes that control relative electrical conductivity were located on MIL-IB030 by forward genetics combined with a weighted gene co-expression network analysis. The results of the phenotypic, genotypic, gene expression, and functional verification suggest that two candidate genes positively regulate cold tolerance in MIL-IB030 and could be used to improve the cold tolerance of cultivated maize. This study provides a workable route to introduce and mine excellent genes/QTLs to improve the cold tolerance of maize and also lays a theoretical and practical foundation to improve cultivated maize against low-temperature stress.

HLA-B*07:248 has one nucleotide change from HLA-B*07:18:01 where Tyrosine (Y) is changed to Serine (S).

The aim of the study was to construct and validate 18F-fluorodeoxyglucose (18F-FDG) PET-based radiomics nomogram and use it to predict N2-3b lymph node metastasis in Chinese patients with gastric cancer (GC).A total of 127 patients with pathologically confirmed GC who underwent preoperative 18F-FDG PET/CT imaging between January 2014 and September 2020 were enrolled as subjects in this study. We use the LIFEx software to extract PET radiomic features. A radiomics signature (Rad-score) was developed with the least absolute shrinkage and selection operator algorithm. Then a prediction model, which incorporated the Rad-score and independent clinical risk factors, was constructed and presented with a radiomics nomogram. Receiver operating characteristic (ROC) analysis was used to assess the performance of Rad-score and the nomogram. Finally, decision curve analysis (DCA) was applied to evaluate the clinical usefulness of the nomogram.The PET Rad-score, which includes four selected features, was significantly related to pN2-3b (all P0.05). The prediction model, which comprised the Rad-score and carcinoembryonic antigen (CEA) level, showed good calibration and discrimination [area under the ROC curve: 0.81(95% confidence interval: 0.74-0.89), P0.001)]. The DCA also indicated that the prediction model was clinically useful.This study presents a radiomics nomogram consisting of a radiomics signature based on PET images and CEA level that can be conveniently used for personalized prediction of high-risk N2-3b metastasis in Chinese GC patients.

Sugarcane is an established industrial crop providing sugar, ethanol and biomass‐derived electricity worldwide. Cane sugar content is an important breeding target, but its improvement remains very slow in many breeding programmes. Biotechnology strategies to improve sucrose accumulation made little progress at the crop level, mainly due to the limited understanding of its regulation. miRNAs regulate many metabolic processes in plants. However, their roles and target genes associated with sugarcane sucrose accumulation remain unknown. Here, we conducted high‐throughput sequencing of transcriptome, small RNAs and degradome of leaves and stem of two early‐maturing sugarcane genotypes with contrasting sucrose content from the early to late stages of sucrose accumulation stages, which provided more insights into miRNA‐associated gene regulation during sucrose accumulation. The stem sucrose content in both genotypes increased steadily with time during sucrose accumulation stage. Transcriptome analysis identified 18,722 differentially expressed genes (DEGs) between both genotypes during sucrose accumulation. The major DEGs identified were involved in starch and sucrose metabolism, and photosynthesis. miRNA sequencing identified 563 known and 281 novel miRNAs from both genotypes during sucrose accumulation. Of these, 311 miRNAs were differentially expressed. A combined transcriptome and miRNA data analysis revealed differentially expressed miRNA‐target mRNA pairs related to sugar metabolism, of which 46 targets were transcription factors (TFs). miR172, miR164, miR396 and miR169 appear to regulate AP2/ERF, NAC, GRF and bZIP TF members associated with sugar metabolism. This is the first report of sugarcane miRNAs associated with sugar accumulation.

First introduced in 1976, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has become an indispensable tool for diagnosis and prognostic evaluation of tumors, heart disease, as well as other conditions, including inflammation and infection. Because 18F-FDG can accurately reflect the glucose metabolism level of organs and tissues, it is known as a "century molecule" and is currently the main agent for PET imaging. The degree of 18F-FDG uptake by cells is related to both the rate of glucose metabolism and glucose transporter expression. These, in turn, are strongly influenced by hypoxia, in which cells meet their energy needs through glycolysis, and 18F-FDG uptake increased due to hypoxia. 18F-FDG uptake is a complex process, and hypoxia may be one of the fundamental driving forces. The correct interpretation of 18F-FDG uptake in PET imaging can help clinics make treatment decisions more accurately and effectively. In this article, we review the application of 18F-FDG PET in tumors, myocardium, and inflammation. We discuss the relationship between 18F-FDG uptake and hypoxia, the possible mechanism of 18F-FDG uptake caused by hypoxia, and the associated clinical implications.

The glycan loop of Zika virus (ZIKV) envelope protein (E) contains the glycosylation site and has been well documented to be important for viral pathogenesis and transmission. In the present study, we report that deletions in the E glycan loop, which were recorded in African ZIKV strains previously, have re-emerged in their contemporary Asian lineages. Here, we generated recombinant ZIKV containing specific deletions in the E glycan loop by reverse genetics. Extensive in vitro and in vivo characterization of these deletion mutants demonstrated an attenuated phenotype in an adult A129 mouse model and reduced oral infections in mosquitoes. Surprisingly, these glycan loop deletion mutants exhibited an enhanced neurovirulence phenotype, and resulted in a more severe microcephalic brain in neonatal mouse models. Crystal structures of the ZIKV E protein and a deletion mutant at 2.5 and 2.6 Å, respectively, revealed that deletion of the glycan loop induces encephalitic flavivirus-like conformational alterations, including the appearance of perforations on the surface and a clear change in the topology of the loops. Overall, our results demonstrate that the E glycan loop deletions represent neonatal mouse neurovirulence markers of ZIKV. IMPORTANCE Zika virus (ZIKV) has been identified as a cause of microcephaly and acquired evolutionary mutations since its discovery. Previously deletions in the E glycan loop were recorded in African ZIKV strains, which have re-emerged in the contemporary Asian lineages recently. The glycan loop deletion mutants are not glycosylated, which are attenuated in adult A129 mouse model and reduced oral infections in mosquitoes. More importantly, the glycan loop deletion mutants induce an encephalitic flavivirus-like conformational alteration in the E homodimer, resulting in a significant enhancement of neonatal mouse neurovirulence. This study underscores the critical role of glycan loop deletion mutants in ZIKV pathogenesis, highlighting a need for global virological surveillance for such ZIKV variants.

Psychological stress is linked to infertility by suppressing the hypothalamic GnRH pulse generator. The posterodorsal subnucleus of the medial amygdala (MePD) is an upstream regulator of GnRH pulse generator activity and displays increased neuronal activation during psychological stress. The MePD is primarily a GABAergic nucleus with a strong GABAergic projection to hypothalamic reproductive centers; however, their functional significance has not been determined. We hypothesize that MePD GABAergic signalling mediates psychological stress–induced suppression of pulsatile LH secretion. We selectively inhibited MePD GABA neurons during psychological stress in ovariectomized (OVX) Vgat-cre-tdTomato mice to determine the effect on stress-induced suppression of pulsatile LH secretion. MePD GABA neurons were virally infected with inhibitory hM4DGi-designer receptor exclusively activated by designer drugs (DREADDs) to selectively inhibit MePD GABA neurons. Furthermore, we optogenetically stimulated potential MePD GABAergic projection terminals in the hypothalamic arcuate nucleus (ARC) and determined the effect on pulsatile LH secretion. MePD GABA neurons in OVX female Vgat-cre-tdTomato mice were virally infected to express channelrhodopsin-2 and MePD GABAergic terminals in the ARC were selectively stimulated by blue light via an optic fiber implanted in the ARC. DREADD-mediated inhibition of MePD GABA neurons blocked predator odor and restraint stress-induced suppression of LH pulse frequency. Furthermore, sustained optogenetic stimulation at 10 and 20 Hz of MePD GABAergic terminals in the ARC suppressed pulsatile LH secretion. These results show for the first time that GABAergic signalling in the MePD mediates psychological stress–induced suppression of pulsatile LH secretion and suggest a functionally significant MePD GABAergic projection to the hypothalamic GnRH pulse generator.

Kisspeptin neurons are mainly located in the arcuate (Kiss1ARC, vis-à-vis the GnRH pulse generator) and anteroventral periventricular nucleus (Kiss1AVPV, vis-à-vis the GnRH surge generator). Kiss1ARC send fibre projections that connect with Kiss1AVPV somata. However, studies focused on the role of Kiss1ARC neurons in the LH surge are limited, and the role of Kiss1ARC projections to AVPV (Kiss1ARC→AVPV) in the preovulatory LH surge is still unknown. To investigate its function, this study used optogenetics to selectively stimulate Kiss1ARC→AVPV and measured changes in circulating LH levels. Kiss1ARC in Kiss-Cre-tdTomato mice were virally infected to express channelrhodopsin-2 proteins, and optical stimulation was applied selectively via a fibre optic cannula in the AVPV. Sustained 20 Hz optical stimulation of Kiss1ARC→AVPV from 15:30 to 16:30 h on proestrus effectively induced an immediate increase in LH reaching peak surge-like levels of around 8 ng/ml within 10 min, followed by a gradual decline to baseline over about 40 min. Stimulation at 10 Hz resulted in a non-significant increase in LH levels and 5 Hz stimulation had no effect in proestrous animals. The 20 Hz stimulation induced significantly higher circulating LH levels on proestrus compared with diestrus or estrus, which suggested that the effect of terminal stimulation is modulated by the sex steroid milieu. Additionally, intra-AVPV infusion of glutamate antagonists, AP5+CNQX, completely blocked the increase on LH levels induced by Kiss1ARC→AVPV terminal photostimulation in proestrous animals. These results demonstrate for the first time that optical stimulation of Kiss1ARC→AVPV induces an LH surge-like secretion via glutamatergic mechanisms. In conclusion, Kiss1ARC may participate in LH surge generation by glutamate release from terminal projections in the AVPV.

Objectives To leverage the high clinical heterogeneity of systemic lupus erythematosus (SLE), we developed and validated a new stratification scheme by integrating genome-scale transcriptomic profiles to identify patient subtypes sharing similar transcriptomic markers and drug targets. Methods A normalized compendium of transcription profiles was created from peripheral blood mononuclear cells (PBMCs) of 1046 SLE patients and 86 healthy controls (HCs), covering an intersection of 13 689 genes from six microarray datasets. Upregulated differentially expressed genes were subjected to functional and network analysis in which samples were grouped using unsupervised clustering to identify patient subtypes. Then, clustering stability was evaluated by the stratification of six integrated RNA-sequencing datasets using the same method. Finally, the Xgboost classifier was applied to the independent datasets to identify factors associated with treatment outcomes. Results Based on 278 upregulated DEGs of the transcript profiles, SLE patients were classified into three subtypes (subtype A–C) each with distinct molecular and cellular signatures. Neutrophil activation-related pathways were markedly activated in subtype A (named NE-driving), whereas lymphocyte and IFN-related pathways were more enriched in subtype B (IFN-driving). As the most severe subtype, subtype C [NE-IFN-dual-driving (Dual-driving)] shared functional mechanisms with both NE-driving and IFN-driving, which was closely associated with clinical features and could be used to predict the responses of treatment. Conclusion We developed the largest cohesive SLE transcriptomic compendium for deep stratification using the most comprehensive microarray and RNA sequencing datasets to date. This result could guide future design of molecular diagnosis and the development of stratified therapy for SLE patients.

Kisspeptin neurons in the arcuate nucleus of the hypothalamus generate gonadotrophin-releasing hormone (GnRH) pulses, and act as critical initiators of functional gonadotrophin secretion and reproductive competency. However, kisspeptin in other brain regions, most notably the posterodorsal subnucleus of the medial amygdala (MePD), plays a significant modulatory role over the hypothalamic kisspeptin population; our recent studies using optogenetics have shown that low-frequency light stimulation of MePD kisspeptin results in increased luteinsing hormone pulse frequency. Nonetheless, the neurochemical pathways that underpin this regulatory function remain unknown. To study this, we have utilised an optofluid technology, precisely combining optogenetic stimulation with intra-nuclear pharmacological receptor antagonism, to investigate the neurotransmission involved in this circuitry. We have shown experimentally and verified using a mathematical model that functional neurotransmission of both GABA and glutamate is a requirement for effective modulation of the GnRH pulse generator by amygdala kisspeptin neurons.

To analyze the application characteristics of acupuncture and moxibustion in clinical treatment of Meniere's disease by using complex network technology, so as to provide evidence for selecting acupoints, needling and moxibustion methods and treatment ideas.Articles both in English and Chinese published from the inception of databases of CNKI, Wanfang VIP, Chinese biomedical literature database (SinoMed), PubMed, Embase, EBSCO (Academic Search Pre-mier), Web of Science and Ovid to April of 2021 were retrieved by using key words "acupuncture" or "moxibustion" or "acupuncture and moxibustion" and "Meniere disease" or "Meniere's syndrome" or "Ménières vertigo" or "otogenic vertigo" or "auditory vertigo", followed by screening the literature according to the inclusion and exclusion criteria and establishing a database of clinical li-terature about acupuncture treatment of Meniere's Disease with software Epidata 3.1. Then, the descriptive analysis was conducted first, followed by association rule analysis using SPSS Modeler 18.0, and complex network analysis using Gephi 0.9.2 software.A total of 232 articles were included, containing 152 acupoints [97 body acupoints as Baihui (GV20), Fengchi (GB20), Neiguan (PC6), etc., 28 otopoints as Ershenmen (MA-TF1), Shen (MA-SC), etc., 20 scalp points as Yunting Area, 7 extra-points as Sishencong (EX-HN1), Taiyang (EX-HN5), etc.] which were used to be a total frequency of 1 569. Descriptive analysis showed that the main meridians were the Governor Vessel, Stomach Meridian of Foot Yangming, Trienergizer Meridian of Hand Shaoyang, and Gallbladder Meridian of Foot Shaoyang. Acupuncture was the most commonly used therapy for Meniere's disease. The association analysis showed that the most relevant combination of acupoints was GV20 and GB20, GV20 and PC6, reflecting the principles of local acupoint selection and combination of local and distant acupoints. Finally, "K-core Analytic Hierarchy Process" and "Community Analysis" revealed that 3 core acupoint groups were most frequently used in clinical treatment of Meniere's disease, including 1) auricular acupoints, as MA-TF1, MA-SC, Neier(MA-L), Zhen(MA-AT) and Pizhixia(MA-AT1), 2) acupoints of the 14 meridians and extra-points, as Tinggong(SI19), Yifeng(TE17), GB20, 3) acupoints of the Shaoyang meri-dians of hand and foot, as Shuaigu (GB8), Tinghui (GB2), Zhongzhu (TE3), Ermen (TE21), etc.The principle of acupoint selection is mainly based on the combination of acupoints along the meridians and local areas, while paying attention to the coordination among the auricular points, scalp acupoints and extra-points, which may provide a reference for the clinical treatment and scientific research on acupuncture treatment of Meniere's disease.