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Background: Anti-PD-1 antibody combined with antiangiogenic drugs have demonstrated antitumor activity in advanced triple negative breast cancer (TNBC). Anlotinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has synergistic effect with anti-PD-1 antibody. Preclinical studies showed that metronomic chemotherapy inhibited angiogenesis and enhanced immunotherapy efficacy in TNBC via modulation of tumor immune microenvironment. We hereby conducted a single-arm, multicenter, phase II trial to investigate the efficacy and safety of sintilimab (anti-PD-1 antibody) in combination with anlotinib plus metronomic chemotherapy as a potential novel therapeutic strategy in advanced TNBC and explore potential biomarkers. Methods: Forty-three cases were planning to be included in this trial. The eligible patients who had received no more than two lines of chemotherapy for metastatic disease were enrolled and received sintilimab (200 mg iv q3w) in combination with anlotinib (12 mg po d1-14 q3w) plus capecitabine (500 mg po, tid) or vinorelbine (40 mg po, tiw) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR) and secondary endpoints are disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Blood samples collected at different time points of the baseline, first and second cycle post-treatment, and disease progression were used for next-generation sequencing of ctDNA containing 654 tumor-related genes. Results: As of July 2022, a total of 32 patients were enrolled, and 29 patients were evaluable for efficacy. 2 patients (6.9%) achieved complete response (CR). 6 patients (20.7%) achieved partial response (PR). The ORR is 27.6% (8/29) and DCR is 79.3% (23/29). The median PFS was not reached. The most common grade 1 or 2 adverse events (AEs) include elevated thyroid stimulating hormone (37.0%, 10/27), hand-foot syndrome (18.5%, 5/27), elevated aspartate aminotransferase (14.8%, 4/27), elevated bilirubin (11.1%, 3/27) and hypertension (11.1%, 3/27). Grade 3 AEs include elevated bilirubin (3.7%, 1/27) and hypertension (3.7%, 1/27). No grade 4 or 5 AEs occurred. By analyzing ctDNA mutations of blood samples in 10 patients at baseline, we found that genes with high mutation frequency were HLA-DRB5 (8/10, 80%), TP53 (7/10, 70%), HLA-DRB1 (5/10, 50%) and PIK3CA (4/10, 40%). Among these 10 patients, 2, 3 and 5 patients achieved PR, SD and PD, respectively. The number of gene mutations in patients with PD was higher than that in patients with PR or SD at baseline. This indicate that mutations in ctDNA may be associated with poor efficacy in advanced TNBC. But this still needs further verification. Dynamic analysis of gene mutations at different time points showed that the amplification of HLA-DRB5 or the elimination of KMT2D, RELN and TP53 occurred in patients with PR and SD, but not in patients with PD. Conclusions: Sintilimab in combination with anlotinib plus metronomic chemotherapy has shown favorable efficacy and acceptable safety profile in patients with advanced TNBC. The clinical significance of ctDNA dynamic monitoring needs further validation. Clinical trial information: ChiCTR2100044725 Citation Format: Huihui Li, Qiaorui Tan, Shujuan Sun, Dongdong Zhou, Bo Yu, Mu Su, Baojiang Li, Shu Fang, Ling Qiang, Guohua Ren, Bing Bu, Sha Yin, Xiaochu Man, Pengfei Qiu, Xinzhao Wang, Chao Li, Fangli Cao, Qian Shao, Dali Han, Lihua Song, Bingjie Fan, Baoxuan Zhang, Liang Xu, Xianguang Zhao, Yuqian Liao, Xuemei Xie, Lanping Liu. Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-05-02.

Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Tau pathology, including aberrant tau hyperphosphorylation, aggregation, and mislocalization, is implicated in many neurodegenerative disorders, including Alzheimer’s disease (AD), which is the most prevalent dementia among the elderly. A better understanding of the molecular mechanisms underlying tau pathology should help advance therapies for neurodegenerative diseases. Perturbations in cyclic adenosine monophosphate (cAMP)-dependent signaling play an important role in the pathophysiology of numerous neurological diseases. EPAC2 is an intracellular cAMP receptor whose expression is downregulated in AD. However, the involvement and role of EPAC2 in tau pathology remain unclear. In this study, we report for the 1st time that EPAC2 is downregulated in the hippocampus of Tg2576 mice, a widely used transgenic mouse model of familial AD. Furthermore, genetic deletion of EPAC2 resulted in abnormal hyperphosphorylation at multiple sites on tau. Aberrant tau aggregation and abnormal neuronal morphology were also detected in these EPAC2−/− mice. Administration of inhibitors of CDK5 or calpain effectively rescued the tau pathology in EPAC2−/− mice. This suggests that the activation of CDK5 by calpain plays an important role in the development of tau pathology in these EPAC2−/− mice. Collectively, our findings demonstrate a direct link between EPAC2 and tau pathology, and suggest that the EPAC2 and calpain/CDK5 signaling pathways may have potential as therapeutic targets for AD.

Background: Chemotherapy is the main treatment for metastatic triple-negative breast cancer (mTNBC). However, mTNBC patients (pts) is often associated with chemotherapy resistance and poor prognosis. Biomarkers that can effectively predict the efficacy of chemotherapy for mTNBC are currently lacking. Detection of circulating tumor DNA (ctDNA) in plasma by liquid biopsy is a minimally invasive and highly sensitive method, which has been wildly used in the clinic and plays an important role in tumor diagnosis, efficacy evaluation, residual and recurrent tumor detection, etc. But yet, the clinical application of ctDNA in mTNBC remains relatively scarce. Here, for the first time, we set to explore the possibility of ctDNA as a biomarker for predicting chemotherapy response and prognosis in mTNBC.Methods: From May 2018 to October 2020, 38 mTNBC pts who received less than 3rd line standard chemotherapy were prospectively included. Tumor tissues were obtained prior chemotherapy, and plasma for ctDNA were collected at baseline, a day before the 3rd cycle chemotherapy and at disease progression. Next-generation sequencing (NGS,457 genes panel) was performed on all samples for mutation detection. And the ctDNA fraction, maximum variant allele frequency (max-VAF), tumor mutation burden (TMB) and other variate were calculated, further combined with clinical data, chemotherapy response and survival of pts for statistical analysis.Results: Finally, 109 blood samples and 13 tissue samples were detected by NGS. A total of 214 mutation genes and 397 mutation sites were detected. The mutation types included missense mutation, nonsense mutation, non-/frameshift insertion, non-/frameshift deletion, non-/frameshift substitution, splicing mutation and so on. The genes with the top 5 mutation frequencies were TP53 (32/38, 84.21%), PIK3CA (14/38, 36.84%), KMT2C (8/38, 21.05%), PTEN (6/38, 15.79%), NOTCH4 (6/38, 15.79%), respectively. The same variants were identified in 12 of 13 pts in paired plasma and tissue, with a concordance rate of 92.3%. The mutation rate in plasma ctDNA was significantly lower than that in tissues (15.26% ± 12.52% vs. 28.88 ± 16.54%, P < 0.001) but was still positively correlated with that in tissues (r = 0.306, P = 0.049). The median progression-free survival (mPFS) of pts with GNAS mutation was shorter than GNAS wild-type pts (3.000 vs. 6.100 months, P = 0.014). The area under curve of ctDNA fraction (0.812, P = 0.043), max-VAF (0.817, P = 0.043) and TMB (plasma) (0.759, P = 0.053) in predicting chemotherapy resistance or disease progression were larger than CEA (0.491, P = 0.888), CA125 (0.574, P = 0.243) and CA153 (0.482, P = 0.778). CtDNA fraction (r = 0.482, P < 0.001), max-VAF (r = 0.489, P < 0.001), TMB (plasma). (r = 0.419, P < 0.001) were correlated with chemotherapy response measured by RECIST v1.1 in CT imaging, while CEA (r = -0.024, P = 0.808), CA125 (r = 0.111, P = 0.266) and CA153 (r = -0.017, P = 0.865) had no correlation with chemotherapy response. The mPFS of pts with ctDNA fraction ≤ 50% or max-VAF ≤ 0.4 at baseline was significantly longer than that of pts with ctDNA fraction > 50% (6.100 vs. 3.430 months, P = 0.006) or max-VAF > 0.4 (6.100 vs. 3.430 months, P = 0.047). The elimination of mutations or the decrease of mutation rate in plasma ctDNA after 2 cycles of chemotherapy showed better chemotherapy response, while recurrence of mutations, increase of mutation rate and emergence of new mutations showed chemotherapy resistance.Conclusions: Mutations in tumor tissues and plasma ctDNA of mTNBC pts detected by NGS have high consistency. And compared with CT imaging and traditional tumor markers, dynamic monitoring ctDNA can more aptly reflect the change of whole-body tumor burden, better predict the chemotherapy response and prognosis in mTNBC. Citation Format: Huihui Li, Yajing Chi, Sha Yin, Bo Yu, Mu Su, Baoxuan Zhang, Ling Qiang, Guohua Ren, Lihua Song, Bing Bu, Shu Fang, Mao Shang, Qiaorui Tan, Xiaochu Man. Dynamic monitoring of circulating tumor DNA can predict chemotherapy response and prognosis in metastatic triple-negative breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-27.

Oxytocin (OXT) is a nine amino acid neuropeptide hormone that has become one of the most intensively studied molecules in the past few decades. The vast majority of OXT is synthesized in the periventricular nucleus and supraoptic nucleus of the hypothalamus, and a few are synthesized in some peripheral organs (such as the uterus, ovaries, adrenal glands, thymus, pancreas, etc.) OXT modulates a series of physiological processes, including lactation, parturition, as well as some social behaviors. In addition, more and more attention has recently been focused on the analgesic effects of oxytocin. It has been reported that OXT can relieve tension and pain without other adverse effects. However, the critical role and detailed mechanism of OXT in analgesia remain unclear. Here, this review aims to summarize the mechanism of OXT in analgesia and some ideas about the mechanism.

For L L = ∗ → ( , , ) a complete residuated lattice, a type of L -fuzzy covering rough sets was defined by Li [8] in 2017. In this paper, a further study on rough sets was given. Precisely, a single axiomatic characterization of the L -fuzzy covering rough sets was presented, and the relationships between the -fuzzy covering rough sets and L -fuzzy relation rough sets were established.

We reported an experimental and theoretical study on the promotion role of F doping in the improved catalytic performance of fluorinated graphene(F-GO) for ammonium perchlorate (AP) pyrolysis. F-GO was prepared by using graphite oxide (GO) as carbon sources and CF3COOH as fluorinating agent. Compared with other samples, the F-GO-180 with the highest F doping amounts, more C-F semi-ionic and C-F covalent bond amounts exhibit superior catalytic performance, as 10 wt% of catalyst added in AP, the exothermic peak temperature proceeded in just one step was even lower than the HTD peak temperature for pure AP and the released apparent specific heat of the thermal decomposition of AP catalyzed by F-GO-180 is 4261.2 J/g, which is almost sevenfold of that of pure AP (603.5 J/g). The doping of F atoms in graphene increased surface defects and the content of C-F semi-ionic and C-F covalent bond amounts of F-GO, which provided more active sites during the thermal decomposition of AP. The molecular simulation calculation results further confirmed that the F doping could react with the defect structure of graphene to form more C-F semi-ionic and C-F covalent bond, which could act as catalytic active sites and facilitate the electron transfer ability of the graphene to promote the formation of free radicals in the reaction.

Effective prediction of wastewater treatment is beneficial for precise control of wastewater treatment processes. The nonlinearity of pollutant indicators such as chemical oxygen demand (COD) and total phosphorus (TP) makes the model difficult to fit and has low prediction accuracy. The classical deep learning methods have been shown to perform nonlinear modeling. However, there are enormous numerical differences between multi-dimensional data in the prediction problem of wastewater treatment, such as COD above 3000 mg/L and TP around 30 mg/L. It will make current normalization methods challenging to handle effectively, leading to the training failing to converge and the gradient disappearing or exploding. This paper proposes a multi-factor prediction model based on deep learning. The model consists of a combined normalization layer and a codec. The combined normalization layer combines the advantages of three normalization calculation methods: z-score, Interval, and Max, which can realize the adaptive processing of multi-factor data, fully retain the characteristics of the data, and finally cooperate with the codec to learn the data characteristics and output the prediction results. Experiments show that the proposed model can overcome data differences and complex nonlinearity in predicting industrial wastewater pollutant indicators and achieve better prediction accuracy than classical models.

Summary Central nervous system injury and neurodegenerative diseases cause irreversible loss of neurons. Overexpression of exogenous specific transcription factors can reprogram somatic cells into functional neurons for regeneration and functional reconstruction. However, these practices are potentially problematic due to the integration of vectors into the host genome. Here, we showed that the activation of endogenous genes Ngn2 and Isl1 by CRISPRa enabled reprogramming of mouse spinal astrocytes and embryonic fibroblasts to motor neurons. These induced neurons showed motor neuronal morphology and exhibited electrophysiological activities. Furthermore, astrocytes in the spinal cord of the adult mouse can be converted into motor neurons by this approach with high efficiency. These results demonstrate that the activation of endogenous genes is sufficient to induce astrocytes into functional motor neurons in vitro and in vivo. This direct neuronal reprogramming approach may provide a novel potential therapeutic strategy for treating neurodegenerative diseases and spinal cord injury., Graphical abstract, Highlights • Activation of Ngn2 and Isl1 by CRISPRa in astrocytes induced motor neurons in culture • CRISPRa-AAV-injected mice showed induced motor neurons in the spinal cord • Converted motor neurons exhibited correct identities and axonal projection • Neurons cannot be induced in the spinal cord white matter, In the current study, Bin Zhang and colleagues use a CRISPRa system to activate two transcriptional factors in astrocytes and convert these cells into motor neurons in vitro and in vivo. The converted neurons can function as endogenous motor neurons, thus providing a novel approach to the repair of injured spinal cord and establishment of a motor neuron-related disease model.

This study was to probe the role of penehyclidine hydrochloride (PHC) mediating the impact of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signalling pathway on myocardial ischaemia-reperfusion injury (MI/RI) in rats through miR-199a-3p. The rat MI/RI model was established through ligating left anterior descending (LAD) coronary artery. PHC was injected preoperatively into the model rats, and injected with miR-199a-3p lentiviral vector or TLR4 antagonist (TAK-242). Next, cardiac function of rats was examined by echocardiography, and rat serum indicators, oxidative stress levels and inflammatory factors were detected. HE staining was applied to detect pathological tissue structure, TUNEL staining to detect apoptosis rate, qRCR and western blot to detect miR-199a-3p and TLR4/MyD88/NF-κB expressions in rat myocardial tissues. Dual luciferase reporter experiment was conducted to confirm the relationship between miR-199a-3p and TLR4. In conclusion, PHC suppresses TLR4/MyD88/NF-κB signalling pathway through miR-199a-3p, thereby improving MI/RI in rats.

Employees' emotions have an important effect on their job performance, thus leaders can influence subordinates' emotions through emotional contagion and emotional appeal and ultimately affect their job performance. Based on the affective events theory, this study examines the impact of emotional leadership on the subordinates' job performance, the mediating role of subordinates' positive emotions, and the moderating role of susceptibility to positive emotion. Hierarchical regression analysis of 362 valid questionnaires showed that: (1) emotional leadership has a significant positive effect on subordinates' job performance; (2) subordinates' positive emotion partially mediated the relationship between emotional leadership and subordinates' job performance; (3) subordinates' susceptibility to positive emotion positively moderated the relationship between emotional leadership and positive emotions, i.e., the higher the subordinates' susceptibility to positive emotion, the greater the effect of emotional leadership on their positive emotions. This study validates affective events theory, deepens the understanding of the influence mechanism and boundary conditions of emotional leadership on subordinates' job performance, and provides some references for employee performance management.

Current Siamese-based trackers mainly formulate the visual tracking into two independent subtasks, including classification and localization. They learn the classification subnetwork by processing each sample separately and neglect the relationship among positive and negative samples. Moreover, such tracking paradigm takes only the classification confidence of proposals for the final prediction, which may yield the misalignment between classification and localization. To resolve these issues, this paper proposes a ranking-based optimization algorithm to explore the relationship among different proposals. To this end, we introduce two ranking losses, including the classification one and the IoU-guided one, as optimization constraints. The classification ranking loss can ensure that positive samples rank higher than hard negative ones, i.e., distractors, so that the trackers can select the foreground samples successfully without being fooled by the distractors. The IoU-guided ranking loss aims to align classification confidence scores with the Intersection over Union(IoU) of the corresponding localization prediction for positive samples, enabling the well-localized prediction to be represented by high classification confidence. Specifically, the proposed two ranking losses are compatible with most Siamese trackers and incur no additional computation for inference. Extensive experiments on seven tracking benchmarks, including OTB100, UAV123, TC128, VOT2016, NFS30, GOT-10k and LaSOT, demonstrate the effectiveness of the proposed ranking-based optimization algorithm. The code and raw results are available at https://github.com/sansanfree/RBO., To appear in CVPR2022

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer’s disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD., Several micro RNAs have been shown to be deregulated in brain tissue or sera from individuals with Alzheimer’s disease and in AD mouse models. The authors show that miR-135a-5p is downregulated in excitatory pyramidal neurons from AD mice and that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in AD.

Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role of KIF21B and related molecular mechanisms in gastric cancer (GC) remain largely uncovered. In this study, online bioinformatics analysis showed that KIF21B was overexpression in GC and predicted poor prognosis. Consistently, we found that the protein expression of KIF21B was upregulated in GC tissues compared with adjacent tissues by immunohistochemistry. Knockdown of KIF21B significantly suppressed cell proliferation, migration and invasion in GC cell lines (AGS and SNU-5) using Cell counting kit‑8 (CCK-8) assay, colony formation and transwell assay. KIF21B was confirmed as the target of miR-132-3p in GC cells by luciferase reporter assay. Moreover, miR-132-3p was down-regulated and KIF21B expression was upregulated in GC tissues. Overexpression of KIF21B reversed the miR-132-3p-mediated suppressive effects on GC cell proliferation, migration and invasion. Furthermore, miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, proliferating cell nuclear antigen (PCNA) and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. In conclusion, our findings indicate that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in GC, which might be linked to reduced Wnt/β-catenin signaling.

Glutamate receptor, ionotropic, N-methyl-D-aspartate associated protein 1 (GRINA) is a member of the NMDA receptors (NMDARs) and is involved in several neurological diseases, which governs the key processes of neuronal cell death or the release of neurotransmitters. Upregulation of GRINA has been reported in multiple diseases in human beings, such as major depressive disorder (MDD) and schizophrenia (SCZ), with which the underlying mechanisms remain elusive. In this review, we provide a general overview of the expression and physiological function of GRINA in the central nervous system (CNS) diseases, including stroke, depression ,epilepsy, SCZ, and Alzheimer’s disease (AD).

Surface properties and structures of materials are essential for their adsorption of pollutants in water. Humic acids (HA)-supported CeO2 nanosheet composites are synthesised by solvothermal method. The size of CeO2 nanosheets are approximately 100–500 nm. The obtained composite exhibits superior adsorption ability for Congo Red (CR) in water, which can be attributed to its unique structure and highly dispersed CeO2 nanosheet. The composite’s adsorption behaviour of CR follows a pseudo-second-order mode and Langmuir adsorption model well, and the maximum adsorptive capacity for CR achieves 260 mg g−1. The presence of CeO2 nanosheets enhances surface area and enriches the mesoporous structure of the composites, thereby promoting CR adsorption capacity.

Depression is one of the prevalent psychiatric illnesses with a comprehensive performance such as low self-esteem, lack of motivation, anhedonia, poor appetite, low energy, and uncomfortableness without a specific cause. So far, the cause of depression is not very clear, but it is certain that many aspects of biological psychological and social environment are involved in the pathogenesis of depression. Recently, the prefrontal cortex (PFC) has been indicated to be a pivotal brain region in the pathogenesis of depression. And increasing evidence showed that the abnormal activity of the PFC neurons is linked with depressive symptoms. Unveiling the molecular and cellular, as well as the circuit properties of the PFC neurons will help to find out how abnormalities in PFC neuronal activity are associated with depressive disorders. In addition, concerning many antidepressant drugs, in this review, we concluded the effect of several antidepressants on PFC neuronal activity to better understand its association with depression.

Fluorine-doped graphene supported PbO (F-rGO/PbO) composite was prepared through a facile water bath method to study an improvement strategy for its catalytic performance in thermal decomposition of ammonium perchlorate (AP). The characterization results showed that the PbO with the size of 20 ∼ 30 nm are highly dispersed on the surface of F-doped graphene (F-rGO). Compared with other samples, the F-rGO/PbO exhibited superior catalytic performance, as 3 wt% of catalyst added in AP, the peak temperature for HTD reduced by 124°C, and the peak temperature for LTD increased by 8°C. The released apparent specific heat of the thermal decomposition of AP catalyzed by F-rGO/PbO (3603.7 J/g) is five times of that of pure AP (603.5 J/g). The doping of F atoms in graphene increased BET surface areas of the F-rGO carrier and enhanced the content of hydroxyl groups on the surface of graphene, which improved the thermal decomposition rate of AP. While the highly dispersed PbO NPs further increased BET surface areas of F-rGO/PbO to provide more active sites during the thermal decomposition of AP.

Cognitive diagnosis is an essential task in many educational applications. Many solutions have been designed in the literature. The deterministic input, noisy "and" gate (DINA) model is a classical cognitive diagnosis model and can provide interpretable cognitive parameters, e.g., student vectors. However, the assumption of the probabilistic part of DINA is too strong, because it assumes that the slip and guess rates of questions are student-independent. Besides, the question matrix (i.e., Q-matrix) recording the skill distribution of the questions in the cognitive diagnosis domain often requires precise labels given by domain experts. Thus, we propose an explicit student vector estimation (ESVE) method to estimate the student vectors of DINA with a local self-consistent test, which does not rely on any assumptions for the probabilistic part of DINA. Then, based on the estimated student vectors, the probabilistic part of DINA can be modified to a student dependent model that the slip and guess rates are related to student vectors. Furthermore, we propose an unsupervised method called heuristic bidirectional calibration algorithm (HBCA) to label the Q-matrix automatically, which connects the question difficulty relation and the answer results for initialization and uses the fault tolerance of ESVE-DINA for calibration. The experimental results on two real-world datasets show that ESVE-DINA outperforms the DINA model on accuracy and that the Q-matrix labeled automatically by HBCA can achieve performance comparable to that obtained with the manually labeled Q-matrix when using the same model structure., Comment: 9 pages, 6 figures

Supplementary notes

Analysis of human affect plays a vital role in human-computer interaction (HCI) systems. Due to the difficulty in capturing large amounts of real-life data, most of the current methods have mainly focused on controlled environments, which limit their application scenarios. To tackle this problem, we propose our solution based on the ensemble learning method. Specifically, we formulate the problem as a classification task, and then train several expression classification models with different types of backbones--ResNet, EfficientNet and InceptionNet. After that, the outputs of several models are fused via model ensemble method to predict the final results. Moreover, we introduce the multi-fold ensemble method to train and ensemble several models with the same architecture but different data distributions to enhance the performance of our solution. We conduct many experiments on the AffWild2 dataset of the ABAW2022 Challenge, and the results demonstrate the effectiveness of our solution.

Astrocytes constitute a major part of the central nervous system and the delineation of their activity patterns is conducive to a better understanding of brain network dynamics. This study aimed to develop a magnetic resonance imaging (MRI)-based method in order to monitor the brain-wide or region-specific astrocytes in live animals. Adeno-associated virus (AAVs) vectors carrying the human glial fibrillary acidic protein (GFAP) promoter driving the EGFP-AQP1 (Aquaporin-1, an MRI reporter) fusion gene were employed. The following steps were included: constructing recombinant AAV vectors for astrocyte-specific expression, detecting MRI reporters in cell culture, brain regions, or whole brain following cell transduction, stereotactic injection, or tail vein injection. The astrocytes were detected by both fluorescent imaging and Diffusion-weighted MRI. The novel AAV mutation (Site-directed mutagenesis of surface-exposed tyrosine (Y) residues on the AAV5 capsid) significantly increased fluorescence intensity (p 0.01) compared with the AAV5 wild type. Transduction of the rAAV2/5 carrying AQP1 induced the titer-dependent changes in MRI contrast in cell cultures (p 0.05) and caudate-putamen (CPu) in the brain (p 0.05). Furthermore, the MRI revealed a good brain-wide alignment between AQP1 levels and ADC signals, which increased over time in most of the transduced brain regions. In addition, the rAAV2/PHP.eB serotype efficiently introduced AOP1 expression in the whole brain via tail vein injection. This study provides an MRI-based approach to detect dynamic changes in astrocytes in live animals. The novel in vivo tool could help us to understand the complexity of neuronal and glial networks in different pathophysiological conditions.

Background: Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role and related molecular mechanisms underlying gastric cancer (GC) pathogenesis remain largely uncovered. Methods: The expression of KIF21B was investigated by analysis of Oncomine microarray gene expression datasets and clinical specimens. The association between KIF21B and miR-132-3p was assessed by luciferase reporter assay. CCK-8 assay and transwell assay were performed to analyze the functional role of miR-132-3p/KIF21B in GC cells. Related protein expression levels were evaluated by immunohistochemistry and western blot analysis.Results: We first found that the expression of KIF21B was upregulated in GC tissues compared with adjunct normal tissues. Knockdown of KIF21B significantly suppressed the proliferation, migration and invasion in GC cell lines (AGS and SNU-5). KIF21B was confirmed as the target of miR-132-3p in GC cells. Moreover, miR-132-3p was down-regulated and inversely correlated with KIF21B expression in GC tissues. Further functional experiments demonstrated that overexpression of KIF21B remarkedly reversed the suppressive effects of miR-132-3p overexpression on GC cell proliferation, migration and invasion. Furthermore, miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, PCNA and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. Conclusions: In summary, our findings provide the first evidence that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in GC via regulating Wnt/β-catenin signaling.

Recently, kinesin family member 21B (KIF21B) has been reported to be an oncogene in non-small cell lung cancer and hepatocellular carcinoma. However, the functional role and related mechanisms underlying gastric cancer (GC) pathogenesis remain largely uncovered. Here, we first found that the expression of KIF21B was upregulated in GC tissues compared with adjunct normal tissues by analysis of Oncomine microarray gene expression datasets and clinical specimens. Knockdown of KIF21B significantly suppressed the proliferation, migration and invasion in GC cell lines using CCK-8 assay and transwell assay. By luciferase reporter assay, KIF21B was confirmed as the target of miR-132-3p in GC cells and suppressed after miR-132-3p overexpression. Moreover, miR-132-3p was down-regulated and inversely correlated with KIF21B expression in GC tissues. Further functional experiments demonstrated that overexpression of KIF21B remarkedly reversed the suppressive effects of miR-132-3p overexpression on GC cell proliferation, migration and invasion. Furthermore, western blot analysis manifested that miR-132-3p overexpression downregulated the protein levels of Wnt1, c-Myc, β-catenin, PCNA and N-cadherin, and upregulated E-cadherin expression in GC cells, which were all alleviated after KIF21B overexpression. In summary, our findings provide the first evidence that down-regulation of KIF21B by miR-132-3p suppresses cellular functions in gastric cancer via regulating Wnt/β-catenin signaling.

Objective: Pyroptosis represents an emerging inflammatory form of programmed cell death. Herein, specific functions and clinical implications of pyroptosis-related genes were systematically characterized in breast cancer.Methods: Expression, somatic mutation and copy number variation of 33 pyroptosis-related genes were assessed in breast cancer from TCGA dataset. Their interactions, biological functions and prognostic values were then observed. By stepwise Cox regression analysis, a pyroptosis-related gene signature was generated. The predictive efficacy in survival was examined by survival analyses, ROCs, univariate and multivariate analyses and subgroup analyses. Associations between risk score (RS) and cancer immunity cycle, HLA, immune cell infiltrations, and immune checkpoints were analyzed.Results: Most of pyroptosis-related genes were abnormally expressed in breast cancer. CASP8, NLRC4, NLRP3, NLRP2, PLCG1, NLRP1, NLRP7, SCAF11, GSDMC, and NOD1 occurred somatic mutations as well as most of them had high frequency of CNV. There were closely interactions between them. These genes were distinctly enriched in immune-related processes. A three-gene signature was generated, containing IL-18, GSDMC, and TIRAP. High RS predicted poorer overall survival, progression, and recurrence. After verification, this RS was an independent and sensitive predictive index. This RS was negatively correlated to cancer immunity cycle. Also, low RS was characterized by high HLA, immune cell infiltrations and immune checkpoints. A nomogram including age and RS was generated for accurately predicting 5-, 8-, and 10-year survival probabilities.Conclusion: Pyroptosis-related genes exert key roles in cancer immunity and might be applied as a prognostic factor of breast cancer.

Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K

The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons (PGIs) in the dentate gyrus. In a mouse model of Alzheimer's disease (AD mice), VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.

Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.

It has become the top priority for coking industry to rationally use and enlarge coking coal resources because of the shortage of the resources. This review focuses on the potential utilization of oil shale (OS) as a feedstock for coal-blending coking, in which the initial and basic step is pyrolysis. However, OS has a high ash content. If such OS is directly used for coal-blending coking, the coke product will not meet market demand. Therefore, this review firstly summarizes separation and beneficiation techniques for organic matter in OS, and provides an overview on coal and OS pyrolysis through several viewpoints (e.g., pyrolysis process, phenomena, and products). Then the exploratory studies on co-pyrolysis of coal with OS, including co-pyrolysis phenomena and process mechanism, are discussed. Finally, co-pyrolysis of different ranks of coals with OS in terms of coal-blending coking, where further research deserves to be performed, is suggested.

DNA double-strand breaks (DSBs) are common events that were recognized as one of the most toxic lesions in eukaryotic cells. DSBs are widely involved in many physiological processes such as V(D)J recombination, meiotic recombination, DNA replication and transcription. Deregulation of DSBs has been reported in multiple diseases in human beings, such as the neurodegenerative diseases, with which the underlying mechanisms are needed to be illustrated. Here, we reviewed the recent insights into the dysfunction of DSB formation and repair, contributing to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and ataxia telangiectasia (A-T).

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, communication deficits, and restrictive and repetitive behaviors. ASD has a strong genetic basis and many ASD-associated genes have been discovered thus far. Our previous work has shown that loss of expression of the X-linked geneNEXMIF/KIDLIAis implicated in patients with autistic features and intellectual disability (ID). To further determine the causal role of the gene in the disorder, and to understand the cellular and molecular mechanisms underlying the pathology, we have generated a NEXMIF knock-out (KO) mouse. We find that male NEXMIF KO mice demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory. Loss ofNEXMIF/KIDLIAexpression results in a significant decrease in synapse density and synaptic protein expression. Consistently, male KO animals show aberrant synaptic function as measured by excitatory miniatures and postsynaptic currents in the hippocampus. These findings indicate that NEXMIF KO mice recapitulate the phenotypes of the human disorder. The NEXMIF KO mouse model will be a valuable tool for studying the complex mechanisms involved in ASD and for the development of novel therapeutics for this disorder.SIGNIFICANCE STATEMENTAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by behavioral phenotypes. Based on our previous work, which indicated the loss of NEXMIF/KIDLIA was associated with ASD, we generated NEXMIF knock-out (KO) mice. The NEXMIF KO mice demonstrate autism-like behaviors including deficits in social interaction, increased repetitive self-grooming, and impairments in communication and in learning and memory. The KO neurons show reduced synapse density and a suppression in synaptic transmission, indicating a role for NEXMIF in regulating synapse development and function. The NEXMIF KO mouse faithfully recapitulates the human disorder, and thus serves as an animal model for future investigation of the NEXMIF-dependent neurodevelopmental disorders.

Background Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer’s disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder. Methods We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. Results We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. Conclusions miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

In order to accurately calculate the reliability of mechanical components and systems with multiple correlated failure modes and to reduce the computational complexity of these calculations, the Copula function is used to represent related structures among failure modes. Based on a correlation analysis of the failure modes of parts of a system, a life distribution model of components is constructed using the Copula function. The type of Copula model was initially selected using a binary frequency histogram of the life empirical distribution between the two components. The unknown parameters in the Copula model were estimated using the maximum likelihood estimation method and the most suitable Copula model was determined by calculating the square Euclidean distance. The reliability of series, parallel, and series–parallel systems was analyzed based on the Copula function, where life was used as a variable to measure the correlation between components. Thus, a reliability model of a system with life correlations was established. Reliability calculation of a particular diesel crank and connecting rod mechanism was taken as a practical example to illustrate the feasibility of the proposed method.

Urchin-like TiO2 hierarchical microspheres (UTHMs) with an extremely large surface area of 331 m2 g−1 were synthesized via a facile one-pot hydrothermal method and studied for dye-sensitized solar cells (DSSCs) application. In-situ growth of Au nanoparticles (NPs) on the surface of the UTHMs were further conducted to achieve Au-decorated UTHMs (Au-UTHMs). A series of novel composite photoanode films were designed through the combined use of Au-UTHMs and UTHMs at different mass ratios. The DSSC constructed with the composite photoanode prepared under an optimal Au-UTHMs to UTHMs ratio of 2 wt% yields a considerable power conversion efficiency of 7.21%, which was markedly higher than that of the pure P25 NPs based device (5.19%) and pure UTHMs based device (6.10%). The significantly enhanced performance of the composite photoanode based DSSC can be attributed to the synergistic effect of two benefits: (1) the large specific surface area, strong light scattering and fast electron transfer channels arising from the novel hierarchical features of UTHMs, and (2) the enhanced light absorption owing to the localized surface plasmon resonance (LSPR) effect of Au NPs.

BackgroundDysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated six candidate miRNAs in a large collection of brain samples.MethodsBrain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 99 AD patients and 91 controls. Expression of six miRNAs was examined by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was investigated in a transgenic AD mouse model using qPCR and FISH. Total RNA sequencing was used to assess differential expression of miRNA target genes.ResultsMiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC, while miR-125b-5p and miR-501-3p showed no evidence for differential expression in this dataset. In addition, miR-195-5p was significantly upregulated in EC but not STG in AD patients. The brain region-specific pattern of miR-195-5p expression was corroborated in vivo in transgenic AD mice. Total RNA sequencing identified several novel and functionally interesting target genes of these miRNAs involved in synaptic transmission (GABRB1), the immune-system response (HCFC2) or AD-associated differential methylation (SLC16A3).ConclusionsUsing two different methods (qPCR and small RNA-seq) in two separate brain regions in 190 individuals we more than doubled the available sample size for most miRNAs tested. Differential gene expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis and highlight several novel potentially relevant target mRNAs.FundingThis work was supported by the Deutsche Forschungsgemeinschaft (DFG) and the National Science Foundation China (NSFC) as a Joint Sino-German research project (“MiRNet-AD”, #391523883). Additional support was provided by the DFG Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (#423957469) and the Cure Alzheimer’ s Fund (CAF) as part of the CIRCUITS consortium project.

Background: Numerous studies have indicated that the neddylation pathway is closely associated with tumor development. MLN4924 (Pevonedistat), an inhibitor of the NEDD8-activating E1 enzyme, is considered a promising chemotherapeutic agent. Recently, we demonstrated that neddylation of the tumor suppressor PTEN occurs under high glucose conditions and promotes breast cancer development. It has been shown, however, that PTEN protein levels are reduced by 30–40% in breast cancer. Whether this PTEN deficiency affects the anti-tumor function of MLN4924 is unknown.Methods: In the present study, cell counting kit-8 and colony formation assays were used to detect cell proliferation, and a transwell system was used to quantify cell migration. A tumor growth assay was performed in BALB/c nude mice. The subcellular location of PTEN was detected by fluorescence microscopy. The CpG island of the UBA3 gene was predicted by the Database of CpG Islands and UCSC database. Western blotting and qRT-PCR were used to measure the expression of indicated proteins. The Human Protein Atlas database, the Cancer Genome Atlas and Gene Expression Omnibus datasets were used to validate the expression levels of UBA3 in breast cancer.Results: Our data show that the anti-tumor efficacy of MLN4924 in breast cancer cells was markedly reduced with the deletion of PTEN. PI3K/Akt signaling pathway activity correlated positively with UBA3 expression. Pathway activity correlated negatively with NEDP1 expression in PTEN-positive breast cancer patients, but not in PTEN-negative patients. We also demonstrate that high glucose conditions upregulate UBA3 mRNA by inhibiting UBA3 promoter methylation, and this upregulation results in the overactivation of PTEN neddylation in breast cancer cells.Conclusion: These data suggest a mechanism by which high glucose activates neddylation. PTEN is critical, if not indispensable, for MLN4924 suppression of tumor growth; PTEN status thus may help to identify MLN4924-responsive breast cancer patients.

The presence of foreign or misplaced nucleic acids is a dangerous signal that triggers innate immune responses by activating cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and binding to its downstream signaling effector stimulator of interferon genes (STING). Then the cGAS-STING pathway activation links nucleic acid-sensing to immune responses and pathogenic entities clearance. However, the overactivation of this signaling pathway leads to fatal immune disorders and contributes to the progression of many human inflammatory diseases. Therefore, optimal activation of this pathway is crucial for the elimination of invading pathogens and the maintenance of immune homeostasis. In this review, we will summarize its fundamental roles in initiating host defense against invading pathogens and discuss its pathogenic roles in multiple neuro-inflammatory diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurodegenerative diseases.

Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.

The hippocampus is a temporal lobe structure critical for cognition, such as learning, memory, and attention, as well as emotional responses. Hippocampal dysfunction can lead to persistent anxiety and/or depression. However, how millions of neurons in the hippocampus are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing the coagulation factor c homolog (COCH) gene. COCH-expressing neurons or COCH neurons are topographically segregated in the distal region of the ventral CA3 hippocampus and express Mtf1 and Cacna1h. MTF1 activation of Cacna1h transcription in COCH neurons encodes the ability of COCH neurons to burst action potentials and cause social-stress-induced anxiety-like behaviors by synapsing directly with a subset of GABAergic inhibitory neurons in the lateral septum. Together, this study provides a molecular and circuitry-based framework for understanding how COCH neurons in the hippocampus are assembled to engage social behavior.

Semi-supervised Fine-Grained Recognition is a challenge task due to the difficulty of data imbalance, high inter-class similarity and domain mismatch. Recent years, this field has witnessed great progress and many methods has gained great performance. However, these methods can hardly generalize to the large-scale datasets, such as Semi-iNat, as they are prone to suffer from noise in unlabeled data and the incompetence for learning features from imbalanced fine-grained data. In this work, we propose Bilateral-Branch Self-Training Framework (BiSTF), a simple yet effective framework to improve existing semi-supervised learning methods on class-imbalanced and domain-shifted fine-grained data. By adjusting the update frequency through stochastic epoch update, BiSTF iteratively retrains a baseline SSL model with a labeled set expanded by selectively adding pseudo-labeled samples from an unlabeled set, where the distribution of pseudo-labeled samples are the same as the labeled data. We show that BiSTF outperforms the existing state-of-the-art SSL algorithm on Semi-iNat dataset., Comment: arXiv admin note: text overlap with arXiv:2102.09559 by other authors

To explore the efficacy of microwave ablation (MWA) in the treatment of hepatic alveolar echinococcosis (HAE) with a diameter of ≤5 cm.From June 2014 to January 2020, patients diagnosed with HAE were retrospectively analyzed. After balancing the confounding factors by propensity score matching (PSM) , the patients were divided into MWA group (n = 20) and radical operation group (n = 20) by 1:1 matching. The safety and effectiveness of MWA were assessed by comparing the differences between the two groups in terms of postoperative general laboratory indices, grading of postoperative complications, length of postoperative hospitalization, the outcome of treatment, and disease recurrence.After PSM, all confounders were not statistically different (P0.05) . Compared with the radical surgery group, patients in the MWA group had lower postoperative ALT and WBC elevations (P0.001) , shorter postoperative hospital stay (P0.001) ) , lower hospital costs (P0.001) . The effective rate of the two groups was 100%. There was no statistical difference in the incidence of postoperative complications and recurrence rate (P0.05).MWA is a safe and effective means of treating HAE ≤ 5 cm in diameter.

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post‐ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno‐associated virus (AAV) overexpressing cre recombinase into aged Fpn‐floxed mice significantly worsened the symptoms post‐ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR‐124 was identified to regulate Fpn expression post‐ICH. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR‐124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR‐124/Fpn signaling manipulation. Our study demonstrated the critical role of miR‐124/Fpn signaling in iron metabolism and neuronal death post‐ICH in aged murine model. Thus, Fpn upregulation or miR‐124 inhibition might be promising therapeutic approachs for this disease., Brain iron accumulation following ICH induced secondary brain injury and neuronal death. However, the mechanisms underlying iron deregulation in aged ICH model is poorly understood. miR‐124/Fpn signaling was downregulated in aged ICH model mice and patients as a protection mechanism. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged patients. Targeting miR‐124/Fpn signaling could reduce the iron accumulation post‐ICH in aged murine model, thus ameliorated hematoma volume, cell apoptosis and neurologic dysfunction through inhibiting apoptosis and ferroptosis.