Two-dimensional carbon-based heterostructures as bifunctional electrocatalysts for water splitting and metal–air batteries

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have also revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and the astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity across transgenes and in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

Sheep with Partial RXFP2 Knockout Exhibit Normal Horn Phenotype but Unilateral Cryptorchidism1

Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the main causes of reduced long-term survival. Modern methods for predicting the risk of AML relapse after allo-HSCT take into account the data on the pre-transplant level of minimal residual disease (MRD) determined by flow cytometry and molecular biological studies of recurrent genetic abnormalities, which are currently widespread in clinical practice. Recent studies of the expression of genes characteristic of leukemic stem cells (LSCs) have shown prognostic significance for children with AML in relation to treatment response and the risk of relapse. The study of LSC persistence in order to predict the risk of recurrence after allo-HSCT in children with AML in addition to standard MRD detection methods may be of great importance. The aim of the work was to evaluate the impact of MRD status, both using classic methods and taking into account the genes characteristic of LSC, on the results of allo-HSCT in children with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. To assess MRD using standard diagnostic methods, we analyzed the data of 95 children with AML in their 1st–2nd remission (cohort 1). MRD status was negative in 67 (70.6 %) patients; in 28 (29.4 %) children, MRD status was positive according to molecular genetic studies and / or immunophenotyping results. For pre-transplant evaluation of the expression of genes characteristic of LSC, we investigated bone marrow samples of 50 patients (cohort 2) using real-time polymerase chain reaction. The DNMT3B, GPR56, CD34, SOCS2, SPINK2, FAM30A, and ABL genes were studied by real-time polymerase chain reaction, followed by calculation of the pLSC6 value using the formula: DNMT3b × 0.189 + GPR56 × 0.054 + CD34 × 0.0171 + SOCS2 × 0.141 + SPINK2 × 0.109 + FAM30A × 0.0516. At the time of allo-HSCT, 37 (74 %) children with AML were in their 1st or 2nd remission of the disease, 13 (26 %) were out of the 1st–2nd remission. With a median follow-up of 5 years in the group of patients with a positive MRD status, determined by standard methods (cohort 1), overall survival (OS) was 67.9 % vs 73.1 % for patients with a negative MRD status (p = 0.83). The cumulative incidence of relapse was 50 % and 22 %, respectively; p = 0.012. When assessing the level of expression of genes characteristic of LSC (cohort 2), a pLSC6 level was above the median in 18/37 (49 %) patients. The results of linear regression showed that the pre-transplant level of expression of genes characteristic of LSC was not associated with the number of blasts/MRD (odds ratio 1.002; 95 % confidence interval 0.979–1.025). One-year OS rates did not differ significantly in children in the 1st–2nd remission of AML, depending on pLSC6 level: 84.2% in patients with low pLSC6 and 72.2 % – with high pLSC6 (p = 0.4), event-free survival in the corresponding groups – 68.4 % and 61.1 %, respectively (p = 0.34). The cumulative incidence of early relapse after allo-HSCT in the group of AML patients with a high pLSC6 score was significantly higher than in children with a low pLSC6 score before allo-HSCT (22 % and 0 %, respectively; p = 0.03). MRD does not have a statistically significant effect on OS. However, MRD positivity before allo-HSCT increases cumulative incidence of relapse. The level of expression of genes characteristic of LSC, determined before allo-HSCT, showed a prognostic significance in relation to the development of early AML relapse after allo-HSCT.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, but molecular complexity and tumor heterogeneity make predictive models for HCC prognosis ineffective. Many recent studies have suggested that autophagy is important in tumor progression. Using autophagy-related genes (ARGs), we attempted to create a novel signature for individual prognosis prediction in patients with HCC. Differentially expressed ARGs (DE-ARGs) in HCC and normal samples were screened using TCGA datasets. Univariate Cox and multivariate Cox regression analyses were performed to determine ARGs related to survival in HCC. An autophagy-based signature was constructed using LASSO, and its correlation with the prognosis and the immune infiltration of HCC patients was explored. In this study, we screened 32 survival-related DE-ARGs by analyzing TCGA datasets. Functional enrichment indicated that the 32 DE-ARGs may play important functional and regulatory roles in cellular autophagy, the regulation of multiple signaling pathways, as well as in the context of cancer and neurological diseases. Based on PPI Network, we identified several hub genes. LASSO Cox regression analysis selected five genes (CASP8, FOXO1, PRKCD, SPHK1, and SQSTM1) for a novel prognostic model. AUCs of 0.752, 0.686, and 0.665 in the TCGA whole set indicated that the model accurately predicted 1-, 3-, and 5-year overall survival, respectively. Cox regression analysis showed that the five-gene signature is an independent and robust predictor in patients with HCC. The high-risk group demonstrated higher levels of immune cell infiltration and exhibited a strong correlation with the immune microenvironment and tumor stem cells. In addition, we further identified PRKCD and SQSTM1 as critical regulators involved in HCC progression. The expression levels of PRKCD and SQSTM1 genes play a crucial role in chemotherapy drug sensitivity and resistance. We introduce here a novel ARG-based predictive feature for HCC patients. Effective use of this signature will aid in determining a patient's prognosis and may lead to novel approaches to clinical decision-making and therapy.

Dementia is the primary cause of disability and dependence among the elderly population worldwide. The population living with dementia is anticipated to double in the next 17 years. Recent studies show the fact that compared to people without diabetes, people with Type 2 Diabetes (T2D) have about a 60% increased chance of developing dementia. In addition to cholinergic function being downregulated, improper insulin signalling also has a negative impact on synaptic plasticity and neuronal survival. Type 2 diabetes and dementia share various similar pathophysiological components. The ageing of the population and the ensuing rise in dementia prevalence are both results of ongoing medical advancements. It is possible that restoring insulin signaling could be a helpful therapy against dementia, as it is linked to both diminished cognitive function and the development of dementia, including AD. This review article comprehensively focused on scientific literature to analyze the relationship of Dementia with diabetes, recent experimental studies, and insight into incretin-based drug therapy for diabetes-related dementia.

Recent studies have found that Phosphodiesterase-4 (PDE4) is closely related to the pathogenesis of depression, cognitive impairment and neurological impairment. Our objective is to develop potent inhibitors of the high-affinity phosphodiesterase 4D isoform (PDE4D) that can serve as radioligands for Positron Emission Tomography (PET) imaging, thereby advancing research in the field of neurological diseases. We employed a multi-step approach combining three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, classification techniques, and CoMSIA analysis to investigate the conformational relationship of highaffinity PDE4D inhibitors as PET ligands. ADMET and Drug-likeness predictions were also conducted. By utilizing these methods, our aim was to identify more potent PDE4D inhibitors. The results showed that the CoMSIA model with the best principal component scores (n=7) had a cross-validated Q2 value of 0.602 and a non-cross-validated R2 value of 0.976. These results affirmed the excellent predictive capability of the established CoMSIA model. Analysis of the generated 3D-QSAR contour plots highlighted specific regions in the molecular structure of the compounds that can be further optimized and modified. Guided by the contour plots, we designed 100 novel PDE4D inhibitors, and molecular docking was performed for the top 4 compounds with high activity. The molecular docking scores were promising, and ADMET and drug similarity predictions yielded satisfactory results. Taking into consideration these factors, compound 51c was determined to be the optimal compound, laying a solid foundation for further research. For the continued development of PDE4D PET radioligand, these models and new compounds' developing methodology offer a theoretical foundation and crucial references.

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide; however, there is not a convincing treatment for this disease. Limitations of conventional CRC therapies force scientists to develop novel treatment concepts for both primary care alongside adjuvant therapy. Photodynamic therapy (PDT) has been introduced as a promising therapeutic procedure for CRC mediated through theranostic principle in which special dyes, photosensitizers (PSs), are excited by near-infrared (NIR) and visible light. Recent studies showed that PDT has synergistic effects in combination with chemotherapy or immunotherapy in the treatment of CRC patients. Of note, nanoformulation of PS or immunotherapeutic agents could augment the PDT effectiveness. In this review, we summarize PDT application in CRC management with a special focus on the nanoparticles-based delivery system from the perspective of targeting deeper CRC and increased PDT efficiency, which could provide a desirable approach for clinical translation.

The recent studies were carried out in 1992-1994, and aimed at investigating recent status and distribution of the avifauna of Siberut Island. Ninety-six species were recorded during the observations, of which all endemic subspecies and one endemic species were observed. From all species, 11.5% were very common and 37.5% were common in the island, while 28.1 % of them were uncommon and22.9% were rarely found. Protected and endemic species were amongt the rarely found birds, except the nectar feeding birds which were abundant in the island. Most of these birds might have functioned as either secondary or tertiary consumers, which are vulnerable to habitat deterioration. Habitat conservation may be the best measures to be considered.

Southeast Asia is one of the most geologically complex tropical regions on Earth, in which the intricate interactions among plate tectonics, volcanism and Pleistocene climatic fluctuations led to complex patterns of species distribution. An increasing number of biogeographic studies of the Indonesian ichthyofauna have already partially uncovered the potential mechanisms at the origin of present day species distribution. These studies are currently scattered in the literature and the present review aims at presenting recent progress. Here, we propose a review of this literature with the aim to provide a broad overview of the current progress in the field of Indonesian freshwater fishes biogeography. First, we will briefly present the geology of the Indo-Australian Archipelago (IAA) and highlight the time frame of the geographical settlement of the Indonesian archipelago. Second, we will present the palaeoecological history of Sundaland during the Pleistocene. Finally, we will present the results of recent biogeographic studies across the three biogeographic provinces (Sundaland, Wallacea, Sahul) and discuss how these results fit with geological and palaeoecological scenarios in Indonesia.

Background: Polycystic ovarian syndrome (PCOS) has emerged as one of the most common endocrine and metabolic disorders seen in women of childbearing age throughout the whole world. The complex pathophysiology, different diagnostic criteria, and various manifestations attached to several environmental factors, including lifestyle influences, have made it one of the most difficult disorders to treat in recent times. In addition, inadequate knowledge among patients and a lack of dedicated approved medications have only enhanced the difficulties in treating such a heterogeneous disorder. Objective: The main objective of this review-type paper is to provide a detailed overview of PCOS along with the current concept of a clinical stance in this complex multigenic disorder. Method: The following databases were used for literature searches: PubMed, Frontiers, Science Direct, Springer, Wiley, and MDPI. For the purpose of finding pertinent articles and contents, the keywords “PCOS; hirsutism; psychological burden; obesity” and others of a similar nature were utilized. Conclusion: PCOS is a complicated hormonal, metabolic, and psychological condition with many different clinical manifestations. It is among the most prevalent causes of infertility. Before considering any medication choices, lifestyle modifications should be considered the primary therapeutic prescription for PCOS-related infertility. According to recent studies, PCOS does not affect the risk of ovarian or breast cancer, but it does raise the risk of endometrial cancer in women of all ages. These results suggest that PCOS may increase the risk of gynaecological cancer morbidity. The following stage is ovulation stimulation, which is best accomplished with letrozole and is followed by clomiphene citrate. Women who had not responded to the first-line oral ovulatory medicine were given gonadotropins as a backup. Early detection of girls with a high propensity to develop PCOS will be made possible by a comprehensive knowledge of the condition's etiology. Adolescent PCOS will be better managed overall, related comorbidities will be prevented, and quality of life will increase with customized therapeutic approaches.

Arylamine N-Acetyltransferases NAT1 and NAT2 are enzymes mainly known for participating in phase II of the detoxification process. Both enzymes are present in various organs, such as the liver, intestine, lung, skin, and immune cells. Recent stud-ies implicate its possible role in carcinogenesis or cell metabolism; The catalytic activity, representing a substantial influence on the cellular concentration of its Acetyl Coenzyme A cofactor, can influence multiple cellular processes, depending on its cytoplasmic concentration. A review was carried out in the databases ENCODE and PubMed to identify information of interest on the epigenetics of NAT1 and NAT2 promoters and reports proposing the possible mechanisms involved in the diseases under study. The effect of NAT1 on folate metabolism has led to it being proposed as a possible epigenetic regulator.

Margin distribution has been proven to play a crucial role in improving generalization ability. In recent studies, many methods are designed using large margin distribution machine (LDM), which combines margin distribution with support vector machine (SVM), such that a better performance can be achieved. However, these methods are usually proposed based on single-view data and ignore the connection between different views. In this article, we propose a new multiview margin distribution model, called MVLDM, which constructs both multiview margin mean and variance. Besides, a framework is proposed to achieve multiview learning (MVL). MVLDM provides a new way to explore the utilization of complementary information in MVL from the perspective of margin distribution and satisfies both the consistency principle and the complementarity principle. In the theoretical analysis, we used Rademacher complexity theory to analyze the consistency error bound and generalization error bound of the MVLDM. In the experiments, we constructed a new performance metric, the view consistency rate (VCR), for the characteristics of multiview data. The effectiveness of MVLDM was evaluated using both VCR and other traditional performance metrics. The experimental results show that MVLDM is superior to other benchmark methods.

Colorectal cancer is a common malignant tumor, with about one million people diagnosed with it worldwide each year. Recent studies have found that metformin can inhibit the production of inflammatory factors and regulate the polarization of immune cells. However, whether metformin can regulate the inflammatory microenvironment and delay the progression of colorectal cancer by inhibiting the inflammatory response has not been deeply studied yet. This study aimed to explore the molecular mechanism by which metformin inhibits the expression of NLRP3 inflammasome, regulates the inflammatory microenvironment, and delays the progression of colorectal cancer through in vitro cell experiments. In this research, NLRP3 was knocked down in human colorectal cancer cells, and metformin was added to them. Cell proliferation ability was detected by CCK8, and cell migration and invasion abilities were assessed by Transwell assay. The apoptosis rate was determined by flow cytometry. In addition, the expression of NLRP3 inflammatory vesicles and inflammatory factors in each group of cells was studied by qRT-PCR and Western blotting. Finally, clinical colorectal cancer samples were analyzed by immunohistochemistry. The results of the study showed that NLRP3 expression was significantly increased in colorectal cancer cell lines and human colorectal cancer tissues. Knockdown of NLRP3 significantly inhibited tumor cell proliferation, migration, and invasion. In addition, the proliferation, migration and invasion of tumor cells were also significantly reduced by the addition of metformin intervention. Furthermore, qRT-PCR and WB results demonstrated that the expression of IL-1β, IL-6, TNF- α, TGF-β, and IL-10 was down-regulated in LS1034 tumor cells after NLRP3 knockdown. In addition, metformin intervention also resulted in different degrees of downregulation of NLRP3 and inflammatory factor expression (p π0.05). Notably, the reduction in inflammatory factors was more pronounced after the combination of NLRP3 knockdown and metformin intervention. Metformin can inhibit the expression of NLRP3 inflammasome, thereby suppressing the expression of inflammation-related factors, reducing the damage of the inflammatory microenvironment to normal cells, and delaying the progression of colorectal cancer.

Transformers have astounding representational power but typically consume considerable computation which is quadratic with image resolution. The prevailing Swin transformer reduces computational costs through a local window strategy. However, this strategy inevitably causes two drawbacks: 1) the local window-based self-attention (WSA) hinders global dependency modeling capability and 2) recent studies point out that local windows impair robustness. To overcome these challenges, we pursue a preferable trade-off between computational cost and performance. Accordingly, we propose a novel factorization self-attention (FaSA) mechanism that enjoys both the advantages of local window cost and long-range dependency modeling capability. By factorizing the conventional attention matrix into sparse subattention matrices, FaSA captures long-range dependencies, while aggregating mixed-grained information at a computational cost equivalent to the local WSA. Leveraging FaSA, we present the factorization vision transformer (FaViT) with a hierarchical structure. FaViT achieves high performance and robustness, with linear computational complexity concerning input image spatial resolution. Extensive experiments have shown FaViT's advanced performance in classification and downstream tasks. Furthermore, it also exhibits strong model robustness to corrupted and biased data and hence demonstrates benefits in favor of practical applications. In comparison to the baseline model Swin-T, our FaViT-B2 significantly improves classification accuracy by 1% and robustness by 7%, while reducing model parameters by 14%. Our code will soon be publicly available: at https://github.com/q2479036243/FaViT.

Diabetic nephropathy (DN) has gradually become one of the main causes of end-stage renal disease (ESRD). However, there is still a lack of effective preventive measures to delay its progression. As the energy factory in the cell, mitochondria play an irreplaceable role in maintaining cell homeostasis. Interestingly, recent studies have shown that in addition to maintaining homeostasis in cells in which mitochondria reside, when mitochondrial perturbations occur in one tissue, distal tissues can also sense and act through mitochondrial stress response pathways through a group of proteins or peptides called "mitokines". Here, we reviewed the mitokines that have been found thus far and summarized their research progress in DN. Finally, we explored the possibility of mitokines as potential therapeutic targets for DN.

Recent studies reported that terminal nucleotidyltransferase 5A (TENT5A) is highly expressed in glioblastoma and associated with poor prognosis. In this work, we aim to specify the expression level of TENT5A in different grades of glioma and explore its role in glioma progression. GEPIA online tools were used to perform the bioinformatic analysis. qRT-PCR, Western blot, and Immunohistochemistry were performed in glioma cells or tissues. Furthermore, CCK8, colony formation, transwell, flow cytometry and scratch assays were performed. TENT5A was highly expressed in glioma and its level was associated with the pathological grade of glioma. Knockdown of TENT5A suppressed cell proliferation, colony formation ability, cell invasion and migration. Overexpression of TENT5A was lethal to the glioma cells. Our data showed that the expression of TENT5A is associated with the pathological grade of glioma. Knockdown of TENT5A decreased the ability of proliferation, invasion and migration of glioma cells. High levels of TENT5A in glioma cells are lethal. Therefore, TENT5A could be a new target for glioma treatment.

A recent study suggests that enhancing career development is a key motivator for students entering university (Kandiko & Mawer, 2013). This article discusses the place of career development learning within the ‘employability’ agenda. It draws upon social learning and constructivist theories of career development in a qualitative case study exploring undergraduate students’ experiences of placements in relation to their career development learning and employability. Findings suggest significant value in providing authentic work experiences and opportunities for career exploration (to ‘broaden their horizons’ rather than narrowing down choices) to inform career identities and increase self-efficacy and motivation.

Type 1 diabetes mellitus (T1DM) is a condition marked by elevated blood sugar levels and primarily recognized by the destruction of beta cells caused by an autoimmune attack, which is a significant characteristic of T1DM. Recent studies have demonstrated the regenerative potential of conditioned medium therapy. In light of this, the current research sought to assess the impact of Mesenchymal Stem Cell conditioned media (CM) and CM with resveratrol (CM+ Resveratrol) on the management of T1DM in Swiss albino mice. By leveraging and modifying existing conditioned medium therapy, this study aims to evaluate its effectiveness in treating T1DM. Diabetes was induced in animals using the diabetes-inducing agent streptozotocin (STZ). The animals were then divided into five groups: Normal control, Disease Control, Resveratrol, Condition Media, and CM + Resveratrol. Treatments were given to the animals accordingly. The study period was 28 days. During this time, the animals were monitored for foodwater intake twice a week, blood glucose levels, and body weight. At the conclusion of the 28-day study period, biochemical estimations were performed for serum insulin levels, C-peptide levels, anti-inflammatory cytokines levels and pro-inflammatory cytokines levels. Additionally, histopathology of the pancreas was performed. The test groups showed a significant decrease in blood glucose levels, an increase in Cpeptide levels, and a decrease in pro-inflammatory cytokine levels compared to the disease group. However, no statistically significant change within groups was observed in terms of serum insulin and anti-inflammatory cytokine levels. The improvement in diabetic symptoms, such as polyphagia, polydipsia, and weight loss, was observed in the treatment group, along with pancreatic regeneration, which indicated improved insulin secretion. In the current investigation, we concluded that CM and CM+ Resveratrol, as natural immunomodulators, have the capacity to regenerate injured pancreatic beta cells and have antidiabetic action, together with immunomodulating impact. Nonetheless, future studies on this therapy appear to be promising.

Leukotriene receptor antagonists are recommended to treat asthma and allergic rhinitis. Although they had been used for a long time, recent studies have reported neuropsychiatric adverse drug reactions are associated with montelukast. This study analyzed the adverse drug reactions of montelukast and pranlukast, which are the two most frequently prescribed leukotriene receptor antagonists, respectively in Korea. This study retrospectively reviewed ADRs of 5,426 montelukast and 1,146 pranlukast reported in the Korea Adverse Event Reporting System between January 2014 and December 2018. When both drugs are classified by system organ class, the most adverse drug reactions were related to the gastro-intestinal system, followed by psychiatric events. The reported adverse drug reactions for both drugs were more common in women, and the ratio of adverse drug reactions to prescriptions was highest in the elderly. Women aged 19 to 64 years reported more than twice as many adverse drug reactions than men of the same age, and more than 5 times in insomnia. When prescribing montelukast and pranlukast, attention would need to digestive and sleep disorders, especially women aged 19 to 64. After prescribing montelukast, physicians would need to pay more attention to agitation (5/396378 vs 0/82475), bad or vivid dreams (6/396378 vs 0/82475), anxiety (11/396378 vs 0/82475), depression (14/396378 vs 1/82475), tremor (53/396378 vs 7/82475), irritability (5/396378 vs 1/82475), insomnia (159/396378 vs 25/82475), and headache (68/396378 vs 10/82475), compared to when prescribing pranlukast. Further prospective research needs to elucidate the relationship between neuropsychiatric events and montelukast.