Discovery and characterization of stereodefined PMO-gapmers targeting tau.

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurodegenerative diseases, new chemical modifications that improve activity and safety profiles are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with a defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers.

Knowledge and attitudes towards eating disorders: A survey of psychiatrists and psychiatry trainees in New South Wales.

Objective: To evaluate New South Wales (NSW) psychiatrists' and psychiatry trainees' knowledge and attitudes towards eating disorders (EDs).

Method: A total of 1781 psychiatrists and trainees in NSW were invited to complete an anonymous questionnaire assessing ED confidence, knowledge and attitudes.

Results: A total of 51 doctors responded to the survey, with 38 completing all items.

Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy.

Background: TFP5 is a Cdk5 inhibitor peptide, which could restore insulin production. However, the role of TFP5 in diabetic nephropathy (DN) is still unclear.

Objective: This study aims to characterize the transcriptome profiles of mRNA and lncRNA in TFP5-treated DN mice to mine key lncRNAs associated with TFP5 efficacy.

Platelet-to-albumin ratio is a potential biomarker for predicting diabetic nephropathy in patients with type 2 diabetes.

To evaluate whether platelet-to-albumin ratio (PAR) can predict diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM). A total of 140 patients with T2DM and 40 healthy individuals were enrolled retrospectively. T2DM patients were divided into three groups based on the urinary albumin-to-creatinine ratio, PAR was compared and receiver operating characteristic curve was constructed to evaluate the predictive value of PAR in DN in T2DM.

Cdk5 activation promotes Cos-7 cells transition towards neuronal-like cells.

Objectives: Cyclin-dependent kinase 5 (Cdk5) activity is specifically active in neurogenesis, and Cdk5 and neocortical neurons migration related biomarker are expressed in Cos-7 cells. However, the function of Cdk5 on the transformation of immortalized Cos-7 cells into neuronal-like cells is not clear.

Methods: Cdk5 kinase activity was measured by [γ-P] ATP and p81 phosphocellulose pads based method.

TFP5 attenuates cyclin-dependent kinase 5-mediated islet β-cell damage in diabetes.

Islet β-cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin-dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet β-cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death.

TFP5-Mediated CDK5 Activity Inhibition Improves Diabetic Nephropathy NGF/Sirt1 Regulating Axis.

Diabetic nephropathy (DN) is one of the leading causes of chronic kidney disease (CKD), during which hyperglycemia is composed of the major force for the deterioration to end-stage renal disease (ESRD). However, the underlying mechanism triggering the effect of hyperglycemia on DN is not very clear and the clinically available drug for hyperglycemia-induced DN is in need of urgent development. Here, we found that high glucose (HG) increased the activity of cyclin-dependent kinase 5 (CDK5) dependent on P35/25 and which upregulated the oxidative stress and apoptosis of mouse podocytes (MPC-5).

Reticulon-1A mediates diabetic kidney disease progression through endoplasmic reticulum-mitochondrial contacts in tubular epithelial cells.

Recent epidemiological studies suggest that some patients with diabetes progress to kidney failure without significant albuminuria and glomerular injury, suggesting a critical role of kidney tubular epithelial cell (TEC) injury in diabetic kidney disease (DKD) progression. However, the major risk factors contributing to TEC injury and progression in DKD remain unclear. We previously showed that expression of endoplasmic reticulum-resident protein Reticulon-1A (RTN1A) increased in human DKD, and the increased RTN1A expression promoted TEC injury through endoplasmic reticulum (ER) stress response.

Characterizing partisan political narrative frameworks about COVID-19 on Twitter.

Unlabelled: The COVID-19 pandemic is a global crisis that has been testing every society and exposing the critical role of local politics in crisis response. In the United States, there has been a strong partisan divide between the Democratic and Republican party's narratives about the pandemic which resulted in polarization of individual behaviors and divergent policy adoption across regions. As shown in this case, as well as in most major social issues, strongly polarized narrative frameworks facilitate such narratives.

FrameAxis: characterizing microframe bias and intensity with word embedding.

Framing is a process of emphasizing a certain aspect of an issue over the others, nudging readers or listeners towards different positions on the issue even without making a biased argument. Here, we propose FrameAxis, a method for characterizing documents by identifying the most relevant semantic axes ("microframes") that are overrepresented in the text using word embedding. Our unsupervised approach can be readily applied to large datasets because it does not require manual annotations.

ECG Heartbeat Classification Based on an Improved ResNet-18 Model.

Based on a convolutional neural network (CNN) approach, this article proposes an improved ResNet-18 model for heartbeat classification of electrocardiogram (ECG) signals through appropriate model training and parameter adjustment. Due to the unique residual structure of the model, the utilized CNN layered structure can be deepened in order to achieve better classification performance. The results of applying the proposed model to the MIT-BIH arrhythmia database demonstrate that the model achieves higher accuracy (96.

Tubular HIPK2 is a key contributor to renal fibrosis.

We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo.

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression.

While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of full-length protein by preventing naturally occurring non-productive alternative splicing and promoting generation of productive mRNA. Bioinformatics analysis of RNA sequencing data identifies non-productive splicing events in 7,757 protein-coding human genes, of which 1,246 are disease-associated.

Global labor flow network reveals the hierarchical organization and dynamics of geo-industrial clusters.

Groups of firms often achieve a competitive advantage through the formation of geo-industrial clusters. Although many exemplary clusters are the subjects of case studies, systematic approaches to identify and analyze the hierarchical structure of geo-industrial clusters at the global scale are scarce. In this work, we use LinkedIn's employment history data from more than 500 million users over 25 years to construct a labor flow network of over 4 million firms across the world, from which we reveal hierarchical structure by applying network community detection.

Transcriptome and physiological analyses for revealing genes involved in wheat response to endoplasmic reticulum stress.

Background: Wheat production is largely restricted by adverse environmental stresses. Under many undesirable conditions, endoplasmic reticulum (ER) stress can be induced. However, the physiological and molecular responses of wheat to ER stress remain poorly understood.

Hsp90β knockdown in DIO mice reverses insulin resistance and improves glucose tolerance.

Background: Inhibition of Hsp90 has been shown to improve glucose tolerance and insulin sensitivity in mouse models of diabetes. In the present report, the specific isoform Hsp90ab1, was identified as playing a major role in regulating insulin signaling and glucose metabolism.

Methods: In a diet-induced obese (DIO) mouse model of diabetes, expression of various Hsp90 isoforms in skeletal tissue was examined.

Knockdown of Expression of Cdk5 or p35 (a Cdk5 Activator) Results in Podocyte Apoptosis.

Podocytes are terminally differentiated glomerular epithelial cells. Podocyte loss has been found in many renal diseases. Cdk5 is a cyclin-dependent protein kinase which is predominantly regulated by p35.

Sexual dysfunction in selective serotonin reuptake inhibitors (SSRIs) and potential solutions: A narrative literature review.

Sexual dysfunction is an underdiscussed adverse effect to selective serotonin reuptake inhibitors (SSRIs) and may increase the risk for discontinuation and nonadherence to antidepressant pharmacotherapy. Given the prevalence of depression, health care providers should educate patients about SSRI-associated sexual dysfunction in order to promote patient awareness and medication adherence. This study evaluated primary literature from 1997 to 2015 to identify SSRI-related sexual side effects, therapeutic alternatives, and treatment strategies.

Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.

Sirt3 is an NAD(+)-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion of Sirt3 led to impaired glucose oxidation in muscle, which was associated with decreased pyruvate dehydrogenase (PDH) activity, accumulation of pyruvate and lactate metabolites, and an inability of insulin to suppress fatty acid oxidation.

Platform-independent and label-free quantitation of proteomic data using MS1 extracted ion chromatograms in skyline: application to protein acetylation and phosphorylation.

Despite advances in metabolic and postmetabolic labeling methods for quantitative proteomics, there remains a need for improved label-free approaches. This need is particularly pressing for workflows that incorporate affinity enrichment at the peptide level, where isobaric chemical labels such as isobaric tags for relative and absolute quantitation and tandem mass tags may prove problematic or where stable isotope labeling with amino acids in cell culture labeling cannot be readily applied. Skyline is a freely available, open source software tool for quantitative data processing and proteomic analysis.