Differential substrate specificity of ERK, JNK, and p38 MAP kinases toward Connexin 43.

Phosphorylation of connexin 43 (Cx43) is an important regulatory mechanism of gap junction (GJ) function. Cx43 is modified by several kinases on over 15 sites within its ∼140 amino acid-long C-terminus (CT). Phosphorylation of Cx43CT on S255, S262, S279, and S282 by ERK has been widely documented in several cell lines, by many investigators.

Effects of TRPC1's Lysines on Heteromeric TRPC5-TRPC1 Channel Function.

Background: TRPC5 proteins form plasma membrane cation channels and are expressed in the nervous and cardiovascular systems. TRPC5 activation leads to cell depolarization and increases neuronal excitability, whereas a homologous TRPC1 inhibits TRPC5 function via heteromerization. The mechanism underlying the inhibitory effect of TRPC1 in TRPC5/TRPC1 heteromers remains unknown.

Anti-social behavior and soccer identities: different continents, same mindset?

Although most soccer fans support their teams peacefully, anti-social fan behavior continues to appear across the globe. We tested the roles of identity fusion and membership to an extreme fan group (ultras) in explaining fan disorder in two understudied contexts: Indonesia (Study 1) and Australia (Study 2). Incidents of violence and antisocial behavior were rarely reported among general Indonesian (9%) or Australian fans (6%) but were significantly higher among their respective ultras groups (37%; 20%).

Atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic skin disorder that can significantly impact the quality of life (QoL) of affected individuals as well as their families. Although the pathogenesis of the disorder is not yet completely understood, it appears to result from the complex interplay between defects in skin barrier function, environmental and infectious agents, and immune dysregulation. There are no diagnostic tests for AD; therefore, the diagnosis is based on specific clinical criteria that take into account the patient's history and clinical manifestations.

Dorzolamide intermediates with potential anti-inflammatory activity.

Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug's ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK).

Complete genome of pv. strain CCRMTAQ13 (causal agent of angular leaf spot in cashew) from Brazil using long-read Nanopore technology.

Here, we present a single contiguous genome sequence of pv. (; strain CCRMTAQ13), the causal agent of angular leaf spot in cashew, an important commodity crop in Brazil. Oxford Nanopore Sequencing Technology was used to assemble the genome of the in a single contig of 5,086,757 bp with a 64.

Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome.

Tyrosine phosphorylation of metabolic enzymes is an evolutionarily conserved posttranslational modification that facilitates rapid and reversible modulation of enzyme activity, localization, or function. Despite the high abundance of tyrosine phosphorylation events detected on metabolic enzymes in high-throughput mass spectrometry-based studies, functional characterization of tyrosine phosphorylation sites has been limited to a subset of enzymes. Since tyrosine phosphorylation is dysregulated across human diseases, including cancer, understanding the consequences of metabolic enzyme tyrosine phosphorylation events is critical for informing disease biology and therapeutic interventions.

Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression.

Background: Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.

Methods: We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms.

The long-term effects of limbic non-convulsive status epilepticus in peri-adolescent rats.

To optimize the clinical approach to non-convulsive status epilepticus (NCSE), it is essential to gain insight into its long-term effects on cognition and behaviors. Here, we investigated limbic NCSE-induced hippocampal injury and behavioral deficits in peri-adolescent rats. NCSE was induced in P43 Sprague Dawleyrats with intrahippocampal subconvulsive doses of kainic acid (NCSE group, n = 14) under continuous epidural cortical electroencephalography (EEG).

Validation and quantification of peptide antigens presented on MHCs using SureQuant.

Vaccines and immunotherapies that target peptide-major histocompatibility complexes (peptide-MHCs) have the potential to address multiple unmet medical needs in cancer and infectious disease. Designing vaccines and immunotherapies to target peptide-MHCs requires accurate identification of target peptides in infected or cancerous cells or tissue, and may require absolute or relative quantification to identify abundant targets and measure changes in presentation under different treatment conditions. Internal standard parallel reaction monitoring (also known as 'SureQuant') can be used to validate and/or quantify MHC peptides previously identified by using untargeted methods such as data-dependent acquisition.

Development of Machine Learning Algorithms Using EEG Data to Detect the Presence of Chronic Pain.

Chronic pain impacts more than one in five adults in the United States (US) and the costs associated with the condition amount to hundreds of billions of dollars annually. Despite the tremendous impact of chronic pain in the US and worldwide, the standard of care for diagnosis depends on subjective self-reporting of pain state, with no effective objective assessment procedure available. This study investigated the application of signal processing and machine learning to electroencephalography (EEG) data for the development of classification algorithms capable of differentiating subjects in pain from pain free subjects.

PathMHC: a workflow to selectively target pathogen-derived MHC peptides in discovery immunopeptidomics experiments for vaccine target identification.

Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobials-resistant (AMR) microbial pathogens and viruses with pandemic potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on major histocompatibility complexes (MHCs) can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self peptides in the MHC repertoire and may be missed in untargeted MS analyses.

High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable.

Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses.

Aging is associated with systemic chronic, low-grade inflammation, termed 'inflammaging'. This pattern of inflammation is multifactorial and is driven by numerous inflammatory pathways, including the inflammasome. However, most studies to date have examined changes in the transcriptomes that are associated with aging and inflammaging, despite the fact that inflammasome activation is driven by a series of post-translational activation steps, culminating in the cleavage and activation of caspase-1.

Influence of commercial inactivated or modified-live virus vaccination at time of AI on corpus luteum development and function in beef cattle.

Our objective was to evaluate the effect of vaccination with an inactivated virus vaccine (IVV) or modified-live virus (MLV) vaccine on the corpus luteum (CL). On d0, synchronized beef cows were treated with MLV (n = 70; BoviShield Gold FP5VL5), IVV (n = 16; ViraShield 6VL5HB), or were unvaccinated controls (n = 5). Plasma was collected from treated animals on d0 and every other day through d22.

White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study.

Introduction: Post-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individual's quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH.

Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition.

A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a human -mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal.

PYTA: a universal chelator for advancing the theranostic palette of nuclear medicine.

To clinically advance the growing arsenal of radiometals available to image and treat cancer, chelators with versatile binding properties are needed. Herein, we evaluated the ability of the py[18]dieneN macrocycle PYTA to interchangeably bind and stabilize Ac, [Lu]Lu, [In]In and [Sc]Sc, a chemically diverse set of radionuclides that can be used complementarily for targeted alpha therapy, beta therapy, single-photon emission computed tomography (SPECT) imaging, and positron emission tomography (PET) imaging, respectively. Through NMR spectroscopy and X-ray diffraction, we show that PYTA possesses an unusual degree of flexibility for a macrocyclic chelator, undergoing dramatic conformational changes that enable it to optimally satisfy the disparate coordination properties of each metal ion.

Targeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional Network.

Unlabelled: Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs.

Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease.

Background: Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3-5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials.

Pain, Return to Community Status, and 90-Day Mortality Among Hospitalized Patients With Heart Failure.

Background: Pain is common among patients with heart failure but has not been examined with short-term discharge outcomes. The purpose was to examine whether pain at discharge predicts return to community status and 90-day mortality among hospitalized patients with heart failure.

Methods: Data from medical records of 2169 patients hospitalized with heart failure were analyzed in this retrospective cohort study.