Activity

etric properties, and its sensitivity to detect symptom changes after treatment ensure NSS-P future use in clinical and research settings.

We validated a brief instrument to assess NT1 symptom frequency, severity and consequences in ≥10-year-old children and adolescents, with four clinically relevant severity score ranges. This scale constitutes a relevant tool to improve and provide guidance for NT1 management in pediatric populations. The ease of administration, its good psychometric properties, and its sensitivity to detect symptom changes after treatment ensure NSS-P future use in clinical and research settings.

Knowledge regarding psychiatric disorders in children and adolescents with psychogenic nonepileptic seizures (PNES) is limited. This study outlines the spectrum and risk of psychiatric disorders in childhood-onset PNES.

A nationwide matched cohort study of children and adolescents with PNES aged 5-17 years at time of diagnosis between January 1, 1996 and December 31, 2014. Two matched comparison groups were included children and adolescents with epilepsy (ES), and children and adolescents without PNES or epilepsy, termed healthy controls (HC). Outcomes were prevalent psychiatric disorders prior to index (i.e. date of diagnosis or corresponding date for HCs), and incident psychiatric disorders two years after index. Relative risks (RRs) were calculated and adjusted for potential confounders.

We included 384 children and adolescents with validated PNES, 1,152 with epilepsy, and 1,920 healthy controls. Among the PNES cases, 153 (39.8%) had prevalent psychiatric disorders and 150 (39.1%) incident psychiatric disorders. As compared to the epilepsy and healthy controls, children and adolescents with PNES had elevated risks of both prevalent psychiatric disorders (adjusted RR

1.87, 95% CI 1.59-2.21, adjusted RR

5.54, 95% CI 4.50-6.81), and incident psychiatric disorders (adjusted RR

2.33, 95% CI 1.92-2.83, adjusted RR

8.37, 95% CI 6.31-11.11). A wide spectrum of specific psychiatric disorders displayed elevated RRs.

Children and adolescents with PNES are at higher risk of a wide range of psychiatric disorders as compared to children and adolescents with epilepsy and healthy controls. A careful psychiatric evaluation is warranted to optimize and individualize treatment.

Children and adolescents with PNES are at higher risk of a wide range of psychiatric disorders as compared to children and adolescents with epilepsy and healthy controls. A careful psychiatric evaluation is warranted to optimize and individualize treatment.

To test the hypothesis that increased aortic stiffening is associated with greater cerebrospinal fluid (CSF) evidence of core Alzheimer’s disease pathology (Aβ, phosphorylated tau (p-tau)), neurodegeneration (total tau (t-tau)), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light (NFL)), and neuroinflammation (YKL-40, sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.

Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic pulse wave velocity (PWV, m/sec) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations adjusting for age, race/ethnicity, education, apolipoprotein (

) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis,

-ε4, and hypertension on greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.

To undertake a genomewide association study (GWAS) to identify genetic variants for stroke in Indians.

In a hospital-based case-control study, eight teaching hospitals in India recruited 4,088 subjects, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed using logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked.

Association of vascular risk factors with stroke were similar to previous reports, and show modifiable risk factors like hypertension, smoking, and alcohol consumption having the highest effect. Single-marker based association revealed two loci for cardioembolic stroke (1p21 and 16q24), two for small vessel disease stroke (3p26 and 16p13), and four for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at P<5×10

. The index SNP of 1p21 is an eQTL (P

=1.74×10

) for

involved in SUMOlation and is associated with platelet distribution width (1.15×10

) and 18-carbon fatty acid metabolism (P=7.36×10

). In gene-based analysis we identified three genes (

,

) at P<2.7×10

. 11 of 32 candidate gene loci studied in Indians replicated (P<0.05), and 21 of 32 loci identified through previous GWAS replicated based on directionality of effect.

This first GWAS of stroke in Indians identified novel loci and replicated previously known loci. For the first time, genetic variants in the SUMOlation pathway which has been implicated in brain ischemia were identified.

This first GWAS of stroke in Indians identified novel loci and replicated previously known loci. For the first time, genetic variants in the SUMOlation pathway which has been implicated in brain ischemia were identified.Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief. Here, we showed the effect of ABIN-1 in modulating morphine function. We used hotplate tests and CPP tests to show that overexpression of ABIN-1 in the mice brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1-β-arrestin2 complexes, which accelerate β-arrestin2 degradation by ubiquitination. With the degradation of β-arrestin2, ABIN-1 overexpression also decreased MOR phosphorylation and internalization following opioid treatment, affecting the β-arrestin2-dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in β-arrestin2 knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and β-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence. Significance Statement ABIN-1 overexpression in mice brain attenuated morphine tolerance and dependence. The mechanism may be that ABIN-1-β-arrestin-2 complex formation facilitated β-arrestin-2 degradation by ubiquitination. ABIN-1 targeted β-arrestin2 to regulate morphine tolerance Therefore, inhibiting of ABIN-1 is an important strategy to prevent morphine tolerance and dependence.The 14-3-3 proteins constitute a family of regulatory adapter proteins with many binding partnersand biological functions, and are considered promising drug targets in cancer and neuropsychiatry.By screening 1280 small-molecule drugs using differential scanning fluorimetry (DSF), we found 15 compounds that decreased the thermal stability of 14-3-3ζ. Among these compounds, ebselen was identified as a covalent, destabilizing ligand of 14-3-3 isoforms ζ, ε, γ and η. Ebselen bonding decreased 14-3-3ζ binding to its partner Ser19-phosphorylated tyrosine hydroxylase. GDC-0879 in vitro Characterization of site-directed mutants at cysteine residues in 14-3-3ζ (C25, C94, and C189) by DSF and mass spectroscopy revealed covalent modification by ebselen of all cysteines. C25 was identified as the preferential site of ebselen interaction in vitro, whereas modification of C94 was mainly responsible for the protein destabilization. At therapeutic relevant concentrations ebselen caused a decrease of 14-3-3 levels in both SHSY5Y cells and zebr cancer, bipolar disorder and the virus infection Covid-19, covalently bonds to cysteine residues in 14-3-3 adaptor proteins, triggering 14-3-3 destabilization and degradation in cells and intact brain tissue when used in therapeutic concentrations, potentially explaining the behavioral and anti-neoplastic effects of this drug.The non-taxane microtubule inhibitor, eribulin, is an approved therapeutic for metastatic breast cancer and liposarcoma. Eribulin was previously tested in unselected lung cancer patients and yielded a modest objective response rate of ~5-12 percent. Because lung cancers represent diverse histologies and driving oncogenic mutations, we postulated that eribulin may exhibit properties of a precision oncology agent with a previously undefined specificity for a molecularly distinct subset of lung cancers. Herein, we screened a panel of 44 non-small cell and small cell lung cancer cell lines for in vitro growth sensitivity to eribulin. The results revealed a greater than 15,000-fold range in eribulin sensitivity (IC50 = 0.005 – 89 nM) amongst the cell lines that was not correlated with their sensitivity to the taxane-based inhibitor, paclitaxel. The quartile of cell lines exhibiting the lowest eribulin IC50 values was not enriched for specific histologies, epithelial-mesenchymal differentiation or specific oncogene highest sensitivity to eribulin bear TP53 null phenotypes, supporting a rationale to consider the status of this tumor suppressor in the clinical setting.Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and carries a very poor prognosis. Understanding PAH pathogenesis is needed to develop new therapeutic strategies. TGF-β drives vascular remodeling and increases vascular resistance by regulating differentiation and proliferation of smooth muscle cells (SMCs). Also, sphingosine-1-phosphate (S1P) has been implicated in PAH but the relation between these two signaling mechanisms is not well understood. Here, we characterize the signaling networks downstream of TGF-β in human pulmonary arterial smooth muscle cells (HPASMCs) which involves SMAD signaling as well as Rho GTPases. Activation of Rho GTPases regulates myocardin-related transcription factor (MRTF) and serum response factor (SRF) transcription activity and results in upregulation of contractile gene expression. Our data show that in HPASMCs, upregulation of alpha smooth muscle actin (αSMA) by TGF-β is dependent on both SMAD and Rho/MRTF-A/SRF transcriptional m pathway is a signaling node in the αSMA regulatory network and is a potential therapeutic target for the treatment of PAH.