What is "Normal," Anyway?

In psychology and psychiatry, it really means "average" or "typical," but we too easily think of it as a synonym for "how everyone is supposed to think and feel."

-- Read more on ScientificAmerican.com

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IJMS, Vol. 19, Pages 619: Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy

IJMS, Vol. 19, Pages 619: Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy

International Journal of Molecular Sciences doi: 10.3390/ijms19020619

Authors: Mercè Izquierdo-Serra Antonio Martínez-Monseny Laura López Julia Carrillo-García Albert Edo Juan Ortigoza-Escobar Óscar García Ramón Cancho-Candela M Carrasco-Marina Luis Gutiérrez-Solana Daniel Cuadras Jordi Muchart Raquel Montero Rafael Artuch Celia Pérez-Cerdá Belén Pérez Belén Pérez-Dueñas Alfons Macaya José Fernández-Fernández Mercedes Serrano

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients’ group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

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Scientists discover new nanoparticle, dubbed exomeres

A new cellular messenger discovered by Weill Cornell Medicine scientists may help reveal how cancer cells co-opt the body's intercellular delivery service to spread to new locations in the body. In a paper published in Nature Cell Biology, the scientists...

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Five novel genetic changes linked to pancreatic cancer risk

In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other institutions worldwide discovered...

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New interaction mechanism of proteins discovered

Proteins are among the most important biomolecules and are the key mediators of molecular communication between and within cells. For two proteins to be able to bind, specific regions of their three-dimensional structure have to exactly match one another...

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Mental Health of Long Term Survivors of Childhood and Young Adult Cancer: A Systematic Review

Abstract

Childhood cancer is increasing in prevalence whilst survival rates are improving. The prevalence of adult survivors of childhood cancer is consequently increasing. Many survivors suffer long-term consequences of their cancer treatment. Whilst many of these are well documented, relatively little is known about the mental health of survivors of childhood cancer.

This article aimed to describe the prevalence and spectrum of mental health problems found in adult survivors of childhood cancer using a systematic review methodology.

Our review included 67 papers, describing a number of problems, including depression, anxiety, behavioural problems and drug misuse. Factors increasing the likelihood of mental health problems included treatment with high dose anthracyclines, cranial irradiation, diagnoses of sarcoma or central nervous system tumours and ongoing physical ill health.

There were numerous limitations to the studies we found, including use of siblings of survivors as a control group, self-report methodology and lack of indications for prescriptions when prescribing data was used.

This review has identified many mental health problems experienced by survivors of childhood cancer, however the exact incidence, prevalence and risk-factors for their development remain unclear. Further work to identify childhood cancer patients who are at risk of developing late mental health morbidity is essential. This article is protected by copyright. All rights reserved.

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Spatiotemporal homogeneity and distinctness of the T-cell receptor β-chain repertoires in Epstein-Barr virus-associated primary and metastatic nasopharyngeal carcinomas

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated lymphoepithelioma. The aim of the present study was to characterize the homogeneity and distinctness of the T-cell repertoires within and between primary and metastatic NPCs. We used ultra-deep sequencing of the hypervariably rearranged antigen-binding CDR3 regions of T-cell receptor beta (TCR_beta) to comprehensively profile the T-cell repertoires in NPC patients receiving definitive chemoradiotherapy with long-term follow-up. We observed not only various spatially heterogeneous patient-specific TCR_beta clone compositions that changed with time but also several commonly enriched TCR_beta subclones that were constantly shared between primary NPCs in the head and neck regions, locally recurrent tumors after treatment, and later-developed distant metastatic tumors in the liver, lung and bone. Comparison of the overlap frequency of the T-cell clonality between TCR_beta repertoires enabled us to calculate the pairwise genetic distance between primary NPCs of different patients and different sites of metastatic or recurrent NPCs. The constructed NPC phylogeny clearly differentiated the low-risk patients without relapse from the high-risk patients with distant metastasis after chemoradiotherapy. In contrast to the rather low frequency of non-silent somatic mutations in NPC cells, the degrees of similarity and divergence of NPC-infiltrating lymphocyte TCR_beta repertoires among different patients showed prognostication. Moreover, the persistent presence of commonly NPC-shared in-frame TCR_beta CDR3 gene sequences spatiotemporally identified in the NPC-infiltrating lymphocytes within varied EBV-positive NPCs and their metastases suggest the existence of frequently shared epitopes of neoantigens virally or non-virally displayed on cancer cells, thereby providing opportunities for the development of precisely tumor-targeted immunotherapy for distant metastasis. This article is protected by copyright. All rights reserved.

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