Tubulin is actively exported from the nucleus through the Exportin1/CRM1 pathway

Microtubules of all eukaryotic cells are formed by α- and β-tubulin heterodimers. In addition to the well known cytoplasmic tubulins, a subpopulation of tubulin can occur in the nucleus. So far, the potential function of nuclear tubulin has remained elusive. In this work, we show that α- and β-tubulins of various organisms contain multiple conserved nuclear export sequences, which are potential targets of the Exportin 1/CRM1 pathway. We demonstrate exemplarily that these NES motifs are sufficient to mediate export of GFP as model cargo and that this export can be inhibited by leptomycin B, an inhibitor of the Exportin 1/CRM1 pathway. Likewise, leptomycin B causes accumulation of GFP-tagged tubulin in interphase nuclei, in both plant and animal model cells. Our analysis of nuclear tubulin content supports the hypothesis that an important function of nuclear tubulin export is the exclusion of tubulin from interphase nuclei, after being trapped by nuclear envelope reassembly during telophase

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

International audienceBackground: Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism.Methodology/Principal Findings: The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity.Conclusions/Significance: The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Abstract: Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

Évaluation de l’attitude des soignants face à la spiritualité des patients en fin de vie : enquête réalisée au sein de 4 services hospitaliers de l’aire toulonnaise

Introduction : des études récentes montrent que les patients atteints de maladies graves et en fin de vie souhaitent que leur spiritualité soit intégrée dans les soins, que les soignants s’y intéressent. L’objectif principal de cette étude est d’évaluer l’attitude des soignants face à la spiritualité des patients en fin de vie.Matériels et méthode : cette étude descriptive transversale incluait 110 soignants exerçant en région toulonnaise au sein de 4 services hospitaliers : une unité de soins palliatifs et 3 services de médecine bénéficiant de Lits Identifiés de Soins Palliatifs (LISP). Ils étaient interrogés entre mai et juin 2017 via un questionnaire recueilli de façon anonymisée.Résultats : 62 questionnaires ont été analysés. Plus de ¾ des soignants percevaient des aspirations spirituelles chez leurs patients en fin de vie et pensaient qu’ils avaient besoin d’un accompagnement spirituel. 60% affirmaient ne pas savoir évaluer l’état spirituel de leurs patients : 50% ne recherchaient pas de signes de souffrance spirituelle, ¾ n’essayaient pas comprendre la place de la spiritualité dans la vie de leurs patients, deux tiers essayaient d’identifier leurs ressources spirituelles (lieu de réconfort, projets, soutien, valeurs) mais de manière incomplète puisque plus de 80% ne suscitaient pas d’échanges profonds avec eux (sens donné à l’épreuve, à leur vie, à l’au-delà). 90% des soignants affirmaient que leurs patients pouvaient parler de religion avec eux mais 50% ne connaissaient pas la religion de leurs patients et ne trouvaient pas cette information importante, 80% ignoraient le degré de pratique de leurs patients et ne s’intéressaient pas à la place de leur foi dans leur vie ni à son influence dans leur maladie. Face à un patient croyant, seulement 22% des soignants prévenaient un représentant du culte. Trois quarts des soignants ne connaissaient pas les différents rites et croyances propres à chaque religion et relatifs à la mort. Les principales formes d’accompagnement spirituel étaient les visites des représentants du culte (90%), celles des bénévoles (74%) et la psychothérapie (40%). 70% des soignants pensaient qu’accompagner les patients sur le plan spirituel était leur rôle. 38% affirmaient les accompagner souvent eux-mêmes. Un tiers des soignants exprimait un sentiment d’incompétence et un manque de temps. Quasiment aucun soignant n’était formé à l’accompagnement spirituel (n=53), y compris parmi ceux qui avaient suivi une formation diplômante en soins palliatifs. 60% des soignants n’exprimaient pas de besoin de formation.Conclusion : la dimension spirituelle des patients en fin de vie est souvent perçue par les soignants mais n’est que rarement prise en compte dans tous ses aspects, notamment en ce qui concerne la question religieuse. Il apparaît nécessaire de former les soignants dans ce domaine. Dans le contexte sociétal actuel, il nous semble également important de poursuivre la réflexion sur la nouvelle articulation soins/spiritualité au sein des services hospitaliers. Nous devons aussi promouvoir l’accès aux soins palliatifs pour tous les patients, en encourageant la mise en place d’équipes mobiles de soins palliatifs au sein de tous les établissements de santé

Travail avec les parents dans la consultation de pédopsychiatrie

Cet article montre en quoi le travail avec les parents est un élément constitutif de la consultation en pédopsychiatrie. Le pédopsychiatre est confronté, dans un premier temps, à une clinique de situation où les différents éléments de la demande sont dispersés sur plusieurs membres du groupe familial. Le symptôme, quant à lui, relève d’une approche multidimensionnelle, la dimension environnementale et familiale y a son importance. Les auteurs précisent le cadre de la consultation et sa fonction dans le traitement de l’enfant. Les parents y tiennent une place complexe : à l’origine de la demande, ils sont immanquablement impliqués dans le problème de l’enfant et, surtout, dans l’aide qui lui est apportée. Ils participent avec l’enfant et le consultant à une co-création de nouvelles représentations du problème de l’enfant