137 research outputs found
Process for generation of high-producing CHO cell lines for biomanufacturing of biologics using our CHOrcTA platform
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RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy
BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible proâapoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by necrosis and inflammatory infiltrates, nonâapoptotic pathways may be also involved. METHODS: We explored DUX4âmediated cell death by focusing on the role of one regulated necrosis pathway called necroptosis, which is regulated by RIPK3. We investigated the effect of necroptosis on cell death in vitro and in vivo experiments using RIPK3 inhibitors and a RIPK3âdeficient transgenic mouse model. RESULTS: We showed in vitro that DUX4 expression causes a caspaseâindependent and RIPK3âmediated cell death in both myoblasts and myotubes. In vivo, RIPK3âdeficient animals present improved body and muscle weights, a reduction of the aberrant activation of the DUX4 network genes, and an improvement of muscle histology. CONCLUSIONS: These results provide evidence for a role of RIPK3 in DUX4âmediated cell death and open new avenues of research
The Relation Between Depressive Symptoms and Semantic Memory in Amnestic Mild Cognitive Impairment and in Late-Life Depression
Semantic deficits have been documented in the prodromal phase of Alzheimerâs disease, but it is unclear whether these deficits are associated with non-cognitive manifestations. For instance, recent evidence indicates that cognitive deficits in elders with amnestic mild cognitive impairment (aMCI) are modulated by concomitant depressive symptoms. The purposes of this study were to (i) investigate if semantic memory impairment in aMCI is modulated according to the presence (aMCI-D group) or absence (aMCI group) of depressive symptoms, and (ii) compare semantic memory performance of aMCI and aMCI-D groups to that of patients with late-life depression (LLD). Seventeen aMCI, 16 aMCI-D, 15 LLD, and 26 healthy control participants were administered a semantic questionnaire assessing famous person knowledge. Results showed that performance of aMCI-D patients was impaired compared to the control and LLD groups. However, in the aMCI group performance was comparable to that of all other groups. Overall, these findings suggest that semantic deficits in aMCI are somewhat associated with the presence of concomitant depressive symptoms. However, depression alone cannot account solely for the semantic deficits since LLD patients showed no semantic memory impairment in this study. Future studies should aim at clarifying the association between depression and semantic deficits in older adults meeting aMCI criteria.Instituts de recherche en santĂ© du Canada (IRSC) IAO-8467
Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium
The HMG-box transcription factor Sox9 is expressed in the intestinal epithelium, specifically, in stem/progenitor cells and in Paneth cells. Sox9 expression requires an active ÎČ-cateninâTcf complex, the transcriptional effector of the Wnt pathway. This pathway is critical for numerous aspects of the intestinal epithelium physiopathology, but processes that specify the cell response to such multipotential signals still remain to be identified. We inactivated the Sox9 gene in the intestinal epithelium to analyze its physiological function. Sox9 inactivation affected differentiation throughout the intestinal epithelium, with a disappearance of Paneth cells and a decrease of the goblet cell lineage. Additionally, the morphology of the colon epithelium was severely altered. We detected general hyperplasia and local crypt dysplasia in the intestine, and Wnt pathway target genes were up-regulated. These results highlight the central position of Sox9 as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis
The continuum of fetal alcohol spectrum disorders in a community in South Africa: Prevalence and characteristics in a fifth sample
The prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in a fifth sample in a South African community
Breastfeeding and maternal alcohol use: Prevalence and effects on child outcomes and fetal alcohol spectrum disorders
Determine any effects that maternal alcohol consumption during the breastfeeding period has on child outcomes
Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)
The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia
Biallelic loss-of-function variants in <i>CACHD1 </i>cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities
Purpose We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. Methods We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. Results Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. Conclusion Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities
Revival of the magnetar PSR J1622-4950: observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR
New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and
NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a
quiescent state since at least early 2015, reactivated between 2017 March 19
and April 5. The radio flux density, while variable, is approximately 100x
larger than during its dormant state. The X-ray flux one month after
reactivation was at least 800x larger than during quiescence, and has been
decaying exponentially on a 111+/-19 day timescale. This high-flux state,
together with a radio-derived rotational ephemeris, enabled for the first time
the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV
pulsed fraction is comparable to the smallest observed for magnetars. The
overall pulsar geometry inferred from polarized radio emission appears to be
broadly consistent with that determined 6-8 years earlier. However, rotating
vector model fits suggest that we are now seeing radio emission from a
different location in the magnetosphere than previously. This indicates a novel
way in which radio emission from magnetars can differ from that of ordinary
pulsars. The torque on the neutron star is varying rapidly and unsteadily, as
is common for magnetars following outburst, having changed by a factor of 7
within six months of reactivation.Comment: Published in ApJ (2018 April 5); 13 pages, 4 figure
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