SciCombinator

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α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson’s disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.

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Chronic idiopathic constipation (CIC) is one of the most common gastrointestinal disorders, with a global prevalence of 14%. It is commoner in women and its prevalence increases with age. There are three subtypes of CIC: dyssynergic defaecation, slow transit constipation and normal transit constipation, which is the most common subtype. Clinical assessment of the patient with constipation requires careful history taking, in order to identify any red flag symptoms that would necessitate further investigation with colonoscopy to exclude colorectal malignancy. Screening for hypercalcaemia, hypothyroidism and coeliac disease with appropriate blood tests should be considered. A digital rectal examination should be performed to assess for evidence of dyssynergic defaecation. If this is suspected, further investigation with high resolution anorectal manometry should be undertaken. Anorectal biofeedback can be offered to patients with dyssynergic defaecation as a means of correcting the associated impairment of pelvic floor, abdominal wall and rectal functioning. Lifestyle modifications, such as increasing dietary fibre, are the first step in managing other causes of CIC. If patients do not respond to these simple changes, then treatment with osmotic and stimulant laxatives should be trialled. Patients not responding to traditional laxatives should be offered treatment with prosecretory agents such as lubiprostone, linaclotide and plecanatide, or the 5-HT4 receptor agonist prucalopride, where available. If there is no response to pharmacological treatment, surgical intervention can be considered, but it is only suitable for a carefully selected subset of patients with proven slow transit constipation.

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Hypokinetic dysarthria in Parkinson disease (PD) hinders the ability to verbally communicate and interferes with activities of daily living. SPEAK OUT!® is a therapy program designed to improve functional communicative ability. In contrast to the Lee Silverman Voice Treatment program, SPEAK OUT!® promotes speaking with intent to effect loud speech. This study evaluated the efficacy of SPEAK OUT!® in persons with idiopathic PD in 3 domains: self-reported voice handicap, clinical ratings of dysarthria and prosody, and acoustic analysis of prosody.

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To describe liver disease related mortality in the United States during 1999-2016 by age group, sex, race, cause of liver disease, and geographic region.

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To assess the efficacy of arthroscopic subacromial decompression (ASD) by comparing it with diagnostic arthroscopy, a placebo surgical intervention, and with a non-operative alternative, exercise therapy, in a more pragmatic setting.

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To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes.

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Diabetes is a common complication of pregnancy, and the prevalence of all types of the disease is increasing worldwide. Diabetes in pregnancy is associated with short term and long term adverse effects for mother and child. The goal of treatment of diabetes in pregnancy is to minimize maternal and fetal adverse events related to hyperglycemia. Treatment options vary by type of diabetes, from a focus on lifestyle modifications in gestational diabetes to continuous glucose monitoring and insulin pumps in pregestational diabetes. Nevertheless, given the commonality of hyperglycemia, considerable overlap exists in the treatment of different types of diabetes in pregnancy. Also, despite ongoing research on treatment of diabetes in pregnancy for decades, changes in the characteristics of the patient population have highlighted the limited effectiveness of different therapies. Specifically, despite the co-occurrence of obesity and diabetes, treatment recommendations including glycemic targets are not altered in such cases and a single optimal treatment strategy for each type of diabetes in pregnancy does not seem to exist. Rather, the approach to treating pregnant women with diabetes likely needs to be individualized to maximize the short term and long term health of mother and child. This article will review recent clinical studies to summarize established treatment strategies and introduce novel therapies for diabetes in pregnancy.

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Nucleosomes present a barrier for the binding of most transcription factors (TFs). However, special TFs known as nucleosome-displacing factors (NDFs) can access embedded sites and cause the depletion of the local nucleosomes as well as repositioning of the neighboring nucleosomes. Here, we developed a novel high-throughput method in yeast to identify NDFs among 104 TFs and systematically characterized the impact of orientation, affinity, location, and copy number of their binding motifs on the nucleosome occupancy. Using this assay, we identified 29 NDF motifs and divided the nuclear TFs into three groups with strong, weak, and no nucleosome-displacing activities. Further studies revealed that tight DNA binding is the key property that underlies NDF activity, and the NDFs may partially rely on the DNA replication to compete with nucleosome. Overall, our study presents a framework to functionally characterize NDFs and elucidate the mechanism of nucleosome invasion.

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The modulator of retrovirus infection (MRI or CYREN) is a 30-kDa protein with a conserved N-terminal Ku-binding motif (KBM) and a C-terminal XLF-like motif (XLM). We show that MRI is intrinsically disordered and interacts with many DNA damage response (DDR) proteins, including the kinases ataxia telangiectasia mutated (ATM) and DNA-PKcs and the classical non-homologous end joining (cNHEJ) factors Ku70, Ku80, XRCC4, XLF, PAXX, and XRCC4. MRI forms large multimeric complexes that depend on its N and C termini and localizes to DNA double-strand breaks (DSBs), where it promotes the retention of DDR factors. Mice deficient in MRI and XLF exhibit embryonic lethality at a stage similar to those deficient in the core cNHEJ factors XRCC4 or DNA ligase IV. Moreover, MRI is required for cNHEJ-mediated DSB repair in XLF-deficient lymphocytes. We propose that MRI is an adaptor that, through multivalent interactions, increases the avidity of DDR factors to DSB-associated chromatin to promote cNHEJ.