09/17/2024


Non-homologous end joining (NHEJ) is the predominant pathway that repairs DNA double-strand breaks in vertebrates. During NHEJ DNA ends are held together by a multi-protein synaptic complex until they are ligated. Here, we use Xenopus laevis egg extract to investigate the role of the intrinsically disordered C-terminal tail of the XRCC4-like factor (XLF), a critical factor in end synapsis. We demonstrate that the XLF tail along with the Ku-binding motif (KBM) at the extreme C-terminus are required for end joining. Although the underlying sequence of the tail can be varied, a minimal tail length is required for NHEJ. Single-molecule FRET experiments that observe end synapsis in real-time show that this defect is due to a failure to closely align DNA ends. Our data supports a model in which a single C-terminal tail tethers XLF to Ku, while allowing XLF to form interactions with XRCC4 that enable synaptic complex formation.An inadequate supply of amino acids leads to accumulation of uncharged tRNAs, which can bind and activate GCN2 kinase to reduce translation. Here, we show that glutamine-specific tRNAs selectively become uncharged when extracellular amino acid availability is compromised. In contrast, all other tRNAs retain charging of their cognate amino acids in a manner that is dependent upon intact lysosomal function. In addition to GCN2 activation and reduced total translation, the reduced charging of tRNAGln in amino-acid-deprived cells also leads to specific depletion of proteins containing polyglutamine tracts including core-binding factor α1, mediator subunit 12, transcriptional coactivator CBP and TATA-box binding protein. Treating amino-acid-deprived cells with exogenous glutamine or glutaminase inhibitors restores tRNAGln charging and the levels of polyglutamine-containing proteins. Together, these results demonstrate that the activation of GCN2 and the translation of polyglutamine-encoding transcripts serve as key sensors of glutamine availability in mammalian cells.Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.Zinc and copper are involved in neuronal differentiation and synaptic plasticity but the molecular mechanisms behind these processes are still elusive due in part to the difficulty of imaging trace metals together with proteins at the synaptic level. We correlate stimulated-emission-depletion microscopy of proteins and synchrotron X-ray fluorescence imaging of trace metals, both performed with 40 nm spatial resolution, on primary rat hippocampal neurons. We reveal the co-localization at the nanoscale of zinc and tubulin in dendrites with a molecular ratio of about one zinc atom per tubulin-αβ dimer. We observe the co-segregation of copper and F-actin within the nano-architecture of dendritic protrusions. In addition, zinc chelation causes a decrease in the expression of cytoskeleton proteins in dendrites and spines. Overall, these results indicate new functions for zinc and copper in the modulation of the cytoskeleton morphology in dendrites, a mechanism associated to neuronal plasticity and memory formation.Our knowledge about the repertoire of ribosomal RNA modifications and the enzymes responsible for installing them is constantly expanding. Previously, we reported that NSUN-5 is responsible for depositing m5C at position C2381 on the 26S rRNA in Caenorhabditis elegans. Here, we show that NSUN-1 is writing the second known 26S rRNA m5C at position C2982. Depletion of nsun-1 or nsun-5 improved thermotolerance and slightly increased locomotion at midlife, however, only soma-specific knockdown of nsun-1 extended lifespan. Moreover, soma-specific knockdown of nsun-1 reduced body size and impaired fecundity, suggesting non-cell-autonomous effects. While ribosome biogenesis and global protein synthesis were unaffected by nsun-1 depletion, translation of specific mRNAs was remodeled leading to reduced production of collagens, loss of structural integrity of the cuticle, and impaired barrier function. We conclude that loss of a single enzyme required for rRNA methylation has profound and highly specific effects on organismal development and physiology.The subcortical sensory pathways are the fundamental channels for mapping the outside world to our minds. Sensory pathways efficiently transmit information by adapting neural responses to the local statistics of the sensory input. The long-standing mechanistic explanation for this adaptive behaviour is that neural activity decreases with increasing regularities in the local statistics of the stimuli. An alternative account is that neural coding is directly driven by expectations of the sensory input. Here, we used abstract rules to manipulate expectations independently of local stimulus statistics. The ultra-high-field functional-MRI data show that abstract expectations can drive the response amplitude to tones in the human auditory pathway. These results provide first unambiguous evidence of abstract processing in a subcortical sensory pathway. They indicate that the neural representation of the outside world is altered by our prior beliefs even at initial points of the processing hierarchy.
We aimed to describe the clinical features of narcolepsy in patients referred to our sleep center between 2009 and 2016, and to compare these features across age groups and between sporadic versus AS03-adjuvanted H1N1 influenza vaccine-related cases.

This is a retrospective, consecutive study of adult and pediatric narcolepsy cases in the Republic of Ireland. All participants underwent structured assessments, including polysomnography and multiple sleep latency testing. Brain MRI, hypocretin levels and HLA typing were also carried out on the majority of patients. Patients were compared across age groups as well as aetiology.

Forty (74%) patients were vaccine-related. The median age was 13.5 years and time from symptom onset to diagnosis was 112 weeks. Median time from vaccination to symptom onset was 26 weeks. In children, hypnogogic hallucinations and sleep paralysis were less frequent than in adults (17% vs. 67%, p = 0.018 and 0% vs. 75%, p < 0.0005). MSLT sleep latency was shorter in children than adults (median 1.75 vs. 4 mins, p = 0.011). Vaccine-related and sporadic cases had typical clinical presentations. Vaccine-related cases had longer PSG latency (median 10.5 vs 5 mins, p = 0.043), longer stage 2 sleep (209.6 ± 44.6 vs. 182.3 ± 34.2 mins, p = 0.042), and a trend towards longer total sleep times (p = 0.09). No differences were noted in relation to MSLT, hypocretin, HLA typing and MRI.

Results show that vaccine-related cases greatly outnumbered sporadic cases during the study period and suggest that sporadic and vaccine-related narcolepsy are clinically similar entities.
Results show that vaccine-related cases greatly outnumbered sporadic cases during the study period and suggest that sporadic and vaccine-related narcolepsy are clinically similar entities.
Urinary incontinence affects one in three women worldwide. Pelvic floor muscle training is an effective treatment. Electromyography biofeedback (providing visual or auditory feedback of internal muscle movement) is an adjunct that may improve outcomes.

To determine the clinical effectiveness and cost-effectiveness of biofeedback-mediated intensive pelvic floor muscle training (biofeedback pelvic floor muscle training) compared with basic pelvic floor muscle training for treating female stress urinary incontinence or mixed urinary incontinence.

A multicentre, parallel-group randomised controlled trial of the clinical effectiveness and cost-effectiveness of biofeedback pelvic floor muscle training compared with basic pelvic floor muscle training, with a mixed-methods process evaluation and a longitudinal qualitative case study. Group allocation was by web-based application, with minimisation by urinary incontinence type, centre, age and baseline urinary incontinence severity. Participants, therapy provide other ways to intensify pelvic floor muscle training to improve continence outcomes.

Current Controlled Trial ISRCTN57746448.

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 70. See the NIHR Journals Library website for further project information.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 70. See the NIHR Journals Library website for further project information.Dracunculiasis, slated for global eradication, typically is acquired by drinking stagnant water containing microscopic crustaceans (copepods) infected with Dracunculus medinensis larvae, causing clusters of case persons with worms emerging from the skin. Following a 10-year absence of reported cases, 9-17 sporadic human cases with few epidemiologic links have been reported annually in Chad since 2010; dog infections have also been reported since 2012. We conducted an investigation of human cases in Chad to identify risk factors. We conducted a case-control study using a standardized questionnaire to assess water and aquatic animal consumption, and links to dog infections. Case persons had laboratory-confirmed D. medinensis during 2013-2017. Each case person was matched to one to three controls without history of disease by age, gender, and residency in the village where the case person was likely infected. We estimated odds ratios (ORs) using simple conditional logistic regression. We enrolled 25 case persons with 63 matched controls. Dracunculiasis was associated with consumption of untreated water from hand-dug wells (OR 13.4; 95% CI 1.7-108.6), but neither with consumption of aquatic animals nor presence of infected dogs in villages. Unsafe water consumption remains associated with dracunculiasis. Education of populations about consuming safe water and using copepod filters to strain unsafe water should continue and expand, as should efforts to develop and maintain safe drinking water sources. Nevertheless, the peculiar epidemiology in Chad remains incompletely explained. Future studies of dogs might identify other risk factors.Diarrhea remains a significant cause of child morbidity and mortality in Iraq. The objective of this study was to examine the current practices of home-based management of diarrheal illnesses among Iraqi children. We surveyed mothers of children aged less than 5 years to identify the sociodemographic factors associated with maternal healthcare-seeking practices. A total of 500 mother-child pairs were interviewed in a cross-sectional household survey in Thi-Qar Governorate, southeastern Iraq, between March 2016 and February 2017. Logistic and multinomial regression models were used to infer sociodemographic predictors of the healthcare-seeking and alternative management practices adopted by the mothers. The interviewees reported that 35.2% of their children had diarrhea in the 2 weeks before the survey. https://www.selleckchem.com/products/l-ascorbic-acid-2-phosphate-sesquimagnesium-salt-hydrate.html The least likelihood of reported occurrence of diarrhea was among mother-child pairs where the mothers had received university education, as compared with mothers who were illiterate or received only primary or secondary education.