Mchughthrane7776

The cost of parentage assignment precludes its application in many selective breeding programmes and molecular ecology studies, and/or limits the circumstances or number of individuals to which it is applied. Pooling samples from more than one individual, and using appropriate genetic markers and algorithms to determine parental contributions to pools, is one means of reducing the cost of parentage assignment. This paper describes and validates a novel maximum likelihood (ML) parentage-assignment method, that can be used to accurately assign parentage to pooled samples of multiple individuals-previously published ML methods are applicable to samples of single individuals only-using low-density single nucleotide polymorphism (SNP) 'quantitative' (also referred to as 'continuous') genotype data. It is demonstrated with simulated data that, when applied to pools, this 'quantitative maximum likelihood' method assigns parentage with greater accuracy than established maximum likelihood parentage-assignment approaches, which rely on accurate discrete genotype calls; exclusion methods; and estimating parental contributions to pools by solving the weighted least squares problem. Quantitative maximum likelihood can be applied to pools generated using either a 'pooling-for-individual-parentage-assignment' approach, whereby each individual in a pool is tagged or traceable and from a known and mutually exclusive set of possible parents; or a 'pooling-by-phenotype' approach, whereby individuals of the same, or similar, phenotype/s are pooled. Although computationally intensive when applied to large pools, quantitative maximum likelihood has the potential to substantially reduce the cost of parentage assignment, even if applied to pools comprised of few individuals.Children with acute myeloid leukemia (AML) commonly develop extramedullary disease (EMD), which comprises central nervous system (CNS) lesions and myeloid sarcoma (MS). In this retrospective analysis, we aimed to determine the effect of EMD on the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 678 pediatric patients with de novo AML (median age, 7 years; range, 0.3-15 years) between 2006 and 2016. We compared the outcomes between patients with (EMD group, n = 158; CNS lesion, n = 47, CNS lesion + MS, n = 9, and MS, n = 102) and without EMD at diagnosis (non-EMD group, n = 520). Survivors were followed for a median of 4.5 years, and the 4-year overall survival (OS) rates were 60.6% and 56.4% in the EMD and non-EMD groups, respectively (P = 0.60). No significant differences in OS were observed with respect to the EMD site, except bone lesions, which were associated with poor OS after HCT in a non-remission status. A multivariate analysis revealed that EMD did not affect the outcomes of HCT. In conclusion, the study findings suggest that EMD should not be considered a poor prognostic factor in HCT for children with AML.Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.Academic institutions play a central role in the biotech industry through technology licensing and the creation of startups, but few data are available on their performance and the magnitude of their impact. Here we present a systematic study of technology licensing by one such institution, the Massachusetts Institute of Technology (MIT). Using data on the 76 therapeutics-focused life sciences companies formed through MIT's Technology Licensing Office from 1983 to 2017, we construct several measures of impact, including MIT patents cited in the Orange Book, capital raised, outcomes from mergers and acquisitions, patents granted to MIT intellectual property licensees, drug candidates discovered and US drug approvals-a key benchmark of innovation in the biopharmaceutical industry. As of December 2017, Orange Book listings for four approved small-molecule drugs cite MIT patents, but another 31 FDA-approved drugs (excluding candidates acquired after phase 3) had some involvement of MIT licensees. Fifty-five percent of the latter were either a new molecular entity or a new biological entity, and 55% were granted priority review, an indication that they address an unmet medical need. learn more The methodology described here may be a useful framework for other academic institutions to track outcomes of intellectual property in the therapeutics domain.Bladder cancer is the tenth most common cancer worldwide, where its burden remains a challenge and needs new novel therapies. Several reports indicate expression of CYP4Z1 and CYP1B1 in many tumours. Their expressions are associated with a poor prognosis, and therefore proposed as promising biomarkers or targets for anticancer therapy. By using immunohistochemistry, expression of CYP4Z1 and CYP1B1 was evaluated in a panel of different types of bladder cancer, and the enzymes' relation to histopathological features were assessed. Results showed an increased expression of CYP4Z1 (54.3%) and CYP1B1 (76.9%) in the majority of bladder cancers compared to weak or lack of expression of both enzymes in normal tissues. CYP4Z1expression was significantly associated with tumour grade and stage where the expression was markedly increased in a high grade and advanced stage of the disease (p  less then  0.05). Additionally, CYP1B1 expression was also associated with TNM staging (p  less then  0.05) and its expression was increased in patients with lymph node metastasis. The expression profiles of CYP4Z1 and CYP1B1 suggest that both enzymes have the potential to be biomarkers or targets for novel anticancer therapy for bladder cancer. Nevertheless, further studies are needed to better delineate whether these enzymes are druggable targets.Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) promoter for targeted expression in Schwann cells. Lumbar intrathecal injection of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral nervous system including lumbar roots, sciatic and femoral nerves, as well as in Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated improved motor performance and sciatic nerve conduction velocities along with improved myelination and reduced inflammation in peripheral nerve tissues. Blood biomarker levels were also significantly ameliorated in treated mice. This study provides evidence that a clinically translatable AAV9-mediated gene therapy approach targeting Schwann cells could potentially treat CMT1X.In the adult vertebrate brain, enzymatic removal of the extracellular matrix (ECM) is increasingly recognized to promote learning, memory recall, and restorative plasticity. The impact of the ECM on translaminar dynamics during cortical circuit processing is still not understood. Here, we removed the ECM in the primary auditory cortex (ACx) of adult Mongolian gerbils using local injections of hyaluronidase (HYase). Using laminar current-source density (CSD) analysis, we found layer-specific changes of the spatiotemporal synaptic patterns with increased cross-columnar integration and simultaneous weakening of early local sensory input processing within infragranular layers Vb. These changes had an oscillatory fingerprint within beta-band (25-36 Hz) selectively within infragranular layers Vb. To understand the laminar interaction dynamics after ECM digestion, we used time-domain conditional Granger causality (GC) measures to identify the increased drive of supragranular layers towards deeper infragranular layers. These results showed that ECM degradation altered translaminar cortical network dynamics with a stronger supragranular lead of the columnar response profile.Prostate cancer is a global health problem, but incidence varies considerably across different continents. Asia is traditionally considered a low-incidence area, but the incidence and mortality of prostate cancer have rapidly increased across the continent. Substantial differences in epidemiological features have been observed among different Asian regions, and incidence, as well as mortality-to-incidence ratio, is associated with the human development index. Prostate cancer mortality decreased in Japan and Israel from 2007 to 2016, but mortality has increased in Thailand, Kyrgyzstan and Uzbekistan over the same period. Genomic analyses have shown a low prevalence of ERG oncoprotein in the East Asian population, alongside a low rate of PTEN loss, high CHD1 enrichments and high FOXA1 alterations. Contributions from single-nucleotide polymorphisms to prostate cancer risk vary with ethnicity, but germline mutation rates of DNA damage repair genes in metastatic prostate cancer are comparable in Chinese and white patients from the USA and UK. Pharmacogenomic features of testosterone metabolism might contribute to disparities seen in the response to androgen deprivation between East Asian men and white American and European men. Overall, considerable diversity in epidemiology and genomics of prostate cancer across Asia defines disease characteristics in these populations, but studies in this area are under-represented in the literature. Taking into account this intracontinental and intercontinental heterogeneity, translational studies are required in order to develop ethnicity-specific treatment strategies.Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by episodic involuntary movement attacks triggered by sudden movements, acceleration, or intention to move. We ascertained two Japanese familial cases with PKD. The proband is a 22-year-old woman who had noted sudden brief ( T [p.Arg2866Trp] in NBEA). Real time quantitative PCR analysis of Nbea mRNA levels in the developing rat brain revealed peak at postnatal day 28 and decline at postnatal day 56. This result might match the most common clinical course of PKD from the point of view of the most common age at remission. NBEA has been reported to be responsible for neurodevelopmental disease accompanied by epilepsy. We concluded the variant in NBEA most likely to be responsible for our familial cases of PKD.