The engineered AAV-PHP.B family of adeno-associated virus efficiently delivers genes throughout the mouse central nervous system. To guide their application across disease models, and to inspire the ...development of translational gene therapy vectors for targeting neurological diseases in humans, we sought to elucidate the host factors responsible for the CNS tropism of the AAV-PHP.B vectors. Leveraging CNS tropism differences across 13 mouse strains, we systematically determined a set of genetic variants that segregate with the permissivity phenotype, and rapidly identified LY6A as an essential receptor for the AAV-PHP.B vectors. Interfering with LY6A by CRISPR/Cas9-mediated Ly6a disruption or with blocking antibodies reduced transduction of mouse brain endothelial cells by AAV-PHP.eB, while ectopic expression of Ly6a increased AAV-PHP.eB transduction of HEK293T and CHO cells by 30-fold or more. Importantly, we demonstrate that this newly discovered mode of AAV binding and transduction can occur independently of other known AAV receptors. These findings illuminate the previously reported species- and strain-specific tropism characteristics of the AAV-PHP.B vectors and inform ongoing efforts to develop next-generation AAV vehicles for human CNS gene therapy.
Existing benchmark datasets for use in evaluating variant-calling accuracy are constructed from a consensus of known short-variant callers, and they are thus biased toward easy regions that are ...accessible by these algorithms. We derived a new benchmark dataset from the de novo PacBio assemblies of two fully homozygous human cell lines, which provides a relatively more accurate and less biased estimate of small-variant-calling error rates in a realistic context.
The libraries of the Fatimid caliphs in Egypt (r. 969–1171) are known to have been extraordinarily large, containing hundreds of thousands of volumes on all branches of knowledge. Of these fabled ...manuscripts, only a handful are known to survive. It has long been assumed that a substantial number of the secular manuscripts would have been illustrated, as many later Islamic manuscripts are illustrated, but no examples are known to have survived, although somewhat more than 150 paper fragments bearing images have been attributed to the period, as well as representations in other media, ranging from carved ivories to ceramics. In the absence of surviving illustrated manuscripts, scholars have deployed several strategies to attempt to reconstruct the lost art of painting in the Fatimid period, most notably Richard Ettinghausen in his seminal 1942 article “Painting in the Fatimid Period” and Ernst Grube in a subsequent series of articles and chapters. This article examines the evidence and explores how scholars have interpreted it within the broader contexts of representation and manuscript illustration in Islamic art.
We conducted a multicenter evaluation of a novel remote foot-temperature monitoring system to characterize its accuracy for predicting impending diabetic foot ulcers (DFU) in a cohort of patients ...with diabetes with previously healed DFU.
We enrolled 132 participants with diabetes and prior DFU in this 34-week cohort study to evaluate a remote foot-temperature monitoring system (ClinicalTrials.gov Identifier NCT02647346). The study device was a wireless daily-use thermometric foot mat to assess plantar temperature asymmetries. The primary outcome of interest was development of nonacute plantar DFU, and the primary efficacy analysis was the accuracy of the study device for predicting the occurrence of DFU over several temperature asymmetry thresholds.
Of the 129 participants who contributed evaluable data to the study, a total of 37 (28.7%) presented with 53 DFU (0.62 DFU/participant/year). At an asymmetry of 2.22°C, the standard threshold used in previous studies, the system correctly identified 97% of observed DFU, with an average lead time of 37 days and a false-positive rate of 57%. Increasing the temperature threshold to 3.20°C decreased sensitivity to 70% but similarly reduced the false-positive rate to 32% with approximately the same lead time of 35 days. Approximately 86% of the cohort used the system at least 3 days a week on average over the study.
Given the encouraging study results and the significant burden of DFU, use of this mat may result in significant reductions in morbidity, mortality, and resource utilization.
Early Islamic religious architecture in North Africa displays a marked change from earlier Classical and Christian buildings in their general neglect of exteriors in favour of interior (i.e., ...courtyard) façades. This feature may be due partly to the nature of Islamic worship, as it was common to virtually all early mosques, yet builders in the central and eastern lands of Islam soon began to adopt such exteriorizing features as domes, towers, and colourful decoration. Maghribi builders, however, maintained their preference for modest exteriors for many centuries, mostly focusing decoration on interior façades and spaces, and differentiating it from much Islamic architecture elsewhere.
We examined the additional value of preoperative prostate multiparametric magnetic resonance imaging and transrectal ultrasound/multiparametric magnetic resonance imaging fusion guided targeted ...biopsy when performed in combination with clinical nomograms to predict adverse pathology at radical prostatectomy.
We identified all patients who underwent 3 Tesla multiparametric magnetic resonance imaging prior to fusion biopsy and radical prostatectomy. The Partin and the MSKCC (Memorial Sloan Kettering Cancer Center) preradical prostatectomy nomograms were applied to estimate the probability of organ confined disease, extraprostatic extension, seminal vesicle invasion and lymph node involvement using transrectal ultrasound guided systematic biopsy and transrectal ultrasound/multiparametric magnetic resonance imaging fusion guided targeted biopsy Gleason scores. With radical prostatectomy pathology as the gold standard we developed multivariable logistic regression models based on these nomograms before and after adding multiparametric magnetic resonance imaging to assess any additional predictive ability.
A total of 532 patients were included in study. When multiparametric magnetic resonance imaging findings were added to the systematic biopsy based MSKCC nomogram, the AUC increased by 0.10 for organ confined disease (p <0.001), 0.10 for extraprostatic extension (p = 0.003), 0.09 for seminal vesicle invasion (p = 0.011) and 0.06 for lymph node involvement (p = 0.120). Using Gleason scores derived from targeted biopsy compared to systematic biopsy provided an additional predictive value of organ confined disease (Δ AUC 0.07, p = 0.003) and extraprostatic extension (Δ AUC 0.07, p = 0.048) at radical prostatectomy with the MSKCC nomogram. Similar results were obtained using the Partin nomogram.
Magnetic resonance imaging alone or in addition to standard clinical nomograms provides significant additional predictive ability of adverse pathology at the time of radical prostatectomy. This information can be greatly beneficial to urologists for preoperative planning and for counseling patients regarding the risks of future therapy.
Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated ...with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.
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