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Leber congenital amaurosis type 10 is a severe retinal dystrophy caused by mutations in the CEP290 gene1,2. We developed EDIT-101, a candidate genome-editing therapeutic, to remove the aberrant splice donor created by the IVS26 mutation in the CEP290 gene and restore normal CEP290 expression. Key to this therapeutic, we identified a pair of Staphylococcus aureusCas9 guide RNAs that were highly active and specific to the human CEP290 target sequence. In vitro experiments in human cells and retinal explants demonstrated the molecular mechanism of action and nuclease specificity. Subretinal delivery of EDIT-101 in humanized CEP290 mice showed rapid and sustained CEP290 gene editing. A comparable surrogate non-human primate (NHP) vector also achieved productive editing of the NHP CEP290 gene at levels that met the target therapeutic threshold, and demonstrated the ability of CRISPR/Cas9 to edit somatic primate cells in vivo. These results support further development of EDIT-101 for LCA10 and additional CRISPR-based medicines for other inherited retinal disorders.

Dismounted military operations often involve prolonged load carriage over complex terrain, which can result in excessive metabolic costs that can directly impair soldiers' performance. Although estimating these demands is a critical interest for mission planning purposes, it is unclear whether existing estimation equations developed from controlled laboratory- and field-based studies accurately account for energy costs of traveling over complex terrain. This study investigated the accuracy of the following equations for military populations when applied to data collected over complex terrain with two different levels of load carriage: American College of Sports Medicine (2002), Givoni and Goldman (1971), Jobe and White (2009), Minetti et al (2002), Pandolf et al (1977), and Santee et al (2003).

CandidatusMidichloria mitochondrii, symbiont of the sheep tick Ixodes ricinus, was the first described member of the family CandidatusMidichloriaceae,order Rickettsiales. Recent reports are expanding our view of this family, now including numerous bacteria of great biological and medical interest, indicating a widespread distribution with an increasing range of hosts, with ticks being strongly represented.

Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described.

ABSTRACTThe virulence and fitness in vivoof the major human pathogen Staphylococcus aureusare associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agrlocus. Here we show, in a wax moth larva virulence model, that (i) QS in S. aureusis a cooperative social trait that provides a benefit to the local population of cells, (ii) agrmutants, which do not produce or respond to QS signal, are able to exploit the benefits provided by the QS of others (“cheat”), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agrmutants (“cheats”) in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agrmutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram-positive bacterium, our results suggest convergent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria.

The values of length of synodic month, obtained from tidally controlled periodical growth patterns in mollusks and stromatolites for several geologic periods, indicate that the deceleration rate of the earth's rotation has not been constant. Two breaks in slope, in the Pennsylvanian and Cretaceous, may be related to changes in distribution of continents, oceans, and adjacent shallow seas.

AbstractAimsMental disorders are common in people living with HIV (PLWH) but often remain untreated. This study aimed to explore the treatment gap for mental disorders in adults followed-up in antiretroviral therapy (ART) programmes in South Africa and disparities between ART programmes regarding the provision of mental health services.MethodsWe conducted a cohort study using ART programme data and linked pharmacy and hospitalisation data to examine the 12-month prevalence of treatment for mental disorders and factors associated with the rate of treatment for mental disorders among adults, aged 15–49 years, followed-up from 1 January 2012 to 31 December 2017 at one private care, one public tertiary care and two pubic primary care ART programmes in South Africa. We calculated the treatment gap for mental disorders as the discrepancy between the 12-month prevalence of mental disorders in PLWH (aged 15–49 years) in South Africa (estimated based on data from the Global Burden of Disease study) and the 12-month prevalence of treatment for mental disorders in ART programmes. We calculated adjusted rate ratios (aRRs) for factors associated with the treatment rate of mental disorders using Poisson regression.ResultsIn total, 182 285 ART patients were followed-up over 405 153 person-years. In 2017, the estimated treatment gap for mental disorders was 40.5% (95% confidence interval [CI] 19.5–52.9) for patients followed-up in private care, 96.5% (95% CI 95.0–97.5) for patients followed-up in public primary care and 65.0% (95% CI 36.5–85.1) for patients followed-up in public tertiary care ART programmes. Rates of treatment with antidepressants, anxiolytics and antipsychotics were 17 (aRR 0.06, 95% CI 0.06–0.07), 50 (aRR 0.02, 95% CI 0.01–0.03) and 2.6 (aRR 0.39, 95% CI 0.35–0.43) times lower in public primary care programmes than in the private sector programmes.ConclusionsThere is a large treatment gap for mental disorders in PLWH in South Africa and substantial disparities in access to mental health services between patients receiving ART in the public vsthe private sector. In the public sector and especially in public primary care, PLWH with common mental disorders remain mostly untreated.