Point of View: What’s in a name?

Numerous concerns have been raised about the sustainability of the biomedical research enterprise in the United States. Improving the postdoctoral training experience is seen as a priority in addressing these concerns, but even identifying who the postdocs are is made difficult by the multitude of different job titles they can carry. Here, we summarize the detrimental effects that current employment structures have on training, compensation and benefits for postdocs, and argue that academic research institutions should standardize the categorization and treatment of postdocs. We also present brief case studies of two institutions that have addressed these challenges and can provide models for other institutions attempting to enhance their postdoctoral workforces and improve the sustainability of the biomedical research enterprise

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

We describe a novel frameshift mutation in the mitochondrial ATP6 gene in a 4-year-old girl associated with ataxia, microcephaly, developmental delay and intellectual disability. A heteroplasmic frameshift mutation in the MT-ATP6 gene was confirmed in the patient's skeletal muscle and blood. The mutation was not detectable in the mother's DNA extracted from blood or buccal cells. Enzymatic and oxymetric analysis of the mitochondrial respiratory system in the patients' skeletal muscle and skin fibroblasts demonstrated an isolated complex V deficiency. Native PAGE with subsequent immunoblotting for complex V revealed impaired complex V assembly and accumulation of ATPase subcomplexes. Whilst northern blotting confirmed equal presence of ATP8/6 mRNA, metabolic S-35-labelling of mitochondrial translation products showed a severe depletion of the ATP6 protein together with aberrant translation product accumulation. In conclusion, this novel isolated complex V defect expands the clinical and genetic spectrum of mitochondrial defects of complex V deficiency. Furthermore, this work confirms the benefit of native PAGE as an additional diagnostic method for the identification of OXPHOS defects, as the presence of complex V subcomplexes is associated with pathogenic mutations of mtDNA. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe

Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production

Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause atrophy of the optic nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils (Opa1(N Delta)), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD(+) availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show that Opa1(N Delta) mice exhibit a reduced antibacterial defense capability against Pseudomonas aeruginosa.Peer reviewe

Red Supergiants in the Andromeda Galaxy (M31)

Red supergiants are a short-lived stage in the evolution of moderately massive stars (10-25Mo), and as such their location in the H-R diagram provides an exacting test of stellar evolutionary models. Since massive star evolution is strongly affected by the amount of mass-loss a star suffers, and since the mass-loss rates depend upon metallicity, it is highly desirable to study the physical properties of these stars in galaxies of various metallicities. Here we identify a sample of red supergiants in M31 (the most metal-rich of the Local Group galaxies) and derive their physical properties by fitting MARCS atmosphere models to moderate resolution optical spectroscopy, and from V-K photometry.Comment: Accepted for publication in the Astrophysical Journa

Early Evolution of Stellar Groups and Clusters: Environmental Effects on Forming Planetary Systems

This paper studies the dynamical evolution of young stellar clusters with $N$ = 100 - 1000 members. We use N-body simulations to explore how evolution depends on system size $N$ and the initial conditions. Motivated by recent observations of extremely young systems, this study compares subvirial and virial starting states. Multiple realizations of equivalent cases (100 simulations per case) are used to build up a robust statistical description of these systems, e.g., distributions of closest approaches, mass profiles, and distributions of radial locations. These results provide a framework from which to assess the effects of these clusters on star and planet formation. The distributions of radial positions are used in conjunction with distributions of FUV luminosities (also calculated here) to determine the radiation exposure of circumstellar disks. The distributions of closest approaches are used in conjunction with scattering cross sections (calculated here from $10^5$ scattering experiments) to determine the probability of solar system disruption. We also use the nearby cluster NGC 1333 as a test case. Our main conclusion is that clusters in this size range have only a modest effect on forming planetary systems: Interaction rates are low so that the typical solar system experiences a single encounter within 1000 AU. Radiation exposure is low, with median FUV flux $G_0$ = 900, so that photoevaporation of disks is only important beyond 30 AU. Given the low interaction rates and modest radiation levels, we suggest that solar system disruption is a rare event in these clusters.Comment: 54 pages; accepted to Ap

Real-Life Therapeutic Concentration Monitoring of Long-Acting Cabotegravir and Rilpivirine: Preliminary Results of an Ongoing Prospective Observational Study in Switzerland

SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy

Real-Life Therapeutic Concentration Monitoring of Long-Acting Cabotegravir and Rilpivirine: Preliminary Results of an Ongoing Prospective Observational Study in Switzerland.

SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy

Models for Massive Stellar Populations with Rotation

We present and discuss evolutionary synthesis models for massive stellar populations generated with the Starburst99 code in combination with a new set of stellar evolution models accounting for rotation. The new stellar evolution models were compiled from several data releases of the Geneva group and cover heavy-element abundances ranging from twice solar to one fifth solar. The evolution models were computed for rotation velocities on the zero-age main-sequence of 0 and 300 km/s and with the latest revision of stellar mass-loss rates. Since the mass coverage is incomplete, in particular at non-solar chemical composition, our parameter study is still preliminary and must be viewed as exploratory. Stellar population properties computed with Starburst99 and the new evolution models show some marked differences in comparison with models obtained using earlier tracks. Since individual stars now tend to be more luminous and bluer when on the blue side of the Hertzsprung-Russell diagram, the populations mirror this trend. For instance, increases by factors of two or more are found for the light-to-mass ratios at ultraviolet to near-infrared wavelengths, as well as for the output of hydrogen ionizing photons. If these results are confirmed once the evolution models have matured, recalibrations of certain star-formation and initial mass function indicators will be required.Comment: Accepted for publication in Ap