Atoms to phenotypes: Molecular design principles of cellular energy metabolism

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore’s structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells

Precompetitive consensus building to facilitate the use of digital health technologies to support Parkinson Disease drug development through regulatory science

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies

Comparison of polytetrafluoroethylene patch aortoplasty and end-to-end anastomosis for coarctation of the aorta.

OBJECTIVES: Although aneurysm formation and recoarctation after Dacron patch aortoplasty have been reported on extensively, less is known about these outcomes after polytetrafluoroethylene patch repair, which was compared with resection and end-to-end anastomosis in this study. METHODS: Two hundred sixty-two children had surgical repair of coarctation of the aorta by means of either resection and end-to-end anastomosis (n = 137; mean age, 1.85 +/- 3.1 years) or polytetrafluoroethylene patch aortoplasty (n = 118; mean age, 1.09 +/- 1.9 years) during a 28-year period. Coarctation was isolated in 109 (41.6%), associated with ventricular septal defect in 77 (29.4%), and associated with complex intracardiac anomalies in 76 (29.0%) patients. Follow-up ranged from 2 days to 29.3 years (median, 11.9 years). Seven patients were lost to follow-up. Kaplan-Meier survival curves were estimated, and multivariable Cox regression analysis was performed for several outcome variables. RESULTS: Mortality was 8.2% and was associated with intracardiac pathology in all cases. Recoarctation occurred in 53 patients, 23 after resection and anastomosis and 30 after patch repair, not differing statistically (P =.4, log-rank test). Aneurysm formation occurred in 8 patients after patch repair that included ridge resection in 7 of the 8 patients. Late hypertension occurred in less patients (n = 3) after resection and anastomosis than after patch repair (n = 8) (P <.03). Arch hypoplasia (P <.01) and age less than 1 month (P <.001) were found to be independent risk factors for recoarctation. CONCLUSIONS: Polytetrafluoroethylene patch repair including coarctation ridge resection was found to be a risk factor for aneurysm formation and late hypertension. Arch hypoplasia and young age must be considered to predispose to recoarctation

Dimension is compression

Effective fractal dimension was defined by Lutz (2003) in order to quantitatively analyze the structure of complexity classes. Interesting connections of effective dimension with information theory were also found, in fact the cases of polynomial-space and constructive dimension can be precisely characterized in terms of Kolmogorov complexity, while analogous results for polynomial-time dimension haven’t been found. In this paper we remedy the situation by using the natural concept of reversible time-bounded compression for finite strings. We completely characterize polynomial-time dimension in terms of polynomial-time compressors.

Competição intraespecífica em Boophilus microplus Intra-specific competition in Boophilus microplus

O presente trabalho foi desenvolvido no Campo Experimental da Embrapa Gado de Leite, Coronel Pacheco, Minas Gerais, Brasil, tendo como objetivo a verificação da ocorrência de competição intra-específica durante a fase parasitária do carrapato bovino Boophilus microplus e a confirmação da correlação positiva entre o peso da fêmea ingurgitada e o peso da massa de ovos. Foram feitas observações em bovinos infestados naturalmente e experimentalmente, com cargas parasitárias e intervalos diferenciados. Os animais infestados permaneceram em baias individuais durante todo o período de queda das fêmeas ingurgitadas, para que estas pudessem ser coletadas diariamente. As diferenças observadas entre as médias de peso das fêmeas ingurgitadas, no decorrer dos dias de queda, sugeriram a ocorrência de competição durante a fase de alimentação. Observou-se também que o potencial de oviposição está diretamente relacionado a sua capacidade de alimentação.<br>This study was developed in the Experimental Station of Embrapa Dairy Cattle, Coronel Pacheco, Minas Gerais, Brazil, and had the aim of verifying the occurrence of intra-specific competition in the cattle tick Boophilus microplus during its parasite life and to confirm the relation between the weight of engorged females and the egg mass laid. Observations were done with cattle naturally and experimentally infested with different quantities of larvae during different intervals of time. The infested animals remained in individual stalls for the whole period of engorged females drop-off, in order to collect them daily. The observed differences among weight of engorged females during drop-off days suggested the competition occurrence during the feeding phase. It was also seen that the oviposition potential of an engorged female is directly related to its feeding capacity