Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1G93A mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.

"Round, red globules floating in a crystalline fluid" - Antoni van Leeuwenhoek's observations of red blood cells and hemocytes.

This article addresses a deficit in the cell biology and hematology literature, specifically regarding Antoni van Leeuwenhoek's central role in observing and describing red blood cells and hemocytes. While the existing literature on the history of hematology usually mentions Antoni van Leeuwenhoek, typically, it is an incomplete summary of his contributions. Leeuwenhoek is cited as one of the three individuals who first saw and described red blood cells through their microscope lenses. Jan Swammerdam and Marcello Malpighi also documented red blood cells in human blood before Leeuwenhoek. The literature fails to mention that Leeuwenhoek commented on red blood "globules," as well as arthropod hemocytes, at least thirty-five times in thirty-one letters spanning thirty-nine years of correspondence to The Royal Society and others. Some of his descriptive passages were extensive. His observations on blood circulation are a separate set of observations in his letters and are not covered here. Leeuwenhoek viewed various creatures to see if there were characteristics to their blood cells that he could share with the recipients of his letters. He also would view the cells in different chemical and physical environments to understand their properties. Leeuwenhoek's observations of blood corpuscles are discussed in chronological order. Comments included in footnotes by the Committee of Dutch Scientists, who edited the published seventeen volumes of Leeuwenhoek's Alle de Brieven, are also discussed when their comments are relevant.

Antoni van Leeuwenhoek: defining proportion in the microscopic realm during the 17th century.

This article examines comparisons Antoni van Leeuwenhoek made between everyday objects, such as grains of sand, millet seeds, and hairs, and the structures and objects he observed through his single-lens microscopes. These comparisons, their possible origins in commerce, and the variety of Leeuwenhoek's observations have not been appreciated widely for their elegance. His measurements of the microscopic world might have grown out of his time as an apprentice to William Davidson, an international cloth merchant in Amsterdam, Leeuwenhoek's surveying licensure, drapery business, and other commercial experiences in Delft. Leeuwenhoek initiated the use of comparisons in his 28 April 1673 letter to the Royal Society, his first letter describing his observations. He compared animalcules, blood cells, fat globules, veins and arteries, insect, plant, and mineral structures to a range of conventional, although tiny objects such as fine and coarse grains of sand, millet grains, human hairs, and other items. In many of his comparisons, he arrived at size estimates for the objects that are very close to the sizes found using current instruments and techniques. Examples of Leeuwenhoek's comparisons will be provided.

SARS-CoV: Lessons learned; opportunities missed for SARS-CoV-2.

SARS-CoV-2 and Covid-19 have made a retrospective analysis of other coronavirus diseases important, so this article reviews the history of the SARS-CoV viral disease from 2003. Standard and clinical chemistry diagnostics were developed in response to the outbreak. The response to SARS is examined to determine if there were lessons learned before it disappeared in June and July 2003. Various diagnostic approaches were developed and implemented to assist in the rapid identification of patients and treatment of their illness, yet many of the approaches required days or weeks from the onset of fever to show statistical significance. Most of the therapeutic methods used during the outbreak relied on treating symptoms of the underlying illness, such as lower respiratory infections and systemic infection, rather than effectively suppressing or curtailing replication of the virus. Retrospective studies are examined to determine how the SARS outbreak was viewed 10 years on and what the authors hoped would be instructive patterns for possible future pandemics. Implementation of some of these recommendations might have helped ease the current pandemic but were overlooked for budgetary reasons that seem short-sighted at present.

Antoni van Leeuwenhoek and measuring the invisible: The context of 16th and 17th century micrometry.

This article explores the impact of 16th and 17th-century developments in micrometry on the methods Antoni van Leeuwenhoek employed to measure the microscopic creatures he discovered in various samples collected from his acquaintances and from local water sources. While other publications have presented Leeuwenhoek's measurement methods, an examination of the context of his techniques is missing. These previous measurement methods, driven by the need to improve navigation, surveying, astronomy, and ballistics, may have had an impact on Leeuwenhoek's methods. Leeuwenhoek was educated principally in the mercantile guild system in Amsterdam and Delft. He rose to positions of responsibility within Delft municipal government. These were the years that led up to his first investigations using the single-lens microscopes he became expert at creating, and that led to his first letter to the Royal Society in 1673. He also took measures to train in surveying and liquid assaying practices existing in his time, disciplines that were influenced by Pedro Nunes, Pierre Vernier, Rene Descartes, and others. While we may never know what inspired Leeuwenhoek's methods, the argument is presented that there were sufficient influences in his life to shape his approach to measuring the invisible.

Variation in Childhood Diarrheal Morbidity and Mortality in Africa, 2000-2015.

BACKGROUND: Diarrheal diseases are the third leading cause of disease and death in children younger than 5 years of age in Africa and were responsible for an estimated 30 million cases of severe diarrhea (95% credible interval, 27 million to 33 million) and 330,000 deaths (95% credible interval, 270,000 to 380,000) in 2015. The development of targeted approaches to address this burden has been hampered by a paucity of comprehensive, fine-scale estimates of diarrhea-related disease and death among and within countries. METHODS: We produced annual estimates of the prevalence and incidence of diarrhea and diarrhea-related mortality with high geographic detail (5 km2) across Africa from 2000 through 2015. Estimates were created with the use of Bayesian geostatistical techniques and were calibrated to the results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. RESULTS: The results revealed geographic inequality with regard to diarrhea risk in Africa. Of the estimated 330,000 childhood deaths that were attributable to diarrhea in 2015, more than 50% occurred in 55 of the 782 first-level administrative subdivisions (e.g., states). In 2015, mortality rates among first-level administrative subdivisions in Nigeria differed by up to a factor of 6. The case fatality rates were highly varied at the national level across Africa, with the highest values observed in Benin, Lesotho, Mali, Nigeria, and Sierra Leone. CONCLUSIONS: Our findings showed concentrated areas of diarrheal disease and diarrhea-related death in countries that had a consistently high burden as well as in countries that had considerable national-level reductions in diarrhea burden. (Funded by the Bill and Melinda Gates Foundation.).

Feasibility of a multigroup deterministic solution method for three-dimensional radiotherapy dose calculations.

PURPOSE: To investigate the potential of a novel deterministic solver, Attila, for external photon beam radiotherapy dose calculations. METHODS AND MATERIALS: Two hypothetical cases for prostate and head-and-neck cancer photon beam treatment plans were calculated using Attila and EGSnrc Monte Carlo simulations. Open beams were modeled as isotropic photon point sources collimated to specified field sizes. The sources had a realistic energy spectrum calculated by Monte Carlo for a Varian Clinac 2100 operated in a 6-MV photon mode. The Attila computational grids consisted of 106,000 elements, or 424,000 spatial degrees of freedom, for the prostate case, and 123,000 tetrahedral elements, or 492,000 spatial degrees of freedom, for the head-and-neck cases. RESULTS: For both cases, results demonstrate excellent agreement between Attila and EGSnrc in all areas, including the build-up regions, near heterogeneities, and at the beam penumbra. Dose agreement for 99% of the voxels was within the 3% (relative point-wise difference) or 3-mm distance-to-agreement criterion. Localized differences between the Attila and EGSnrc results were observed at bone and soft-tissue interfaces and are attributable to the effect of voxel material homogenization in calculating dose-to-medium in EGSnrc. For both cases, Attila calculation times were <20 central processing unit minutes on a single 2.2-GHz AMD Opteron processor. CONCLUSIONS: The methods in Attila have the potential to be the basis for an efficient dose engine for patient-specific treatment planning, providing accuracy similar to that obtained by Monte Carlo.