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We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy.
We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with
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molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, ab initio Car-Parrinello molecular dynamics (CPMD) simulation was used to identify which
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molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Dexamethasone Subsequently, the femto- to nanosecond reactions of ROS were simulated by usinge would be reduced in an environment with physoxic oxygen levels. Hence irradiation at UHDRs would be more effective for sparing physoxic normal tissues but not tumors containing regions of hypoxia. At much higher levels of oxygen (e.g., >10-15%), oxygen depletion by UHDRs may not be sufficient for tissue sparing.
10-15%), oxygen depletion by UHDRs may not be sufficient for tissue sparing.Acetylcholine acts as a neurotransmitter/neuromodulator of many central nervous system processes such as learning and memory, attention, motor control, and sensory processing. The present study describes the spatial distribution of cholinergic neurons throughout the brain of the weakly electric fish, Apteronotus leptorhynchus, using in situ hybridization of choline acetyltransferase mRNA. Distinct groups of cholinergic cells were observed in the telencephalon, diencephalon, mesencephalon, and hindbrain. These included cholinergic cell groups typically identified in other vertebrate brains, for example, motor neurons. Using both in vitro and ex vivo neuronal tracing methods, we identified two new cholinergic connections leading to novel hypotheses on their functional significance. Projections to the nucleus praeeminentialis (nP) arise from isthmic nuclei, possibly including the nucleus lateralis valvulae (nLV) and the isthmic nucleus (nI). The nP is a central component of all electrosensory feedback pathways to the electrosensory lateral line lobe (ELL). We have previously shown that some neurons in nP, TS, and tectum express muscarinic receptors. We hypothesize that, based on nLV/nI cell responses in other teleosts and isthmic connectivity in A. leptorhynchus, the isthmic connections to nP, TS, and tectum modulate responses to electrosensory and/or visual motion and, in particular, to looming/receding stimuli. In addition, we found that the octavolateral efferent (OE) nucleus is the likely source of cholinergic fibers innervating the ELL. In other teleosts, OE inhibits octavolateral hair cells during locomotion. In gymnotiform fish, OE may also act on the first central processing stage and, we hypothesize, implement corollary discharge modulation of electrosensory processing during locomotion.
Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension isunknown.
To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.
The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020 the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further publishedndent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.Randomized clinical trials are positioned at the highest level of primary clinical evidence, as they are designed to be unbiased with a reduced risk of systematic error. The Consolidated Standards of Reporting Trials (CONSORT) statement was first developed in 1996 to improve the reporting quality of randomized clinical trials with updates being published subsequently. Recently, the Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) 2020 guidelines were developed exclusively for the field of Endodontics to address the suboptimal quality of randomized clinical trials submitted to Endodontic journals, which result in many being rejected. A principal flaw in submissions is the fact that many authors are unclear on the keys terms that should be used when developing manuscripts for publication. Clearly, authors should be aware of the most common terms used when conducting and reporting randomized clinical trials. Hence, the aim of the current paper is to present a comprehensive glossary of the terminology used in randomized clinical trials in order to assist authors when designing, executing and writing-up randomized clinical trials.Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function.
