Miracle-dz/UniFAR-FTUs huggingface dataset:
Probabilistic definition of the clinical target volume—implications for tumor control probability modeling and optimization

Evidence has been presented that moving beyond the binary definition of clinical target volume (CTV) towards a probabilistic CTV can result in better treatment plans. The probabilistic CTV takes the likelihood of disease spread outside of the gross tumor into account. An open question is: how to optimize tumor control probability (TCP) based on the probabilistic CTV. We derive expressions for TCP under the assumptions of voxel independence and dependence. For the dependent case, we make the assumption that tumors grow outward from the gross tumor volume. We maximize the (non-convex) TCP under convex dose constraints for all models. For small numbers of voxels, and when a dose-influence matrix is not used, we use exhaustive search or Lagrange multiplier theory to compute optimal dose distributions. For larger cases we present (1) a multi-start strategy using linear programming with a random cost vector to provide random feasible starting solutions, followed by a local search, and (2) a heuristic strategy that greedily selects which subvolumes to dose, and then for each subvolume assignment runs a convex approximation of the optimization problem. The optimal dose distributions are in general different for the independent and dependent models even though the probabilities of each voxel being tumorous are set to the same in both cases. We observe phase transitions, where a subvolume is either dosed to a high level, or it gets ‘sacrificed’ by not dosing it at all. The greedy strategy often yields solutions indistinguishable from the multi-start solutions, but for the 2D case involving organs-at-risk and the dependent TCP model, discrepancies of around 5% (absolute) for TCP are observed. For realistic geometries, although correlated voxels is a more reasonable assumption, the correlation function is in general unknown. We demonstrate a tractable heuristic that works very well for the independent models and reasonably well for the dependent models. All data are provided.
Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function.

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Synaptic Dysfunction in Huntington’s Disease: Lessons from Genetic Animal Models

The understanding of the functional and structural changes occurring in the cerebral cortex and basal ganglia in Huntington’s disease (HD) has benefited considerably from the generation of genetic animal models. Most studies of synaptic alterations in HD models have focused on the striatum, but a more complete picture of synaptic dysfunction in the cortico-basal ganglia-cortical loop is emerging. Here, we provide a review and analysis of current developments in the study of synaptic alterations in these areas using HD rodent models. Recent evidence indicates that cortical maldevelopment plays a role in synaptic dysfunction along the corticostriatal pathway that may have its roots in the way mutant huntingtin interacts with synaptic proteins. Furthermore, a progressive disconnection in the corticostriatal pathway leads to abnormal function engaging extrasynaptic N-methyl-D-aspartate glutamate receptors that contribute to eventual cell degeneration. In addition, biphasic increases followed by decreases in glutamate and dopamine release in the striatum could explain contrasting symptomatology in early and late stages of the disease. Changes in striatal output regions also are beginning to be examined. Finally, we highlight some therapeutic avenues aimed at rescuing synaptic dysfunction.
Visual disturbances during prolonged space missions

Purpose of review During prolonged spaceflight, astronauts often experience ocular changes, due to constant head-ward fluid shifts in space as compared with Earth. This article reviews symptoms, likely causes, and potential solutions, such as lower body negative pressure, to counteract space-associated neuroocular syndrome (SANS). Recent findings Low gravity conditions and other aspects of spaceflight affect the eye detrimentally, causing SANS which is characterized by optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. SANS is probably caused by altered hemodynamic flows in the head and neck as well as mildly elevated intracranial and intraocular pressures. Carbon dioxide and other chemicals in space-craft may influence SANS as well. SANS may be counteracted by using lower body negative pressure, thigh cuffs, spacecraft engineering, and/or artificial gravity by a centrifuge. Summary Prolonged space missions are associated with optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. Possible causes and countermeasures are currently being researched to reduce the risk of SANS. Although many countermeasures to SANS are under investigation lower body negative pressure exhibits great promise in counteracting the headward fluid shifts in space. Understanding and prevention of SANS is critical to future space exploration, especially to long-duration missions to the moon and Mars.
Association Between Knee- and Hip-Extensor Strength and Running-Related Injury Biomechanics in Collegiate Distance Runners.

CONTEXT Running-related injuries are common in distance runners. Strength training is used for performance enhancement and injury prevention. However, the association between maximal strength and distance-running biomechanics is unclear. OBJECTIVE To determine the relationship between maximal knee- and hip-extensor strength and running biomechanics previously associated with injury risk. DESIGN Cross-sectional study. SETTING Research laboratory. PATIENTS OR OTHER PARTICIPANTS A total of 36 collegiate distance runners (26 men, 10 women; age = 20.0 ± 1.5 years, height = 1.74 ± 0.09 m, mass = 61.97 ± 8.26 kg). MAIN OUTCOME MEASURE(S) Strength was assessed using the 1-repetition maximum (1RM) back squat and maximal voluntary isometric contractions of the knee extensors and hip extensors. Three-dimensional running biomechanics were assessed overground at a self-selected speed. Running variables were the peak instantaneous vertical loading rate; peak forward trunk-lean angle; knee-flexion, internal-rotation, and -abduction angles and internal moments; and hip-extension, internal-rotation, and -adduction angles and internal moments. Separate stepwise linear regression models were used to examine the associations between strength and biomechanical outcomes (ΔR2) after accounting for sex, running speed, and foot-strike index. RESULTS Greater 1RM back-squat strength was associated with a larger peak knee-flexion angle (ΔR2 = 0.110, ΔP = .045) and smaller peak knee internal-rotation angle (ΔR2 = 0.127, ΔP = .03) and internal-rotation moment (ΔR2 = 0.129, ΔP = .03) after accounting for sex, speed, and foot-strike index. No associations were found between 1RM back-squat strength and hip kinematics or kinetics, trunk lean, or vertical loading rate. Hip- and knee-extensor maximal voluntary isometric contractions were also not associated with any biomechanical variables. CONCLUSIONS Greater 1RM back-squat strength was weakly associated with a larger peak knee-flexion angle and smaller knee internal-rotation angle and moment in collegiate distance runners. Runners who are weaker in the back-squat exercise may exhibit running biomechanics associated with the development of knee-related injuries.
Continuous forearm cooling attenuates gastrointestinal temperature increase during cycling

ABSTRACT Hot environmental conditions can challenge thermoregulation resulting in exacerbated heat strain. This study evaluated the influence of continuous inner forearm cooling on gastrointestinal temperature (TGI) and physiological responses to exercise in hot (30°C) and humid (relative humidity: 70%) conditions. Eleven trained cyclists (seven male age: 37±12 years; four female age: 41±15 years; mean±standard deviation) performed two experimental trials, cycling at 66% of their self-reported functional threshold power (average work rate over an hour of maximum effort cycling; 175±34W) for 45 minutes in an environmental chamber. One trial employed continuous inner forearm cooling (COOL) with 5°C water passing through aluminum heat exchangers, while the other had no cooling (CONTROL). Heat was removed from the body at an average rate of 30.3±6.6W during the COOL trial resulting in an attenuation of TGI rise (CONTROL: 2.46±0.70, COOL: 2.03±0.63°C·h−1; p=0.002). The change in heart rate from the 10th minute to the end of exercise, as an indicator of cardiovascular drift, was reduced (CONTROL: 20±7, COOL: 17±6beats·min−1; p=0.050) and end-exercise thermal comfort was improved in the COOL trial with a trend for reduced rating of perceived exertion (p=0.055). Findings suggest that continuous cooling of the inner forearms can attenuate the rise of TGI and help mitigate the risk of heat injury during exercise in hot and humid conditions.
Deployment and Psychological Correlates of Suicide Ideation: A Prospective, Longitudinal Study of Risk and Resilience Among Combat Veterans.

INTRODUCTION Suicide rates among military personnel have risen in part due to war zone deployments. Yet, the degree to which deployment-related stressors, in combination with preexisting and co-occurring psychiatric symptoms and individual resilience factors, contribute to suicide ideation (SI) remains unclear. The current study leverages prospective, longitudinal data to examine both risk and protective factors associated with SI in deployed service members. MATERIALS AND METHODS Participants were 1,805 active duty enlisted Marines and Navy service members assessed before and after a 7-month deployment for SI, preexisting and concurrent symptoms of depression, post-traumatic stress disorder (PTSD), alcohol consumption, as well as prior and deployment-related traumatic brain injury (TBI). Current self-reported psychological resilience and social support were analyzed as potential protective factors. RESULTS Rates of SI were 7.3% and 3.9% before and after deployment, respectively. Of those with post-deployment SI, 68.6% were new-onset cases. Multivariate regression revealed that concurrent mild depression was the strongest risk factor (odds ratio [OR] = 10.03, 95% CI 5.28-19.07). Other significant risk factors included prior SI (OR = 3.36, 95% CI 1.60-7.05), prior subthreshold PTSD (OR = 2.10, 95% CI 1.10-3.99), and deployment TBI (OR = 1.84, 95% CI 1.03-3.28). Controlling for clinical symptoms and TBI, the risk of SI was reduced for those with moderate (OR = 0.50, 95% CI 0.27-0.93) and high psychological resilience scores (OR = 0.25, 95% CI 0.08-0.79) after deployment. CONCLUSIONS Results indicate that even mild symptoms of depression and PTSD may increase the risk of SI. Screening for subthreshold clinical symptoms and TBI while incorporating psychological resilience training would allow for a more multidimensional approach to suicide risk assessment.
Diagnostic Accuracy of FibroScan and Factors Affecting Measurements

Evaluating liver steatosis and fibrosis is important for patients with non-alcoholic fatty liver disease. Although liver biopsy and pathological assessment is the gold standard for these conditions, this technique has several disadvantages. The evaluation of steatosis and fibrosis using ultrasound B-mode imaging is qualitative and subjective. The liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) determined using FibroScan are the evidence-based non-invasive measures of liver fibrosis and steatosis, respectively. The LSM and CAP measurements are carried out simultaneously, and the median values of more than ten valid measurements are used to quantify liver fibrosis and steatosis. Here, we demonstrate that the reliability of the LSM depends on the interquartile range to median ratio (IQR/Med), but CAP values do not depend on IQR/Med. In addition, the LSM is affected by inflammation, congestion, and cholestasis in addition to fibrosis, while CAP values are affected by the body mass index in addition to steatosis. We also show that the M probe provides higher LSM values but lower CAP values than the XL probe in the same population. However, there was no statistically significant difference between the diagnostic accuracies of the two probes. These findings are important to understand the reliability of FibroScan measurements and the factors influencing measurement values for all patients.
The forgotten feeding ground: Patterns in seasonal and depth-specific food intake of adult cod Gadus morhua in the Western Baltic Sea.

We present a study on the diet composition of Western Baltic cod (WBC) Gadus morhua based on 3150 stomachs sampled year-round between 2016 and 2017 using angling, gillnetting, and bottom trawling, which enhanced the spatio-temporal coverage of cod habitats. Cod diet composition in shallow areas (< 20 m depth) was dominated by benthic invertebrate species, mainly the common shore crab Carcinus maneas. Compared to historic diet data from the 1960s and 1980s (limited to depth >20m), the contribution of herring Clupea harengus decreased and round goby Neogobius melanostomus occurred as a new prey species. Statistical modelling revealed significant relationships between diet composition, catch depth, fish length and season. Generalized additive modelling identified a negative relationship between catch depth and stomach content weight, suggesting reduced food intake in winter when cod use deeper areas for spawning and during peak summer when cod tend to avoid high water temperatures. Our results highlight the importance of shallow coastal areas as major feeding habitats of adult cod in the Western Baltic Sea, which were previously unknown because samples were restricted to deeper trawlable areas. Our results strongly suggest that historic stomach analyses overestimated the role of forage fish and underestimated the role of invertebrate prey. Eventually, our study demonstrates the importance of a comprehensive habitat coverage for unbiased stomach sampling programs to provide a more reliable estimation of top predator diet, a key information for food web analyses and multi-species models.
Exploring Excitotoxicity and Regulation of a Constitutively Active TRP Ca2+ Channel in Drosophila

ABSTRACT Unregulated Ca2+ influx affects intracellular Ca2+ homoeostasis, which may lead to neuronal death. In Drosophila, following the activation of rhodopsin the TRP Ca2+ channel is open to mediate the light-dependent depolarization. A constitutively active TRP channel triggers the degeneration of TrpP365 /+ photoreceptors. To explore retinal degeneration, we employed a multidisciplinary approach including live imaging using GFP tagged actin and arrestin 2. Importantly, we demonstrate that the major rhodopsin (Rh1) was greatly reduced before the onset of rhabdomere degeneration; a great reduction of Rh1 affects the maintenance of rhabdomere leading to degeneration of photoreceptors. TrpP365 /+ also led to the up-regulation of CaMKII, which is beneficial as suppression of CaMKII accelerated retinal degeneration. We explored the regulation of TRP by investigating the genetic interaction between TrpP365 /+ and mutants affecting the turnover of diacylglycerol (DAG). We show a loss of phospholipase C in norpAP24 exhibited a great reduction of the DAG content delayed degeneration of TrpP365 /+ photoreceptors. In contrast, knockdown or mutations in DAG lipase (InaE) that is accompanied by slightly reduced levels of most DAG but an increased level of DAG 34:1, exacerbated retinal degeneration of TrpP365 /+. Together, our findings support the notion that DAG plays a role in regulating TRP. Interestingly, DAG lipase is likely required during photoreceptor development as TrpP365 /+; inaEN125 double mutants contained severely degenerated rhabdomeres.
Long-term efficacy of dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: Week 96 results of ART-PRO pilot study.

BACKGROUND In the ART-PRO pilot trial there were no virological failures through 48 weeks of treatment with dolutegravir plus lamivudine in suppressed individuals with and without archived lamivudine resistance-associated mutations (RAMs) detected through next-generation sequencing (NGS) but without evidence of lamivudine RAMs in baseline proviral DNA population sequencing. OBJECTIVES To present 96 week results from ART-PRO. METHODS Open-label, single-arm pilot trial. At baseline, all participants switched to dolutegravir plus lamivudine. Participants were excluded if proviral DNA population genotyping detected lamivudine RAMs. To detect resistance minority variants, proviral DNA NGS was retrospectively performed from baseline samples. For this analysis the efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 96. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. RESULTS Forty-one participants were included, 21 with lamivudine RAMs in historical plasma RNA genotypes. Baseline proviral DNA NGS detected lamivudine RAMs (M184V/I and/or K65R/E/N) above a 5% threshold in 71.4% (15/21) and 15% (3/20) of participants with and without history of lamivudine resistance, respectively. At 96 weeks, 90.2% of participants achieved the efficacy endpoint. Between week 48 and 96 there was one discontinuation due to consent withdrawal and no discontinuations related to adverse events. Two participants had a transient viral rebound, both re-suppressed on dolutegravir plus lamivudine. Through week 96, there were no virological failures. CONCLUSIONS In this pilot trial, dolutegravir plus lamivudine maintained virological suppression at 96 weeks despite historical lamivudine resistance and persisting archived minority lamivudine RAMs.
Speed of phototransduction in the microvillus regulates the accuracy and bandwidth of the rhabdomeric photoreceptor

Phototransduction reactions in the rhabdomeric photoreceptor are profoundly stochastic due to the small number of participating molecules and small reaction space. The resulting quantum bumps (QBs) vary in their timing (latency), amplitudes and durations, and these variabilities within each cell are not correlated. Using modeling and electrophysiological recordings, we investigated how the QB properties depend on the cascade speed and how they influence signal transfer. Parametric analysis in the model supported by experimental data revealed that faster cascades elicit larger and narrower QBs with faster onsets and smaller variabilities than slower cascades. Latency dispersion was stronger affected by modification of upstream than downstream activation parameters. The variability caused by downstream modifications closely matched the experimental variability. Frequency response modeling showed that corner frequency is a reciprocal function of the characteristic duration of the multiphoton response, which, in turn, is a non-linear function of QB duration and latency dispersion. All QB variabilities contributed noise but only latency dispersion slowed and spread multiphoton responses, lowering the corner frequency. Using the discovered QB correlations, we evaluated transduction noise for dissimilar species and two extreme adaptation states, and compared it to photon noise. The noise emitted by the cascade was non-additive and depended non-linearly on the interaction between the QB duration and the three QB variabilities. Increased QB duration strongly suppressed both noise and corner frequency. This trade-off might be acceptable for nocturnal but not diurnal species because corner frequency is the principal determinant of information capacity. To offset the increase in noise accompanying the QB narrowing during light adaptation and the response-expanding effect of latency dispersion, the cascade accelerates. This explains the widespread evolutionary tendency of diurnal fliers to have fast phototransduction, especially after light adaptation, which thus appears to be a common adaptation to contain stochasticity, improve SNR and expand the bandwidth.
Identification of a New QTL Region on Mouse Chromosome 1 Responsible for Male Hypofertility: Phenotype Characterization and Candidate Genes

Male fertility disorders often have their origin in disturbed spermatogenesis, which can be induced by genetic factors. In this study, we used interspecific recombinant congenic mouse strains (IRCS) to identify genes responsible for male infertility. Using ultrasonography, in vivo and in vitro fertilization (IVF) and electron microscopy, the phenotyping of several IRCS carrying mouse chromosome 1 segments of Mus spretus origin revealed a decrease in the ability of sperm to fertilize. This teratozoospermia included the abnormal anchoring of the acrosome to the nucleus and a persistence of residual bodies at the level of epididymal sperm midpiece. We identified a quantitative trait locus (QTL) responsible for these phenotypes and we have proposed a short list of candidate genes specifically expressed in spermatids. The future functional validation of candidate genes should allow the identification of new genes and mechanisms involved in male infertility.