Miracle-dz/UniFAR-FTUs huggingface dataset:
Rod Photoreceptors Avoid Saturation in Bright Light by the Movement of the G Protein Transducin

Rod photoreceptors can be saturated by exposure to bright background light, so that no flash superimposed on the background can elicit a detectable response. This phenomenon, called increment saturation, was first demonstrated psychophysically by Aguilar and Stiles and has since been shown in many studies to occur in single rods. Recent experiments indicate, however, that rods may be able to avoid saturation under some conditions of illumination. Rod photoreceptors can be saturated by exposure to bright background light, so that no flash superimposed on the background can elicit a detectable response. This phenomenon, called increment saturation, was first demonstrated psychophysically by Aguilar and Stiles and has since been shown in many studies to occur in single rods. Recent experiments indicate, however, that rods may be able to avoid saturation under some conditions of illumination. We now show in ex vivo electroretinogram and single-cell recordings that in continuous and prolonged exposure even to very bright light, the rods of mice from both sexes recover as much as 15% of their dark current and that responses can persist for hours. In parallel to recovery of outer segment current is an ∼10-fold increase in the sensitivity of rod photoresponses. This recovery is decreased in transgenic mice with reduced light-dependent translocation of the G protein transducin. The reduction in outer-segment transducin together with a novel mechanism of visual-pigment regeneration within the rod itself enable rods to remain responsive over the whole of the physiological range of vision. In this way, rods are able to avoid an extended period of transduction channel closure, which is known to cause photoreceptor degeneration. SIGNIFICANCE STATEMENT Rods are initially saturated in bright light so that no flash superimposed on the background can elicit a detectable response. Frederiksen and colleagues show in whole retina and single-cell recordings that, if the background light is prolonged, rods slowly recover and can continue to produce significant responses over the entire physiological range of vision. Response recovery occurs by translocation of the G protein transducin from the rod outer to the inner segment, together with a novel mechanism of visual-pigment regeneration within the rod itself. Avoidance of saturation in bright light may be one of the principal mechanisms the retina uses to keep rod outer-segment channels from ever closing for too long a time, which is known to produce photoreceptor degeneration.
Sexual Consent Communication among Sexual and Gender Minority College Students

ABSTRACT Sexual scripts and consent communication methods are seldom explored outside of heterosexual, cisgender relationships. To date, little research has been conducted to determine how sexual and gender minority (SGM) students conceptualize and communicate consent. This study explored SGM undergraduate students’ (n = 81) sexual consent communication scripts using open-ended survey items. We conducted a thematic freelisting analysis to assess the domains of consent and non-consent scripts using Smith’s Salience Score (S). Salient indicators of consent were verbal communication (S = .31; 38%); however, more specific forms of verbal communication were listed as a spectrum, including: asking (a request, S = .16; 23%), saying (a statement, S = .16; 20%), and telling (a command, S = .10; 13%). The most salient indicators of verbal non-consent were on a similar spectrum: saying no (S = .42; 9%), verbal communication broadly (S = .23; 27%), and telling no (S = .06; 7%). Salient physical indicators of both consent and non-consent also followed a spectrum in their descriptions. Future research among SGM college students should explore the meanings, patterns, and differences in consent communication and sexual scripts.
Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance.

Importance Small abdominal aortic aneurysms (AAAs) are common in the elderly population. Their growth rates and patterns, which drive clinical surveillance, are widely disputed. Objective To assess the growth patterns and rates of AAAs as documented on serial computed tomography (CT) scans. Design, Setting, and Participants Cohort study and secondary analysis of the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT), a randomized, double-blind placebo-controlled clinical trial conducted from 2013 to 2018, with CT imaging every 6 months for 2 years. The trial was a multicenter, observational secondary analysis, not related to treatment hypotheses of data collected in the N-TA3CT. Participants included 254 patients with baseline AAA diameter between 3.5 and 5.0 cm. Exposures Patients received serial CT scan measurements, analyzed for maximum transverse diameter, at 6-month intervals. Main Outcomes and Measures The primary study outcome was AAA annual growth rate. Secondary analyses included characterizing AAA growth patterns, assessing likelihood of AAA diameter to exceed sex-specific intervention thresholds over 2 years. Results A total of 254 patients, 35 women with baseline AAA diameter 3.5 to 4.5 cm and 219 men with baseline diameter 3.5 to 5.0 cm, were included. Yearly growth rates of AAA diameters were a median of 0.17 cm/y (interquartile range [IQR], 0.16) and a mean (SD), 0.19 (0.14) cm/y. Ten percent of AAAs displayed minimal to no growth (<0.05 cm/y), 62% displayed low growth (0.05-0.25 cm/y), and 28% displayed high growth (>0.25 cm/y). Baseline AAA diameter accounted for 5.4% of variance of growth rate (P < .001; R2, 0.054). Most AAAs displayed linear growth (70%); large variations in interval growth rates occurred infrequently (3% staccato growth and 4% exponential growth); and some patients' growth patterns were not clearly classifiable (23% indeterminate). No patients with a maximum transverse diameter less than 4.25 cm exceeded sex-specific repair thresholds at 2 years (men, 0 of 92; 95% CI, 0.00-0.055; women, 0 of 25 ; 95% CI, 0.00-0.247). Twenty-six percent of patients with a maximum transverse diameter of at least 4.25 cm exceeded sex-specific repair thresholds at 2 years (n = 12 of 83 men with diameter ranging from 4.25 to <4.75 cm; 95% CI, 0.091-0.264; n = 21 of 44 men with diameter ranging from 4.75-5.0 cm; 95% CI, 0.362-0.669; n = 3 of 10 women with diameter ≥4.25 cm; 95% CI, 0.093-0.726). Conclusions and Relevance Most small AAAs showed linear growth; large intrapatient variations in interval growth rates were infrequently observed over 2 years. Linear growth modeling of AAAs in individual patients suggests smaller AAAs (<4.25 cm) can be followed up with a CT scan in at least 2 years with little chance of exceeding interventional thresholds. Trial Registration ClinicalTrials.gov Identifier: NCT01756833.
Interleukin-4 Induces the Release of Opioid Peptides from M1 Macrophages in Pathological Pain

Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can be protective in inflammatory and neurologic disorders, and can alleviate pain. Classically, IL-4 diminishes pain by blocking the production of proinflammatory cytokines. Here, we uncovered that IL-4 induces acute antinociception by IL-4 receptor α (IL-4Rα)-dependent release of opioid peptides from M1 macrophages at injured nerves. As a model of pathologic pain, we used a chronic constriction injury (CCI) of the sciatic nerve in male mice. A single application of IL-4 at the injured nerves (14 d following CCI) attenuated mechanical hypersensitivity evaluated by von Frey filaments, which was reversed by co-injected antibody to IL-4Rα, antibodies to opioid peptides such as Met-enkephalin (ENK), β-endorphin and dynorphin A 1–17, and selective antagonists of δ-opioid, µ-opioid, and κ-opioid receptors. Injured nerves were predominately infiltrated by proinflammatory M1 macrophages and IL-4 did not change their numbers or the phenotype, assessed by flow cytometry and qRT-PCR, respectively. Macrophages isolated from damaged nerves by immunomagnetic separation (IMS) and stimulated with IL-4 dose dependently secreted all three opioid peptides measured by immunoassays. The IL-4-induced release of ENK was diminished by IL-4Rα antibody, intracellular Ca2+ chelator, and inhibitors of protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), and ryanodine receptors. Together, we identified a new opioid mechanism underlying the IL-4-induced antinociception that involves PKA-mediated, PI3K-mediated, ryanodine receptor-mediated, and intracellular Ca2+-mediated release from M1 macrophages of opioid peptides, which activate peripheral opioid receptors in injured tissue. SIGNIFICANCE STATEMENT Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can ameliorate pain. The IL-4-mediated effects are considered to mostly result from the inhibition of the production of proinflammatory mediators (e.g., IL-1β, tumor necrosis factor, prostaglandin E2). Here, we found that IL-4 injected at the injured nerves attenuates pain by releasing opioid peptides from the infiltrating macrophages in mice. The opioids were secreted by IL-4 in the intracellular Ca2+-dependent manner and activated local peripheral opioid receptors. These actions represent a novel mode of IL-4 action, since its releasing properties have not been so far reported. Importantly, our findings suggest that the IL-4–opioid system should be targeted in the peripheral damaged tissue, since this can be devoid of central and systemic side effects.
Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study)

Abstract Objectives Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear. Methods Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs. Results Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3–4 events in 51% of patients, and no treatment-related deaths occurred. Conclusions TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.
Fluorescent toys ‘n’ tools lighting the way in fungal research

ABSTRACT Although largely overlooked compared to bacterial infections, fungal infections pose a significant threat to the health of humans and other organisms. Many pathogenic fungi, especially Candida species, are extremely versatile and flexible in adapting to various host niches and stressful situations. This leads to high pathogenicity and increasing resistance to existing drugs. Due to the high level of conservation between fungi and mammalian cells, it is hard to find fungus-specific drug targets for novel therapy development. In this respect, it is vital to understand how these fungi function on a molecular, cellular as well as organismal level. Fluorescence imaging allows for detailed analysis of molecular mechanisms, cellular structures and interactions on different levels. In this manuscript, we provide researchers with an elaborate and contemporary overview of fluorescence techniques that can be used to study fungal pathogens. We focus on the available fluorescent labelling techniques and guide our readers through the different relevant applications of fluorescent imaging, from subcellular events to multispecies interactions and diagnostics. As well as cautioning researchers for potential challenges and obstacles, we offer hands-on tips and tricks for efficient experimentation and share our expert-view on future developments and possible improvements.
Whole-body vibration mediates mechanical hypersensitivity through Aβ-fiber and C-fiber thermal sensation in a chronic pain model

Whole-body vibration (WBV), which is widely used as a type of exercise, involves the use of vibratory stimuli and it is used for rehabilitation and sports performance programmes. This study aimed to investigate the effect of WBV treatment in a chronic pain model after 10 WBV sessions. An animal model (chronic pain) was applied in 60 male Wistar rats (±180 g, 12 weeks old) and the animals were treated with low intensity exercise (treadmill), WBV (vibrating platform), and a combined treatment involving both. The controls on the platform were set to a frequency of 42 Hz with 2 mm peak-to-peak displacement, g ≈ 7, in a spiral mode. Before and after the vibration exposure, sensitivity was determined. Aβ-fibers-mediated mechanical sensitivity thresholds (touch-pressure) were measured using a pressure meter. C-fibers-mediated thermal perception thresholds (hot pain) were measured with a hot plate. After each session, WBV influenced the discharge of skin touch-pressure receptors, reducing mechanical sensitivity in the WBV groups (P < 0.05). Comparing the conditions “before vs. after”, thermal perception thresholds (hot pain) started to decrease significantly after the third WBV session (P < 0.05). WBV decreases mechanical hyperalgesia after all sessions and thermal sensitivity after the third session with the use of WBV.
Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system

Significance Aging is the main risk factor for the costliest diseases in today’s world. However, significant gaps remain in understanding how different cell types modulate this most common physiological process. Here, we use published single-cell gene expression data to map the prolongevity roles of two evolutionarily conserved Drosophila transcription factors, FKH and FOXO, onto either neuronal or glial cells. We then demonstrate that neuronal FKH preserves healthy function even under stress. Finally, we identify an autophagy-related gene as one of FKH’s downstream prolongevity effectors. Our results exemplify tapping into publicly available gene expression datasets to extract physiological insights, and highlight the need to shift away from organism-wide approaches and toward cell type-specific strategies to obtain meaningful insights in aging research. Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer’s disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.
The effect of pedometer-supported walking and telemonitoring after disc hernia surgery on pain and disability levels and quality of life.

AIM The aim of this study was to determine the effect of pedometer-supported walking and telemonitoring after lumbar disc hernia surgery on pain and disability levels and quality of life. METHODS This was a randomized controlled trial with two randomly selected groups conducted between March 2018 and January 2019. Sixty-seven participants (33 in the intervention group and 34 in the control group) who had undergone lumbar microdiscectomy were allocated to receive and not to receive walking exercise. Pain and disability levels and quality of life of groups were tested with the McGill Pain Questionnaire, the Oswestry Disability Index and the 36-Item Short Form Survey. Measurements were taken 3 weeks after surgery and following completion of the first, second and third months. RESULTS Compared with the control group, pain level at the first and second months and disability level at the second and third months in the intervention group were significantly lower (p < 0.05), and in the third month, subdimension scores of quality of life (the physical role difficulty, energy and vitality, mental health, social functionality and pain) were higher (p < 0.05). CONCLUSIONS Walking after herniated disc surgery decreased pain and disability levels and increased the quality of life; nurses can encourage adherence to walking as an effective intervention.
OrpR is a σ54‐dependent activator using an iron‐sulfur cluster for redox sensing in Desulfovibrio vulgaris Hildenborough

Enhancer binding proteins (EBPs) are key players of σ54‐regulation that control transcription in response to environmental signals. In the anaerobic microorganism Desulfovibrio vulgaris Hildenborough (DvH), orp operons have been previously shown to be coregulated by σ54‐RNA polymerase, the integration host factor IHF and a cognate EBP, OrpR. In this study, ChIP‐seq experiments indicated that the OrpR regulon consists of only the two divergent orp operons. In vivo data revealed that (i) OrpR is absolutely required for orp operons transcription, (ii) under anaerobic conditions, OrpR binds on the two dedicated DNA binding sites and leads to high expression levels of the orp operons, (iii) increasing the redox potential of the medium leads to a drastic down‐regulation of the orp operons expression. Moreover, combining functional and biophysical studies on the anaerobically purified OrpR leads us to propose that OrpR senses redox potential variations via a redox‐sensitive [4Fe–4S]2+ cluster in the sensory PAS domain. Overall, the study herein presents the first characterization of a new Fe–S redox regulator belonging to the σ54‐dependent transcriptional regulator family probably advantageously selected by cells adapted to the anaerobic lifestyle to monitor redox stress conditions.
Electronic Health Record–Based Prediction of 1-Year Risk of Incident Cardiac Dysrhythmia: Prospective Case-Finding Algorithm Development and Validation Study

Background Cardiac dysrhythmia is currently an extremely common disease. Severe arrhythmias often cause a series of complications, including congestive heart failure, fainting or syncope, stroke, and sudden death. Objective The aim of this study was to predict incident arrhythmia prospectively within a 1-year period to provide early warning of impending arrhythmia. Methods Retrospective (1,033,856 individuals enrolled between October 1, 2016, and October 1, 2017) and prospective (1,040,767 individuals enrolled between October 1, 2017, and October 1, 2018) cohorts were constructed from integrated electronic health records in Maine, United States. An ensemble learning workflow was built through multiple machine learning algorithms. Differentiating features, including acute and chronic diseases, procedures, health status, laboratory tests, prescriptions, clinical utilization indicators, and socioeconomic determinants, were compiled for incident arrhythmia assessment. The predictive model was retrospectively trained and calibrated using an isotonic regression method and was prospectively validated. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Results The cardiac dysrhythmia case-finding algorithm (retrospective: AUROC 0.854; prospective: AUROC 0.827) stratified the population into 5 risk groups: 53.35% (555,233/1,040,767), 44.83% (466,594/1,040,767), 1.76% (18,290/1,040,767), 0.06% (623/1,040,767), and 0.003% (27/1,040,767) were in the very low-risk, low-risk, medium-risk, high-risk, and very high-risk groups, respectively; 51.85% (14/27) patients in the very high-risk subgroup were confirmed to have incident cardiac dysrhythmia within the subsequent 1 year. Conclusions Our case-finding algorithm is promising for prospectively predicting 1-year incident cardiac dysrhythmias in a general population, and we believe that our case-finding algorithm can serve as an early warning system to allow statewide population-level screening and surveillance to improve cardiac dysrhythmia care.
Working memory and hippocampal expression of BDNF, ARC, and P-STAT3 in rats: effects of diet and exercise

ABSTRACT Objectives Mounting evidence suggests diet and exercise influence learning and memory (LM). We compared a high-fat, high-sucrose Western diet (WD) to a plant-based, amylose/amylopectin blend, lower-fat diet known as the Daniel Fast (DF) in rats with and without regular aerobic exercise on a task of spatial working memory (WM). Methods Rats were randomly assigned to the WD or DF at 6 weeks of age. Exercised rats (WD-E, DF-E) ran on a treadmill 3 times/week for 30 min while the sedentary rats did not (WD-S, DF-S). Rats adhered to these assignments for 12 weeks, inclusive of ab libitum food intake, after which mild food restriction was implemented to encourage responding during WM testing. For nine months, WM performance was assessed once daily, six days per week, after which hippocampal sections were collected for subsequent analysis of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal protein (ARC), and signal transducer and activator of transcription 3 (P-STAT3, Tyr705). Results DF-E rats exhibited the best DSA performance. Surprisingly, the WD-S group outperformed the WD-E group, but had significantly lower BDNF and ARC relative to the DF-S group, with a similar trend from the WD-E group. P-STAT3 expression was also significantly elevated in the WD-S group compared to both the DF-S and WD-E groups. Discussion These results support previous research demonstrating negative effects of the WD on spatial LM, demonstrate the plant-based DF regimen combined with chronic aerobic exercise produces measurable WM and neuroprotective benefits, and suggest the need to carefully design exercise prescriptions to avoid over-stressing individuals making concurrent dietary changes.