Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

Significance Nuclear receptors (NRs) are sequence-specific DNA binding proteins that act as intracellular receptors for small molecules such as hormones. Prior work has shown that NRs function as ligand-dependent switches that initiate a cascade of gene expression changes. The extent to which NRs function as direct regulators of downstream genes in these hierarchies remains incompletely understood. Here, we study the role of the NR EcR in metamorphosis of the Drosophila wing. We find that EcR directly regulates many genes at the top of the hierarchy as well as at downstream genes. Furthermore, we find that EcR binds distinct sets of target genes at different developmental times. This work helps inform how hormones elicit tissue- and temporal-specific responses in target tissues. The ecdysone pathway was among the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.
Numerical Simulation of the Interaction between the SeaBreeze Front and Horizontal Convective Rolls . Part II : Alongshore Ambient Flow

A three-dimensional, high-resolution model is employed to examine the interaction between the sea-breeze front (SBF) and horizontal convective rolls (HCRs) aligned parallel to the front. This study extends the perpendicular case that was the focus of Part I. In this situation, the SBF systematically encounters roll downdrafts and updrafts as it propagates inland. The sea-breeze circulation is found to significantly influence HCR strength and development. In turn, the rolls are found to dramatically modulate the overall convective activity, alternately suppressing and enhancing SBFassociated convection. Suppression occurs as the SBF merges with a roll downdraft. This is in part due to the downdraft’s introduction of dry air into the mixed layer that becomes part of the SBF cloud’s inflow. Following suppression, the SBF accelerates as convective heating above the frontal head diminishes. This leads to reinvigorated convection above the front prior to its contact with the next roll updraft, which itself sports a strong, deep cloud of its own by this time. This brings about two strong updrafts obscured by a single, merged cloud shield. During this time, a strong yet brief midlevel downdraft occurs in between the two updrafts; forcing mechanisms for this feature are discussed. The SBF propagation speed also declines significantly during this period; the near-surface portion of the front actually becoming retrograde for a period of a few minutes. Two other, less dramatic roll encounters are also examined.
Protective effect of intraoperative re-dose of prophylactic antibiotics on surgical site infection in diabetic patients: a retrospective cohort study.

Background Surgical site infection (SSI) has a high incidence in diabetic surgical patients. Preoperative antibiotic prophylaxis followed by an intraoperative re-dose was a common strategy in diabetic prolonged procedures. However, there were lacking studies on the relative benefits of this strategy on SSI. Our study aimed to clarify the effect of intraoperative re-dose of prophylactic antibiotics on SSI in diabetic patients. Methods A total of 1,840 diabetic patients with prolonged surgeries were included and Cefazolin was the only type of antibiotic prophylaxis. We assessed the relationship between intraoperative re-dose of cefazolin and 30-day incidence of SSI using a retrospective cohort study method. Results There were 361 diabetic cases with preoperative antibiotics only and 1,479 cases with pre- plus intraoperative antibiotics, in which 60 subjects suffered from SSI. Pre- plus intraoperative prophylaxis group had a lower rate of SSI in the overall and subgroup analyses when compared with preoperative only group. Operation location, combined with hypertension, poor blood glucose control, high WBC count and ASA score >2 were significantly associated with an increased risk of SSI for diabetic surgical patients (all P<0.05). Intraoperative re-dose of prophylactic antibiotics was statistically related to a lower incidence rate of SSI than preoperative prophylaxis alone (crude RR =0.47; 95% CI, 0.27-0.82; P<0.01), while the association remained significant even after adjusting the potential confounders (adjusted RR =0.51; 95% CI, 0.29-0.90; P=0.02). Conclusions For diabetic patients, intraoperative re-dose of prophylactic antibiotics may be an independent protective factor for the prevention of SSI. A specific perioperative antibiotics injection strategy should be encouraged for diabetic patients with prolonged surgeries to minimize the possibility of SSI.
Miniature electroparticle-cuff for wireless peripheral neuromodulation

Objective. Recent developments in peripheral nerve electrodes allow the efficient and selective neuromodulation of somatic and autonomic nerves, which has proven beneficial in specific bioelectronic medical applications. However, current most clinical devices are wired and powered by implantable batteries which suffer from several limitations. We recently developed a sub-millimeter inductively powered neural stimulator (electroparticle; EP), and in this study, we report the integration of the EP onto commercial cuff electrodes (EP-C) allowing the wireless activation of peripheral nerves. Approach. The current output of this device was defined at different magnetic field strenghts, and with respect to external antenna distance and activation angles. In acute in vivo testing, stimulation of the rat sciatic nerve (ScN) with the EP-C was able to evoke motor responses quantified by 3D tracking of the hind limb movement. Motor recruitment curves were obtained in response to variations in magnetic field strength (0–92.91 A m−1), stimulation frequencies (2–7 Hz), and pulse widths (50–200 µs). Main results. The results show constant output voltage throughout 50 400 stimulating cycles on a benchtop setting, and successful ScN motor activation with a 4 cm distance between external antenna and receiver. We achieved optimal motor recruitment indicated by maximizing range of hindlimb movement (6.01 ± 2.92 mm) with a magnetic field of 40.02 ± 2.85 A m−1 and 150 µs pulse width. Stimulating pulse width or frequency did not significantly influence motor recruitment. Significance. We confirmed that continuous stimulation for 14 min using monophasic pulses did not deleteriously affect the evoked motor responses when compared to wired charge-balanced biphasic electrical stimulation. We observed, however, a 36%–44% decrease in the evoked limb movement in both groups over time due to muscle fatigue. This study shows that the EP-C device can be used effectively for peripheral nerve neuromodulation.
Bisphosphonates and cancer: A relationship beyond the antiresorptive effects.

Bisphosphonates (BPs) are stable analogues of the Inorganic Pyrophosphate (PPi), an endogenous regulator of bone mineralization, which can resist the hydrolysis in the gastrointestinal tract. Their conformation allows targeting the bone as a result of their three-dimensional structure, which makes them primary agents against osteoclast-mediated bone loss. They are used in many bone pathological conditions, like bone metastasis, because of its ability to modulate bone metabolism into a less favorable place to cancer cell growth, through the inhibition of osteoclastogenesis and bone resorption. This review is focused on the mechanisms of action through which BPs affect the cellular activity and survival, mainly on their antitumoral effects. In conclusion, BPs are considered the primary therapy for skeletal disorders due to its high affinity for bone, but now they are also considered as potential antitumor agents due to its ability to induce tumor cell apoptosis, inhibition of cell adhesion, invasion and proliferation, modulation of the immune system to target and eliminate cancer cells as well as affect the angiogenic mechanisms. Like any other drug, they also have some adverse effects, but the most common, the acute phase reaction, can be minimized with the intake of calcium and vitamin D.
Intrusive Memories and Voluntary Memory of a Trauma Film: Differential Effects of a Cognitive Interference Task After Encoding

Methods to reduce intrusive memories (e.g., of traumatic events) should ideally spare voluntary memory for the same event (e.g., to report on the event in court). Single-trace memory accounts assume that interfering with a trace should impact both its involuntary and voluntary expressions, whereas separate-trace accounts assume these two can dissociate, allowing for selective interference. This possibility was investigated in 3 experiments. Nonclinical participants viewed a trauma film followed by an interference task (Tetris game-play after reminder cues). Next, memory for the film was assessed with various measures. The interference task reduced the number of intrusive memories (diary-based, Experiments 1 and 2), but spared performance on well-matched measures of voluntary retrieval—free recall (Experiment 1) and recognition (Experiments 1 and 2)—challenging single-trace accounts. The interference task did not affect other measures of involuntary retrieval—perceptual priming (Experiment 1) or attentional bias (Experiment 2). However, the interference task did reduce the number of intrusive memories in a laboratory-based vigilance-intrusion task (Experiments 2 and 3), irrespective of concurrent working memory load during intrusion retrieval (Experiment 3). Collectively, results reveal a robust dissociation between intrusive and voluntary memories, having ruled out key methodological differences between how these two memory expressions are assessed, namely cue overlap (Experiment 1), attentional capture (Experiment 2), and retrieval load (Experiment 3). We argue that the inability of these retrieval factors to explain the selective interference is more compatible with separate-trace than single-trace accounts. Further theoretical developments are needed to account for this clinically important distinction between intrusive memories and their voluntary counterpart.
Inattentional Blindness During Driving in Younger and Older Adults

Age-related changes to perceptual and cognitive abilities have been implicated in an increased risk of collision in older adults. This may be due, in part, to their reduced ability to attend to potentially relevant aspects of their driving environment. An associated general phenomenon of inattentional blindness involves a failure to notice visually presented objects or events when attention is directed elsewhere. Previous studies of inattentional blindness using computer paradigms report higher incidence of this effect in older compared to younger adults. However, little is known about whether these age-related effects are observed during more complex, realistic, everyday tasks, such as driving. Therefore, the goal of this study was to explore whether younger and older adults differ in their awareness of objects in their driving environment when their attention is directed toward another primary driving task. This study took place in a high-fidelity, full field of view, driving simulator. Thirty-two younger (Mage = 25.41) and 32 older (Mage = 73.41) adults drove through 19 short scenarios and were asked to first judge whether their vehicle could fit between two rows of vehicles parked on either side of the road and then to perform the associated driving maneuver (i.e., drive through or drive around). On four critical trials, objects were placed on the side of the road that differed in terms of animacy. Specifically, animate objects consisted of 3D humans standing by a bus shelter and inanimate objects consisted of photographs of the same individuals on a bus shelter advertisement. Inattentional blindness was measured via a post-drive, tablet-based recognition task immediately following the critical trials. Results revealed high rates of inattentional blindness across both age groups, with significantly lower levels of awareness for inanimate objects compared to animate objects. Further, whereas younger adults demonstrated reduced inattentional blindness following the first critical trial, older adults did not show this immediate improvement in recognition performance. Overall, this study provides unique insights into the factors associated with age-related changes to attention and how they may affect important driving-related outcomes.
Assessing drug-induced long QT and proarrhythmic risk using human stem cell-derived cardiomyocytes in a Ca2+ imaging assay: Evaluation of 28 CiPA compounds at three test sites.

INTRODUCTION The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR and HESI was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem cell-derived cardiomyocytes (hSC-CMs). METHODS The potential proarrhythmic risks of the 28 CiPA drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+ -sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of two commercially available hSC-CM lines (Cor.4U® and CDI iCell® Cardiomyocytes) at three different test sites. RESULTS The Ca2+ transient assay, performed at the three sites using the two different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CIPA drugs and detected cellular arrhythmias-like/EAD in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP risk drugs (54.5%) and 0 of 9 low/no TdP risk-drugs (0%). The results were comparable among the three sites and from two hSC-CM cell lines. CONCLUSION The Ca 2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the micro-electrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.
Mechanisms of action of metformin with special reference to cardiovascular protection

Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.
Direct and indirect measures of context in patients with mild-to-severe traumatic brain injury (TBI): The additive contribution of eye tracking

ABSTRACT Introduction: The facilitation of memory for target stimuli due to the similarity of context in the learning and testing phases is known as the “Context-Effect” (CE). Previous studies reported that TBI affects memory for contextual information when tested directly. However, the indirect effect of contextual information on memory of target (i.e., CE) is preserved. Several studies have demonstrated that CE is composed of multiple, distinct cognitive processes. The present study includes four context conditions to enable identification of the exact process affected by TBI. In addition, eye movements were monitored to test three hypotheses: first, that the TBI group’s dwell time on target (DTOT) at encoding would be less than that of controls. Second, that DTOT at encoding would be more highly associated with recognition at test for the control group than for the TBI group. Third, that overall DTOT at encoding on new, as compared to old items (“repetition effect”), would be less pronounced for the TBI group as compared to controls. Methods: Twenty-four patients with mild-to-severe TBI and 23 matched controls participated in this study. We presented participants with photographs of male faces shown wearing distinctive, trial-unique hats (yielding specific Target-Context pairing). Eye movements were recorded throughout the test task. Results: Memory for faces following TBI is impaired compared to that of controls. The magnitude and pattern of CE are the same for both groups. The TBI group has a lower DTOT compared to that of controls. However, the relative length of DTOT in the various conditions is similar in both groups. Conclusions: Behavioral results indicate that although the TBI group has impaired memory for faces, the CE pattern is similar to that of controls. Similarly, in terms of eye movements, although the TBI group focuses less on target, relations between the various conditions are similar in both groups.
Semantic Memory Activation After Acute Exercise in Healthy Older Adults

Abstract Objectives: A growing body of research suggests that regular participation in long-term exercise is associated with enhanced cognitive function. However, less is known about the beneficial effects of acute exercise on semantic memory. This study investigated brain activation during a semantic memory task after a single session of exercise in healthy older adults using functional magnetic resonance imaging (fMRI). Methods: Using a within-subjects counterbalanced design, 26 participants (ages, 55–85 years) underwent two experimental visits on separate days. During each visit, participants engaged in 30 min of rest or stationary cycling exercise immediately before performing a Famous and Non-Famous name discrimination task during fMRI scanning. Results: Acute exercise was associated with significantly greater semantic memory activation (Famous>Non-Famous) in the middle frontal, inferior temporal, middle temporal, and fusiform gyri. A planned comparison additionally showed significantly greater activation in the bilateral hippocampus after exercise compared to rest. These effects were confined to correct trials, and as expected, there were no differences between conditions in response time or accuracy. Conclusions: Greater brain activation following a single session of exercise suggests that exercise may increase neural processes underlying semantic memory activation in healthy older adults. These effects were localized to the known semantic memory network, and thus do not appear to reflect a general or widespread increase in brain blood flow. Coupled with our prior exercise training effects on semantic memory-related activation, these data suggest the acute increase in neural activation after exercise may provide a stimulus for adaptation over repeated exercise sessions. (JINS, 2019, 25, 557–568)
Reducing Harms and Increasing Benefits of Screening for Cervical Cancer and Colorectal Cancer – A Model-based Approach

textabstractScreening is the systematic testing of asymptomatic individuals to identify disease or risk factors for disease. This enables the possibility to act earlier, e.g. by starting treatment of the disease earlier. Screening is especially valuable for diseases like cancer, where prognosis is better in earlier stages. Cervical cancer and colorectal cancer can even be prevented by screening, as their development is usually preceded by a long preclinical phase in which benign lesions can be detected by screening and removed by subsequent treatment. Obviously, this will reduce morbidity and mortality from these types of cancer. However, screening also comes with burden and harm for some of its participants. Undergoing a screening examination can be painful, may lead to complications, and the result is never 100% accurate, meaning that disease will be missed in some individuals while others will unnecessarily be referred for follow-up testing and potentially also treatment. Reducing these harms and further increasing the benefits of screening for cervical cancer and colorectal cancer is the topic of this thesis. Several studies are included in which mathematical modeling has been used to assess the harms, benefits, and harm-benefit ratio of different screening strategies for the early detection of cervical cancer and colorectal cancer.