Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of the mammalian circadian clock

The mammalian circadian system is composed of a central clock situated in the hypothalamic suprachiasmatic nucleus (SCN) and peripheral clocks of each tissue and organ in the body. While much has been learned about the pre‐ and postnatal development of the circadian system, there are still many unanswered questions about how and when cellular clocks start to tick and form the circadian system. Most SCN neurons contain a cell‐autonomous circadian clock with individual specific periodicity. Therefore, the network of cellular oscillators is critical for the coherent rhythm expression and orchestration of the peripheral clocks by the SCN. The SCN is the only circadian clock entrained by an environmental light–dark cycle. Photic entrainment starts postnatally, and the SCN starts to function gradually as a central clock that controls physiological and behavioral rhythms during postnatal development. The SCN exhibits circadian rhythms in clock gene expression from the embryonic stage throughout postnatal life and the rhythm phenotypes remain basically unchanged. However, the disappearance of coherent circadian rhythms in cryptochrome‐deficient SCN revealed changes in the SCN networks that occur in postnatal weeks 2–3. The SCN network consists of multiple clusters of cellular circadian rhythms that are differentially integrated by the vasoactive intestinal polypeptide and arginine vasopressin signaling depending on the period of postnatal development.
Patterns of care and survival outcomes examining radiation therapy for advanced Hodgkin lymphoma

Abstract The use of radiation therapy (RT) and its impact on survival in advanced Hodgkin lymphoma (HL) is controversial. Data were obtained from the surveillance, epidemiology, and end results (SEER) registries from 1988–2011. There were 9467 adults who met inclusion criteria; 19% received RT. Radiation use declined from 25% in 1988 to 16% in 2011. Five-year overall survival (OS) for stage III and IV patients for the no versus RT cohorts were 79% versus 88% (p < 0.0001) and 73% versus 84% (p < 0.0001), respectively. RT was associated with improved OS (HR = 0.76; 0.68–0.85) on multivariable analysis and in patients diagnosed after 2000. Although there was a decline in utilization of RT from 1988 to 2011, RT was associated with a survival benefit in stage III–IV HL.
High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.
The syntax of words

This monograph examines complex words -- compounds and those involving derivational and inflectional affixation -- from a syntactic standpoint that encompasses both the structure of words and the system of rules for generating that structure.The author contends that the syntax of words and the more familiar syntax involving relations among words must be defined by two discrete sets of principles in the grammar, but nevertheless that word structure has the same general formal properties as the larger syntactic structure and is generated by the same sort of rule system.This investigation of word structure and rule systems is based for the most part on the word syntax of English and related languages. One of its major conclusions is that English word structure can be "properly characterized solely in terms of a context-free grammar. " Selkirk points out that the Semitic languages, for example, must be characterized in terms of a more elaborate schema.The first chapter presents a general theory of word structure, and discusses a context-free grammar for words, X theory in word structure, and word structure rules. The second chapter is concerned with compounding, and probes the structure and "headedness" of compounds, verbal compounds, and the category type of English compounds. The third and final chapter, on affixation, investigates the nature of affixes, inflectional affixation, and English derivational morphology.This book is the seventh in the Linguistic Inquiry Monograph series.
The Partial Reinforcement Extinction Effect: The Proportion of Trials Reinforced During Conditioning Predicts the Number of Trials to Extinction

Four experiments compared the extinction of responding to a continuously reinforced (CRf) conditioned stimulus (conditional stimulus [CS]) consistently reinforced on every trial, with extinction of responding to a partially reinforced (PRf) CS that had been inconsistently reinforced. To equate the acquisition of responding between the two CSs, the average duration of the CRf CS was extended so that it scheduled the same overall rate of reinforcement per unit time as the PRf CS. Experiment 1 used a within-subjects design to compare the rates of extinction for a 10-s PRf CS reinforced on 33% of trials versus a 30-s CRf CS. Experiment 2 made the same comparison but using a between-subjects design. Experiment 3 compared extinction in a group trained with a 10-s PRf CS reinforced on 20% of trials and a group trained with a 50-s CRf CS. Experiment 4 compared the rates of extinction following two partial reinforcement schedules: a 10-s PRf CS reinforced on 33% of trial versus a 20-s CRf CS reinforced on 66% of trials. In each experiment, responding took longer to extinguish for the CS that scheduled a lower per-trial probability of reinforcement. Modeling of individual extinction curves using Weibull functions indicated that the latency to initiate extinction was directly related to the per-trial probability of reinforcement learned during acquisition. For example, compared with training with a CRf CS, rats reinforced on 33% of trials took approximately 3 times as many trials to initiate extinction, and rats reinforced on 20% of trials took 5 times as many trials to initiate extinction. These results provide support for trial-based accounts of extinction (e.g., Capaldi & Deutsch, 1967), whereby rats learn about the expected number of trials per reinforcer, and extinction depends on the number of expected reinforcers that have been omitted rather than on the number of extinction trials per se.
A Novel Approach Based on a Weighted Interactive Network to Predict Associations of MiRNAs and Diseases

Accumulating evidence progressively indicated that microRNAs (miRNAs) play a significant role in the pathogenesis of diseases through many experimental studies; therefore, developing powerful computational models to identify potential human miRNA–disease associations is vital for an understanding of the disease etiology and pathogenesis. In this paper, a weighted interactive network was firstly constructed by combining known miRNA–disease associations, as well as the integrated similarity between diseases and the integrated similarity between miRNAs. Then, a new computational method implementing the newly weighted interactive network was developed for discovering potential miRNA–disease associations (WINMDA) by integrating the T most similar neighbors and the shortest path algorithm. Simulation results show that WINMDA can achieve reliable area under the receiver operating characteristics (ROC) curve (AUC) results of 0.9183 ± 0.0007 in 5-fold cross-validation, 0.9200 ± 0.0004 in 10-fold cross-validation, 0.9243 in global leave-one-out cross-validation (LOOCV), and 0.8856 in local LOOCV. Furthermore, case studies of colon neoplasms, gastric neoplasms, and prostate neoplasms based on the Human microRNA Disease Database (HMDD) database were implemented, for which 94% (colon neoplasms), 96% (gastric neoplasms), and 96% (prostate neoplasms) of the top 50 predicting miRNAs were confirmed by recent experimental reports, which also demonstrates that WINMDA can effectively uncover potential miRNA–disease associations.
Growth hormone signaling and action in obese versus lean human subjects.

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, -66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.
Monitoring of direct alcohol markers in alcohol use disorder patients during withdrawal treatment and successive rehabilitation.

Direct and indirect biomarkers are widely applied for the determination of alcohol consumption. They help to assess past or present alcohol consumption. Depending on the window of detection and sensitivity of the investigated marker, punctual alcohol consumption may remain undetected. In this study, different sampling strategies for the intermediary long-term marker phosphatidylethanol (PEth) are evaluated and compared to the determination of the short-term markers ethyl glucuronide (EtG) and ethyl sulfate (EtS) in urine. Samples from 19 patients undergoing alcohol use disorder treatment were collected during the withdrawal treatment and successive rehabilitation (33 ± 26 days (range: 3-74 days)). With liquid chromatography-tandem mass spectrometry (LC-MS/MS) EtG and EtS in urine, PEth in blood, PEth in dried blood spot (DBS) from venous blood, and PEth in DBS from capillary blood were quantified and compared. The use of volumetric capillary DBS, prepared from 20 μL of blood, provided the same results as the use of venous DBS (95% ± 10%, R2 0.9899 for PEth 16:0/18:1). Capillary DBS sampling has the advantage that it can be performed without venipuncture. The use of PEth in DBS proved to prevent post-sampling degradation, providing a longer detection in comparison to PEth in liquid blood, which only showed 67% ± 24% of the PEth DBS 16:0/18:1 concentration. When compared with EtG and EtS in urine, PEth monitoring proved to be advantageous for the detection of relapse situations, as the accumulation of PEth in blood prolongs the detectability. In conclusion, volumetric capillary DBS sampling for PEth is a simple and useful tool for compliance monitoring, and avoids hematocrit issues.
Ribosome specialization and its potential role in the control of protein translation and skeletal muscle size.

The ribosome is typically viewed as a supramolecular complex with constitutive and invariant capacity in mediating translation of mRNA into protein. This view has been challenged by recent research revealing that ribosome composition could be heterogeneous, and this heterogeneity leads to functional ribosome specialization. This review presents the idea that ribosome heterogeneity results from changes in its various components, including variations in ribosomal protein (RP) composition, post-translational modifications of RPs, changes in ribosomal-associated proteins, alternative forms of rRNA and post-transcriptional modifications of rRNAs. Ribosome heterogeneity could be orchestrated at several levels and may depend on numerous factors, such as the subcellular location, cell type and tissue specificity, the development state, cell state, ribosome biogenesis, RP turnover, physiological stimuli and circadian rhythm. Ribosome specialization represents a completely new concept for the regulation of gene expression. Specialized ribosomes could modulate several aspects of translational control, such as mRNA translation selectivity, translation initiation, translational fidelity and translation elongation. Recent research indicates that the expression of Rpl3 is markedly increased, while that of Rpl3l is highly reduced during mouse skeletal muscle hypertrophy. Moreover, Rpl3l overexpression impairs the growth and myogenic fusion of myotubes. Although the function of Rpl3 and Rpl3l in the ribosome remains to be clarified, these findings suggest that ribosome specialization may be potentially involved in the control of protein translation and skeletal muscle size. Limited data concerning ribosome specialization are currently available in skeletal muscle. Future investigations have the potential to delineate the function of specialized ribosomes in skeletal muscle.
Marine Bacterial Polysaccharide EPS11 Inhibits Cancer Cell Growth and Metastasis via Blocking Cell Adhesion and Attenuating Filiform Structure Formation

Our previous results suggested that EPS11, a novel marine bacterial polysaccharide, might be a potential drug candidate for human non-small cell lung carcinoma treatment. In this study, we further investigate the anticancer mechanisms against liver cancer and the anti-metastatic effects in vivo of EPS11. Firstly, we found that EPS11 exerts cytotoxic effects via blocking cell adhesion and destroying filiform structure formation in Huh7.5 cells. Moreover, mass spectrometry-based proteomic analysis of EPS11-treated Huh7.5 cells revealed that expression of many adhesion-related proteins was significantly changed. It is noteworthy that the expression of CD99, a key factor related to cell adhesion, migration and cell death, is remarkably down-regulated after EPS11 treatment. Importantly, over-expression of CD99 partly rescues cell death rate, and improves cell adhesion and migration ability in Huh7.5 treated by EPS11. Thus, we propose that CD99 is a potential action target of EPS11, inhibiting cancer cell proliferation, adhesion and migration. Notably, administration of EPS11 simultaneously with tumor induction evidently reduces tumor nodule formation in the lungs, which strongly indicates that EPS11 has anti-metastatic effects in vivo. Taken together, our results suggest that EPS11 inhibits liver cancer cell growth via blocking cell adhesion and attenuating filiform structure formation, and has potential as an anti-cancer drug, targeting metastasis of cancer cells, in the future.
Detection of the focal spot motion relative to the collimator axis of a linear accelerator under gantry rotation

The potential for delivering high precision radiotherapy using linear accelerators (linacs) has been improved with the development of digital x-ray electronic portal imaging devices (EPID) for acquiring kilovoltage (kV) cone-beam CT and megavoltage (MV) images for patient positioning. EPIDs have also opened the possibilities of developing novel quality assurance and insight into radiotherapy equipment performance. The aim of this work was to measure the offset of the focal spot position (FSP) of a linac under gantry rotation relative to the collimator axis using an EPID. The focal spot was assumed to be a point source of MV x-ray generation. A special phantom was designed for measurement of FSP as a function of gantry angle on clinical linacs. The phantom was designed for attachment to the gantry head and supporting two tungsten-carbide ball-bearings at two different distances from the focal spot. The methodology was demonstrated on a series of images acquired of the phantom on three Elekta linacs in clinical use with 6 MV flattening-filter-free (FFF) beams. The gantry and collimator were rotated 360° in steps of 30°. For each position an image of the phantom was acquired using the EPID. Each series consisted of 169 EPID images. The images were analysed using in-house developed software. Analyses of the EPID images acquired with 6 MV FFF beams showed that the focal spot motion amplitudes relative to the collimator axis during gantry rotation in the longitudinal and lateral directions were less than 0.10 mm and 0.50 mm, respectively, for an optimized 6 MV FFF FSP calibrated linac. In a treatment planning system (TPS) the focal spot is assumed to be located on the rotation axis of the collimator at all gantry angles. This work introduces a method for quantifying the actual variation from this assumption in practice.
PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC).

507Background: Hormonal therapy (HT) is the mainstay for patients (pts) with ER+ BC. P, a cyclin-dependent kinase 4/6 inhibitor, blocks growth of ER+/HER2– BC preclinical models. In PALOMA-1, an open-label Ph 2 trial, addition of P to L improved median PFS vs L alone (20.2 months [mo] vs 10.2 mo) in pts with first-line ER+/HER2– ABC with acceptable safety, leading to accelerated FDA approval. PALOMA-2 is a randomized double-blind Ph 3 trial designed to confirm these results. Methods: 666 postmenopausal pts with no prior systemic therapy for ABC were randomized 2:1 to receive P (oral 125 mg/d; 3 wks on/1 wk off) + L (2.5 mg/d continuously) or PLB + L every 28 days until disease progression, consent withdrawal or death. Pts were stratified by disease site, disease-free interval from end of (neo)adjuvant therapy, and prior HT (yes/no). Primary endpoint: investigator-assessed PFS; key secondary endpoints: overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR=CR + PR + SD ≥24 wks), p.
Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.
Treating Polymicrobial Infections in Chronic Diabetic Wounds

This review provides a comprehensive summary of issues associated with treating polyclonal bacterial biofilms in chronic diabetic wounds. We use this as a foundation and discuss the alternatives to conventional antibiotics and the emerging need for suitable drug delivery systems. SUMMARY This review provides a comprehensive summary of issues associated with treating polyclonal bacterial biofilms in chronic diabetic wounds. We use this as a foundation and discuss the alternatives to conventional antibiotics and the emerging need for suitable drug delivery systems. In recent years, extraordinary advances have been made in the field of nanoparticle synthesis and packaging. However, these systems have not been incorporated into the clinic for treatments other than for cancer or severe genetic diseases. We present a unifying perspective on how the field is evolving and the need for an early amalgamation of engineering principles and a biological understanding of underlying phenomena in order to develop a therapy that is translatable to the clinic in a shorter time.