Miracle-dz/UniFAR-FTUs huggingface dataset:
Protein X-ray Crystallography and Drug Discovery

With the advent of structural biology in the drug discovery process, medicinal chemists gained the opportunity to use detailed structural information in order to progress screening hits into leads or drug candidates. X-ray crystallography has proven to be an invaluable tool in this respect, as it is able to provide exquisitely comprehensive structural information about the interaction of a ligand with a pharmacological target. As fragment-based drug discovery emerged in the recent years, X-ray crystallography has also become a powerful screening technology, able to provide structural information on complexes involving low-molecular weight compounds, despite weak binding affinities. Given the low numbers of compounds needed in a fragment library, compared to the hundreds of thousand usually present in drug-like compound libraries, it now becomes feasible to screen a whole fragment library using X-ray crystallography, providing a wealth of structural details that will fuel the fragment to drug process. Here, we review theoretical and practical aspects as well as the pros and cons of using X-ray crystallography in the drug discovery process.
Environmental factors for establishment of the dormant state in oocytes

Guaranteeing the sustainability of gametogenesis is a fundamental issue for perpetuating the species. In the mammalian ovary, sustainability is accomplished by keeping a number of oocytes “stocked” in the dormant state. Despite the evident importance of this state, the mechanisms underlying the oocyte dormancy are not fully understood, although it is presumed that both intrinsic and extrinsic factors are involved. Here, we review environmental factors involved in the regulation of oocyte dormancy. Consideration of the environmental factors illustrates the nature of the ovarian compartment, in which primordial follicles reside. This should greatly improve our understanding of the mechanisms and also assist in reconstitution of the dormant state in culture. Accumulating knowledge on the dormant state of oocytes will contribute to a wide range of research in fields such as developmental biology, reproductive biology and regenerative medicine.
“He Who Spareth the Rod Hateth His Son”: Perceptions Regarding Corporal Punishment Among Ultra-Orthodox Jewish Fathers in Israel

Based on the findings of substantial research, Western professionals today perceive corporal punishment as a threat to child well-being. They also view it as a violation of children’s rights. Nonetheless, many minority groups in Western societies still consider it to be a legitimate child-rearing practice. In response to this gap, this article presents qualitative findings from an exploratory context-informed study of Ultra-Orthodox Jewish fathers in Israel, regarding their perceptions and ascribed meanings of corporal punishment. Our exploration was guided by the following research question: What are the constructions, perceptions, beliefs, and meanings associated with corporal punishment among Ultra-Orthodox Litvak fathers in Israel? The thematic analysis of 15 in-depth semi-structured interviews yielded two central themes. The first is the view of corporal punishment as an educational tool with legitimacy based on religious sources and emotion-focused rationales. The second theme deals with different limitations on and guidelines regarding this legitimacy. Children were struck as a result of behavior that parents experienced as extreme, and striking the child in response to religious wrongdoing was viewed as problematic. The fathers interviewed stressed the need to suit the punishment to the child, in terms of the intensity of the blow, frequency, and the age of the child. The fathers also emphasized the importance of the child’s subjective experience being one of education as opposed to humiliation. Implications from these findings illustrate the gaps between the Ultra-Orthodox community and professionals who espouse the Western view that prohibits corporal punishment; at the same time, they portray the fathers as expressing an intricate approach toward corporal punishment, with conditions and limitations, as opposed to absolute approval. This article advocates a context-informed approach toward dealing with corporal punishment in minority groups that legitimize the practice. Adopting such an approach may contribute to better cooperation between professionals and their clients from minority groups, and advance child well-being.
Homogeneous Dual-Parametric-Coupled Assay for Simultaneous Nucleotide Exchange and KRAS/RAF-RBD Interaction Monitoring

We have developed a rapid and sensitive single-well dual-parametric method introduced in linked RAS nucleotide exchange and RAS/RAF-RBD interaction assays. RAS mutations are frequent drivers of multiple different human cancers, but the development of therapeutic strategies has been challenging. Traditionally, efforts to disrupt the RAS function have focused on nucleotide exchange inhibitors, GTP-RAS interaction inhibitors, and activators increasing GTPase activity of mutant RAS proteins. As the amount of biological knowledge grows, targeted biochemical assays enabling high-throughput screening have become increasingly interesting. We have previously introduced a homogeneous quenching resonance energy transfer (QRET) assay for nucleotide binding studies with RAS and heterotrimeric G proteins. Here, we introduce a novel homogeneous signaling technique called QTR-FRET, which combine QRET technology and time-resolved Förster resonance energy transfer (TR-FRET). The dual-parametric QTR-FRET technique enables the linking of guanine nucleotide exchange factor-induced Eu3+-GTP association to RAS, monitored at 615 nm, and subsequent Eu3+-GTP-loaded RAS interaction with RAF-RBD-Alexa680 monitored at 730 nm. Both reactions were monitored in a single-well assay applicable for inhibitor screening and real-time reaction monitoring. This homogeneous assay enables separable detection of both nucleotide exchange and RAS/RAF interaction inhibitors using low nanomolar protein concentrations. To demonstrate a wider applicability as a screening and real-time reaction monitoring method, the QTR-FRET technique was also applied for G(i)α GTP-loading and pertussis toxin-catalyzed ADP-ribosylation of G(i)α, for which we synthesized a novel γ-GTP-Eu3+ molecule. The study indicates that the QTR-FRET detection technique presented here can be readily applied to dual-parametric assays for various targets.
Antioxidant Blueberry Anthocyanins Induce Vasodilation via PI3K/Akt Signaling Pathway in High-Glucose-Induced Human Umbilical Vein Endothelial Cells

Blueberries are rich in antioxidant anthocyanins. The hypotensive effects of blueberry anthocyanins in endothelial cells was investigated here. Pretreatment with blueberry anthocyanin extract, malvidin, malvidin-3-glucoside, and malvidin-3-galactoside significantly ameliorated high-glucose-induced damage by enhancing endogenous antioxidant superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), lowering reactive oxygen species (ROS) generation and NADPH oxidase isoform 4 (NOX4) expression, and increasing the cell vitalities. They also effectively induced a vasodilatory effect by increasing the vasodilator nitric oxide (NO) and its promoters endothelial NO synthase (eNOS) and peroxisome proliferator-activated receptor-γ (PPARγ) levels as well as by decreasing the vasoconstrictor angiotensin-converting enzyme (ACE), xanthine oxidase-1 (XO-1), and low-density lipoprotein (LDL) levels. The activation of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and the breakdown of protein kinase C zeta (PKCζ) pathway were involved in the bioactivities. The results indicated blueberry anthocyanins protected endothelial function against high-glucose (HG) injury via antioxidant and vasodilatory mechanisms, which could be promising molecules as a hypotensive nutraceutical for diabetes patients.
Changes in airway diameter and mucus plugs in patients with asthma exacerbation

Background Airway obstruction due to decreased airway diameter and increased incidence of mucus plugs has not been directly observed in asthma exacerbation. We studied the changes in the inner diameter of the airway (Din) and the frequency of mucus plugs by airway generation in patients with asthma exacerbation. We compared these patients to those in a stable phase using high-resolution computed tomography (HRCT). Methods and findings Thirteen patients with asthma were studied by HRCT during asthma exacerbation and in a stable period. The HRCT study was performed on patients who could safely hold their breath for a short while in a supine position 1 hour after initial treatment for asthma exacerbation. Using a curved multiplanar reconstruction (MPR) software, we reconstructed the longitudinal airway images and the images exactly perpendicular to the airway axis to measure the Din and mucus plugs from the second- (segmental) to sixth-generation bronchi in all segments of the lungs.The ratios of Din (exacerbation/stable) were 0.91(P = 0.016), 0.88 (P = 0.002), 0.83 (P = 0.001), 0.80 (P = 0.001), and 0.87 (NS) in the second-, third-, fourth-, fifth-, and sixth-generation bronchi, respectively. The percentages of airway obstruction due to mucus plugs were notably higher in the fourth- and fifth-generation bronchi (17.9%/18.1% in stable phase and 43.2%/45.9% in the exacerbation phase, respectively) than in the other generations of bronchi. Conclusions Among the bronchi examined, the fourth- and fifth-generation bronchi were significantly obstructed during asthma exacerbation compared with the stable phase in terms of a decreased airway diameter and mucus plugs.
The Effects of General Anesthetics on Synaptic Transmission

General anesthetics are a class of drugs that target the central nervous system and are widely used for various medical procedures. General anesthetics produce many behavioral changes required for clinical intervention, including amnesia, hypnosis, analgesia, and immobility; while they may also induce side effects like respiration and cardiovascular depressions. Understanding the mechanism of general anesthesia is essential for the development of selective general anesthetics which can preserve wanted pharmacological actions and exclude the side effects and underlying neural toxicities. However, the exact mechanism of how general anesthetics work is still elusive. Various molecular targets have been identified as specific targets for general anesthetics. Among these molecular targets, ion channels are the most principal category, including ligand-gated ionotropic receptors like γ-aminobutyric acid, glutamate and acetylcholine receptors, voltage-gated ion channels like voltage-gated sodium channel, calcium channel and potassium channels, and some second massager coupled channels. For neural functions of the central nervous system, synaptic transmission is the main procedure for which information is transmitted between neurons through brain regions, and intact synaptic function is fundamentally important for almost all the nervous functions, including consciousness, memory, and cognition. Therefore, it is important to understand the effects of general anesthetics on synaptic transmission via modulations of specific ion channels and relevant molecular targets, which can lead to the development of safer general anesthetics with selective actions. The present review will summarize the effects of various general anesthetics on synaptic transmissions and plasticity.
Machine learning on genome-wide association studies to predict the risk of radiation-associated contralateral breast cancer in the WECARE Study

The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve (AUC) of 0.62 (p = 0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.
What Factors Influence the Sleep of On-call Workers?

ABSTRACT Objective: On-call work is becoming increasingly common in response to service demands. This study had two aims; 1) describe the demographic profile of on-call workers in Australia, and 2) establish the impacts of on-call work on workers’ sleep. Methods: A cross-sectional study was conducted using an online questionnaire completed by Australian on-call workers (n = 228) from various professions. The questionnaire included items on i) demographic and work characteristics, ii) rumination about on-call factors, iii) sleep quantity and quality. Analyses were conducted using mixed effects ordinal regression and multivariable logistic regression. Results: Workers slept <7 hours per night when on-call (80%), and reported sleep was impacted on-call even when no-calls were received (56%). On-call workers rated interruptions to family/leisure time (70%), missing a call (69%), preplanning in case of a call (69%), and not able to make plans (67%) as the main factors they ruminated about. Female on-call workers were more likely to think about the likelihood of being called, report frequent thoughts about what they would need to do if called, and think about interruptions to family/leisure time as a result of a call. Younger workers were more likely to think about the likelihood of being called compared to older adults, however middle-aged workers were less likely to plan for a call compared to younger workers. Conclusions: This study is the first to describe Australia’s on-call population, including factors that specifically impact sleep. Future studies should implement tailored education and support strategies to address the unique challenges facing on-call workers.
Cervical vertebral maturation assessment on lateral cephalometric radiographs using artificial intelligence: comparison of machine learning classifier models.

OBJECTIVES This study aimed to develop five different supervised machine learning classifier models using artificial intelligence (AI) techniques and to compare their performance for cervical vertebral maturation (CVM) analysis. A clinical decision support system (CDSS) was developed for more objective results. METHODS A total of 647 digital lateral cephalometric radiographs with visible C2, C3, C4 and C5 vertebrae were chosen. Newly developed software was used for manually labelling the samples, with the integrated CDSS developed by evaluation of 100 radiographs. On each radiograph, 26 points were marked, and the CDSS generated a suggestion according to the points and CVM analysis performed by the human observer. For each sample, 54 features were saved in text format and classified using logistic regression, support vector machine, random forest, artificial neural network and decision tree models. The weighted κ (κ) coefficient was used to evaluate the concordance of classification and expert visual evaluation results. RESULTS Among the CVM stage classifier models, the best result was achieved using the artificial neural network model (κ = 0.926). Among cervical vertebrae morphology classifier models, the best result was achieved using the logistic regression model (κ = 0.968) for the presence of concavity, and the decision tree model (κ = 0.949) for vertebral body shapes. CONCLUSIONS This study has proposed machine learning models for CVM assessment on lateral cephalometric radiographs, which can be used for the prediction of cervical vertebrae morphology. Further studies should be done especially of forensic applications of AI models through CVM evaluations.
Independent Older Adult’s IADL and Executive Function According to Cognitive Performance

Participation in Instrumental Activities of Daily Living (IADL) is essential in occupational therapy aiming to improve the life situation of elderly. Effective executive function (EF) is important to successful functioning in IADL. The purpose of this study was to examine EF and IADL performance differences according to cognitive levels as measured by the Montreal Cognitive Assessment (MoCA), age, and gender. In all, 80 elderly (49% female; age M = 73.4) were assessed at home, with Weekly Calendar Planning Activity (WCPA-10), IADL scale, and MoCA as a cognitive screening tool for dividing into normal cognitive (NC) level and mild cognitive impairment (MCI). The comparison between the MoCA groups on the WCPA-10 and IADL shows significant differences between the groups; gender and age differed only in IADL. IADL and WCPA-10 performance among independent elderly relates to their cognitive level. We suggest that intervention that will focus on EF may assist in improving performance and maintaining participation in occupation.
Modified models and simulations for estimating dynamic functional connectivity in resting state functional magnetic resonance imaging

As understanding the nature of brain networks through dynamic functional connectivity (dFC) estimation is of paramount significant, the introduction and revision of blood‐oxygen‐level dependent (BOLD) signal simulation methods in brain regions and dFC estimation methods have gained significant ground in recent years. Based on the observation of BOLD signals with multivariate nonnormal distribution in functional magnetic resonance imaging (fMRI) images, we first propose a copula‐based method for the production of these signals, in which nonnormal data are generated with a selected time‐varying covariance matrix. Therefore, we can compare the performance of models in the cases where brain signals have a multivariate nonnormal distribution. Then, two kendallized exponentially weighted moving average (KEWMA) and kendallized dynamic conditional correlation (KDCC) multivariate volatility models are introduced which are based on two well‐known and commonly used exponentially weighted moving average (EMWA) and dynamic conditional correlation (DCC) models. The results show that KDCC model can estimate conditional correlation significantly far better than the former ones (ie, DCC, standardized dynamic conditional correlation, EWMA, and standardized exponentially weighted moving average) on both types of data (ie, multivariate normal and nonnormal). In the next step, the bivariate normal distribution in Iranian resting state fMRI data is confirmed by using statistical tests, and it is shown that the dynamic nature of FC is not optimally detected using prevalent methods. Two alternative Portmanteau and rank‐based tests are proposed for the examination of conditional heteroscedasticity in data. Finally, dFC in these data is estimated by employing the KDCC model.
Safe Navigation Distance Between Marine Routes and Aquaculture Farms in South Korea Using Gaussian Mixture Model

The purpose of this study was to determine the minimum separation distance between aquaculture farms and ship traffic to prevent damage to either the farms or the vessels. A high-risk area in South Korea was selected for the study by overlapping shipping routes with fisheries using satellite and aerial photographs. The annual frequency of damage was calculated based on a probability distribution applied to the sea area, and a safe distance between the aquaculture farms and the traffic was derived. The Kolmogorov–Smirnov (KS) test was conducted to determine whether the Gaussian mixture model (GMM) follows the data of this study. It was found that a safe distance of at least 1000 m is needed to avoid farm or vessel damage. Then, it is possible to prevent damage to vessel propellers and fisheries locating aquaculture farms at the minimum safe distance from the traffic routes. For protection and security of these structures, the installation of a set of wirelessly Internet of Underwater Things (IoUT) sensors that can transmit the farm location to the ship’s navigator were suggested.
Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages

Cryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to be expelled from host cells via a novel non-lytic mechanism known as vomocytosis. Here we show that cryptococcal vomocytosis from macrophages is strongly enhanced by viral coinfection, without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokines interferon alpha or beta (IFNα or IFNβ). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Lastly, our data help resolve previous, contradictory animal studies on the impact of type I interferons on cryptococcal pathogenesis and suggest that secondary viral stimuli may alter patterns of cryptococcal dissemination in the host.
Bold moves: Inevitable saccadic selection in visual short-term memory

Selection for visual short-term memory (vstm) provides a basis for many cognitive functions. Saccadic eye movements sway this selection in favor of stimuli previously seen at locations congruent with their target. In three experiments, we provide converging evidence that this saccadic selection is implemented as a fundamental, inevitable selection process, rather than a top-down strategy. In particular, benefits for congruent over incongruent items were largely constant across set sizes ranging from two to eight items (Experiment 1), showing that saccadic selection imposes priorities on vstm irrespective of memory load and is effective even when only few representations need to be maintained. Moreover, a decrement in performance for incongruent items occurred reliably, whether the congruent location contained a task-relevant item or an irrelevant noise patch (Experiment 2). Finally, saccadic selection was immune to a strong manipulation of the observer's attentional priorities (Experiment 3). Given the prevalence of saccades in natural vision, our results demonstrate a fundamental and ecologically relevant selection mechanism for vstm: Saccades systematically eliminate information seen at non-target locations, while information at the saccade target remains available to recall. This simple heuristic is effective in the absence of informative cues and may incapacitate voluntary selection mechanisms that are incongruent with ongoing movement plans.