Miracle-dz/UniFAR-FTUs huggingface dataset:
How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism‐unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative‐hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.
The Influence of Plant Litter on Soil Water Repellency: Insight from 13C NMR Spectroscopy

Soil water repellency (SWR, i.e. reduced affinity for water owing to the presence of organic hydrophobic coatings on soil particles) has relevant hydrological implications because low rates of infiltration enhance water runoff, and untargeted diffusion of fertilizers and pesticides. Previous studies investigated the occurrence of SWR in ecosystems with different vegetation cover but did not clarify its relationships with litter biochemical quality. Here, we investigated the capability of different plant litter types to induce SWR by using fresh and decomposed leaf materials from 12 species, to amend a model sandy soil over a year-long microcosm experiment. Water repellency, measured by the Molarity of an Ethanol Droplet (MED) test, was tested for the effects of litter species and age, and compared with litter quality assessed by 13C-CPMAS NMR in solid state and elemental chemical parameters. All litter types were highly water repellent, with MED values of 18% or higher. In contrast, when litter was incorporated into the soil, only undecomposed materials induced SWR, but with a large variability of onset and peak dynamics among litter types. Surprisingly, SWR induced by litter addition was unrelated to the aliphatic fraction of litter. In contrast, lignin-poor but labile C-rich litter, as defined by O-alkyl C and N-alkyl and methoxyl C of 13C-CPMAS NMR spectral regions, respectively, induced a stronger SWR. This study suggests that biochemical quality of plant litter is a major controlling factor of SWR and, by defining litter quality with 13C-CPMAS NMR, our results provide a significant novel contribution towards a full understanding of the relationships between plant litter biochemistry and SWR.
Targeting Melanoma with Cancer-Killing Viruses

Melanoma is the deadliest skin cancer with ever-increasing incidence. Despite the development in diagnostics and therapies, metastatic melanoma is still associated with significant morbidity and mortality. Oncolytic viruses (OVs) represent a class of novel therapeutic agents for cancer by possessing two closely related properties for tumor reduction: virus-induced lysis of tumor cells and induction of host anti-tumor immune responses. A variety of viruses, either in “natural” or in genetically modified forms, have exhibited a remarkable therapeutic efficacy in regressing melanoma in experimental and/or clinical studies. This review provides a comprehensive summary of the molecular and cellular mechanisms of action of these viruses, which involve manipulating and targeting the abnormalities of melanoma, and can be categorized as enhancing viral tropism, targeting the tumor microenvironment and increasing the innate and adaptive antitumor responses. Additionally, this review describes the “biomarkers” and deregulated pathways of melanoma that are responsible for melanoma initiation, progression and metastasis. Advances in understanding these abnormalities of melanoma have resulted in effective targeted and immuno-therapies, and could potentially be applied for engineering OVs with enhanced oncolytic activity in future.
Test of Validity of Fitts' Index of Difficulty as a Measure of Task Difficulty

This study investigated the validity of Fitts' index of difficulty as a measure of task difficulty perceived by the performer. Eight subjects performed self-terminated horizontal elbow-extension movements toward targets of three indices of difficulty in two task conditions. In the target-size condition, triceps and biceps activities during acceleration and deceleration respectively decreased with increasing index of difficulty, resulting in a lower peak velocity and longer movement time. In the movement amplitude condition, however, triceps activity after movement onset and biceps activity during deceleration increased with increasing index of difficulty, resulting in a higher peak velocity. The movement time also increased as a function of the index of difficulty given increase in the distance traveled by the limb. These results suggest that Fitts' index of difficulty may not reflect the difficulty of task performance because its effect on the pattern of motor output is dependent upon the task variable manipulated in measuring the index of difficulty.
Maximum Margin Matrix Factorization for Collaborative Ranking

In this paper, we consider collaborative filtering as a ranking problem. We present a method which uses Maximum Margin Matrix Factorization and optimizes ranking instead of rating. We employ structured output prediction to optimize directly for ranking scores. Experimental results show that our method gives very good ranking scores and scales well on collaborative filtering tasks.
Isolation and identification of mycoplasma agalactiae subsp. bovis from arthritic cattle in Iowa and Nebraska

Two strains of Mycoplasma were isolated from synovial fluids of arthritic feeder cattle and were identified as Mycoplasma agalactiae subsp. bovis by growth inhibition and fluorescent antibody tests. The strains (Iowa 1136 and Nebraska 2) could not be distinguished from known strains (Donetta and California 01) by immunoelectrophoresis or by agar gel precipitation.
Oxytocin Cells in the Supraoptic Nucleus Receive Excitatory Synaptic Inputs from the Contralateral Supraoptic and Paraventricular Nuclei in the Lactating Rat

Abstract The present experiments were undertaken to examine whether oxytocin cells in the supraoptic nucleus receive synaptic inputs from the contralateral supraoptic nucleus or paraventricular nucleus. Using urethane-anesthetized lactating rats, extracellular action potentials were recorded from single oxytocin or vasopressin cells in the supraoptic nucleus. Electrical stimulation was applied to the contralateral supraoptic nucleus or paraventricular nucleus, and responses of oxytocin or vasopressin cells were analyzed by peri-stimulus time histogram or by change in firing rate of oxytocin or vasopressin cells. Electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus did not cause antidromic excitation in oxytocin or vasopressin cells but caused orthodromic responses. Although analysis by peri-stimulus time histogram showed that electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus caused orthodromic excitation in both oxytocin and vasopressin cells, the proportion of excited oxytocin cells was greater than that of vasopressin cells. Train stimulation applied to the contralateral supraoptic nucleus or paraventricular nucleus at 10 Hz increased firing rates of oxytocin cells and decreased those of vasopressin cells. The results of the present experiments suggest that oxytocin cells in the supraoptic nucleus receive mainly excitatory synaptic inputs from the contralateral supraoptic nucleus and paraventricular nucleus. Receipt these synaptic inputs to oxytocin cells may contribute to the synchronized activation of oxytocin cells during the milk ejection reflex.
The medullary pacemaker nucleus is unnecessary for electroreceptor tuning plasticity in Sternopygus

Tuberous electroreceptors of the weakly electric fish Sternopygus macrurus are closely tuned to the frequency of electric organ discharge (EOD), which is determined by a medullary pacemaker nucleus (PMN). Previous studies have demonstrated that androgens lower the frequency of PMN discharge and concomitantly lower the best frequencies (BFs) of electroreceptors. In order to determine if the PMN serves as an internal reference for the hormone-mediated returning of electroreceptors, the PMN was lesioned and the change in mean BF was measured for dihydrotestosterone (DHT)-implanted or control animals. DHT-implanted fish showed the characteristic lowering of mean electroreceptor BF by approximately 25%, a significant change compared with controls (p less than 0.01, Mann-Whitney). This result indicates that the PMN is not necessary for the hormone-mediated shift of electroreceptor tuning. In a related study, the contribution of the PMN to the genesis of tuning in regenerating electroreceptors was examined by removing a patch of cheek skin from PMN-lesioned fish. Regenerating electroreceptors became sharply tuned to the previous EOD frequency by 6 weeks in the same fashion as regenerating receptors in intact fish. In addition, intact receptors from PMN-lesioned fish remained tuned for up to 160 d. Together, these results demonstrate that the pacemaker nucleus is unnecessary for the maintenance, development, or hormone- mediated shift of receptor tuning.
The VAR1 locus of Arabidopsis encodes a chloroplastic FtsH and is responsible for leaf variegation in the mutant alleles

Background: A leaf‐variegated mutation var1 of Arabidopsis results in the development of abnormal plastids and the formation of a green/white sector. Genetic analysis of the var1 mutant indicated that it acts synergistically with another mutation var2, suggesting that the two genes are relevant. The VAR2 locus has been shown to encode a chloroplastic FtsH, an ATP‐dependent protease which is possibly involved in the degradation of thylakoid proteins and plastid development.
Identification of a Key Determinant of Ryanodine Receptor Type 1 Required for Activation by 4-Chloro-m-cresol*

4-Chloro-m-cresol (4-CmC) is a potent and specific activator of the intracellular Ca2+ release channel, the ryanodine receptor (RyR). We have previously shown that RyR1 expressed in dyspedic 1B5 myotubes is activated by 4-CmC, whereas RyR3 is not (Fessenden, J. D., Wang, Y., Moore, R. A., Chen, S. R. W., Allen, P. D., and Pessah, I. N. (2000) Biophys. J. 79, 2509–2525). To identify region(s) on RyR1 that are responsible for mediating activation by 4-CmC, we expressed RyR1-RyR3 chimeric proteins in dyspedic 1B5 myotubes and then measured 4-CmC-induced increases in intracellular Ca2+. Substitution of the C-terminal third of RyR1 into RyR3 imparted 4-CmC sensitivity to the resulting chimera, thus suggesting that determinants required for activation by 4-CmC are located in this region. We subdivided the C-terminal third of RyR1 into smaller segments and identified two overlapping regions of RyR1 (amino acids 3769–4180 and 4007–4382) that each imparted 4-CmC sensitivity to RyR3. Substitution of the 173 amino acids of RyR1 common to these two chimeras (amino acids 4007–4180) also weakly restored 4-CmC sensitivity in the resulting chimera. To confirm these findings, we created a complementary set of chimeras containing RyR3 substitutions in RyR1. Substitution of the RyR3 C terminus into RyR1 disrupted 4-CmC sensitivity in the resulting chimera. In addition, substitution of the corresponding RyR3 sequence into positions 4007–4180 of RyR1 disrupted 4-CmC sensitivity. Taken together, these results suggest that essential determinants required for activation of RyR1 by 4-CmC reside within a 173-amino acid region between residues 4007 and 4180.
Prevalence of Diabetic Complications in Rural Goa, India

Objective: To determine the prevalence of diabetes mellitus (DM) and its associated diabetic complications in rural Goa, India. Materials and Methods: A community-based study was carried out in a rural setting in Goa, India. About 1,266 participants were selected by systematic random sampling. The participants were interviewed using a semi-structured questionnaire and were subjected to anthropometric, clinical evaluation and biochemical investigations. American Diabetes Association criteria were used to determine the prevalence of diabetes and standard operational definitions were used to define the diabetic complications. Data was analyzed using SPSS version 14.0 while chi-square and chi-square for trend were the tests used. Results: Among the total 1,266 study participants about 130 (10.3%) were diabetics. The prevalence of the associated diabetic complications were as follows viz. neuropathy (60%), CHD (32.3%) and cataract (20%), retinopathy (15.4%), peripheral vascular disease (11.5%) and cerebrovascular accidents (CVAs) (6.9%). A significant rising trend in the prevalence of all diabetic complications was observed with advancing duration of diabetes. Conclusion: The prevalence of DM and its associated complications was higher among the diabetic individuals in the rural setting of Goa, India. All the associated diabetic complications observed need to be addressed with appropriate prevention and control strategies.
Bmc Medical Research Methodology Open Access Comparison of Bayesian and Classical Methods in the Analysis of Cluster Randomized Controlled Trials with a Binary Outcome: the Community Hypertension Assessment Trial (chat)

Background: Cluster randomized trials (CRTs) are increasingly used to assess the effectiveness of interventions to improve health outcomes or prevent diseases. However, the efficiency and consistency of using different analytical methods in the analysis of binary outcome have received little attention. We described and compared various statistical approaches in the analysis of CRTs using the Community Hypertension Assessment Trial (CHAT) as an example. The CHAT study was a cluster randomized controlled trial aimed at investigating the effectiveness of pharmacy-based blood pressure clinics led by peer health educators, with feedback to family physicians (CHAT intervention) against Usual Practice model (Control), on the monitoring and management of BP among older adults.
Community-Based Innovation among Elite Orienteers

We have studied a form of community innovation within the sport of orienteering, which in the Nordic countries consist of a closely knit group with a strong sense of community. This study shows how the processes for developing new technologies are driven by a strong sense of idealism, with little or no commercial motivation. Thus, this represents a kind of community development and sharing with a number of unique characteristics. While the community is central to participants' endeavours of developing their systems, the participants are not representative of the typical member. On the contrary, they are examples of a minority that put in significant efforts of contributing to the larger group. What we argue is unique about the case we have presented is that the technology development starts out from a few number of highly motivated individuals that through limited collaboration with others builds technologies that get extensive proliferation and use within the community.
Upregulation of neurovascular communication through filamin abrogation promotes ectopic periventricular neurogenesis

Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs’ neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs. We show that by collaborating with β-arrestin, Flna maintains the homeostatic signaling between the vasculature and NPCs, and loss of this function results in escalated Vegfa and Igf2 signaling, which exacerbates both EMT and angiogenesis to further potentiate IPs’ neurogenesis. These results suggest that the neurogenic potential of IPs may be boosted in vivo by manipulating Flna-mediated neurovascular communication. DOI: http://dx.doi. org/10.7554/eLife.17823. 001
Complementary Ensemble Empirical Mode Decomposition: a Novel Noise Enhanced Data Analysis Method

The phenomenon of mode-mixing caused by intermittence signals is an annoying problem in Empirical Mode Decomposition (EMD) method. The noise assisted method of Ensemble EMD (EEMD) has not only effectively resolved this problem but also generated a new one, which tolerates the residue noise in the signal reconstruction. Of course, the relative magnitude of the residue noise could be reduced with large enough ensemble, it would be too time consuming to implement. An improved algorithm of noise enhanced data analysis method is suggested in this paper. In this approach, the residue of added white noises can be extracted from the mixtures of data and white noises via pairs of complementary ensemble IMFs with positive and negative added white noises. Though this new approach yields IMF with the similar RMS noise as EEMD, it effectively eliminated residue noise in the IMFs. Numerical experiments were conducted to demonstrate the new approach and also illustrate the problems of mode splitting and translation.
Wishful Thinking: The Surprisingly Sparse Evidence for a Relationship between Oxidative Stress and Cardiovascular Disease in Hemodialysis Patients

The increased frequency of cardiovascular disease observed in hemodialysis patients is secondary to the combination of many traditional (age, male sex, hypertension, smoking, diabetes mellitus, and dyslipidemia) and novel and uremia‐related (inflammation, uremic toxins, adipokine imbalance, coagulation disorders, protein‐energy wasting, volume overload, endothelial dysfunction, hyperparathyroidism, and subclinical hypothyroidism) risk factors. Usually, in the latter group, oxidative stress is included. However, after decades of research, it remains essentially unknown if oxidative stress has a causative role in the development of cardiovascular disease in long‐term hemodialysis patients because adequate longitudinal studies are lacking. Data deriving from cross‐sectional studies suggest that biomarkers of oxidative stress are associated with cardiovascular disease prevalence. Conversely, conflicting and inconclusive results have been obtained on the association between oxidative stress and coronary artery calcification, atherosclerosis, and all‐cause and cardiovascular disease‐related outcome. It is desirable that further studies are conducted on this topic in the near future.
Consensus Convolutional Sparse Coding

Convolutional sparse coding (CSC) is a promising direction for unsupervised learning in computer vision. In contrast to recent supervised methods, CSC allows for convolutional image representations to be learned that are equally useful for high-level vision tasks and low-level image reconstruction and can be applied to a wide range of tasks without problem-specific retraining. Due to their extreme memory requirements, however, existing CSC solvers have so far been limited to low-dimensional problems and datasets using a handful of low-resolution example images at a time. In this paper, we propose a new approach to solving CSC as a consensus optimization problem, which lifts these limitations. By learning CSC features from large-scale image datasets for the first time, we achieve significant quality improvements in a number of imaging tasks. Moreover, the proposed method enables new applications in high-dimensional feature learning that has been intractable using existing CSC methods. This is demonstrated for a variety of reconstruction problems across diverse problem domains, including 3D multispectral demosaicing and 4D light field view synthesis.
Overexpression of Wild Type But Not an FAD Mutant Presenilin-1 Promotes Neurogenesis in the Hippocampus of Adult Mice

Mutations in the presenilin-1 (PS-1) gene are one cause of familial Alzheimer's disease (FAD). However, the functions of the PS-1 protein as well as how PS-1 mutations cause FAD are incompletely understood. Here we investigated if neuronal overexpression of wild-type or FAD mutant PS-1 in transgenic mice affects neurogenesis in the hippocampus of adult animals. We show that either a wild-type or an FAD mutant PS-1 transgene reduces the number of neural progenitors in the dentate gyrus. However, the wild-type, but not the FAD mutant PS-1 promoted the survival and differentiation of progenitors leading to more immature granule cell neurons being generated in PS-1 wild type expressing animals. These studies suggest that PS-1 plays a role in regulating neurogenesis in adult hippocampus and that FAD mutants may have deleterious properties independent of their effects on amyloid deposition.
Indirect Effects of Social Skills on Health Through Stress and Loneliness

ABSTRACT The social skills deficit vulnerability model predicts that people with inadequate social skills are at risk for a range of psychosocial problems, especially when confronted with stress. People with poor social skills often experience stress and loneliness and these two constructs were tested as potential pathways by which the poor social skills confer a risk for compromised mental and physical health. An online survey was completed by 775 adults, aged 18–91. The sample matched national demographics for race/ethnicity and age, among those over 18. Structural equation modeling revealed indirect effects of social skills on both mental and physical health through both stress and loneliness. The models showed that poor social skills were associated with poor mental and physical health through elevated stress and increased loneliness. The findings reveal that social skills deficits are associated with physical as well as mental health problems.
Rapid Detection of Person Information in a Naturalistic Scene

A preferential-looking paradigm was used to investigate how gaze is distributed in naturalistic scenes. Two scenes were presented side by side: one contained a single person (person-present) and one did not (person-absent). Eye movements were recorded, the principal measures being the time spent looking at each region of the scenes, and the latency and location of the first fixation within each trial. We studied gaze patterns during free viewing, and also in a task requiring gender discrimination of the human figure depicted. Results indicated a strong bias towards looking to the person-present scene. This bias was present on the first fixation after image presentation, confirming previous findings of ultra-rapid processing of complex information. Faces attracted disproportionately many fixations, the preference emerging in the first fixation and becoming stronger in the following ones. These biases were exaggerated in the gender-discrimination task. A tendency to look at the object being fixated by the person in the scene was shown to be strongest at a slightly later point in the gaze sequence. We conclude that human bodies and faces are subject to special perceptual processing when presented as part of a naturalistic scene.