Miracle-dz/UniFAR-FTUs huggingface dataset:
Dyskinesia Matters

Levodopa‐induced dyskinesia (LID) represents a significant source of discomfort for people with Parkinson's disease (PD). It negatively affects quality of life, it is associated with both motor and nonmotor fluctuations, and it brings an increased risk of disability, balance problems, and falls. Although the prevalence of severe LID appears to be lower than in previous eras (likely owing to a more conservative use of oral levodopa), we have not yet found a way to prevent the development of this complication. Advanced surgical therapies, such as deep brain stimulation, ameliorate LID, but only a minority of PD patients qualify for these interventions. Although some have argued that PD patients would rather be ON with dyskinesia than OFF, the deeper truth is that patients would very much prefer to be ON without dyskinesia. As researchers and clinicians, we should aspire to make that goal a reality. To this end, translational research on LID is to be encouraged and persistently pursued. © 2019 International Parkinson and Movement Disorder Society
Carcinogen Metabolism Pathway and Tumor Suppressor Gene Polymorphisms and Gallbladder Cancer Risk in North Indians: A Hospital-Based Case-Control Study

Background: Carcinogen metabolism pathway and tumor suppressor gene polymorphisms have been reported to be associated with increased gallbladder cancer risk. However, the association of genetic variants and gallbladder cancer risk in Indians are not well studied. We examined whether genetic polymorphisms of metabolic enzymes cytochrome P450 1A1 and glutathione S-transferase and tumor suppressor gene p53 (TP53) are associated with an increased risk of gallbladder cancer in North Indians. Methods: This hospital-based case-control study was conducted in 96 gallbladder cancer patients with gallstones (cases) and 93 cholelithiasis patients (controls) at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India from July 2014 through May 2017. Genomic DNA was extracted from white blood cells of each patient using a simple salting-out procedure. The genotypic frequencies of CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 polymorphisms were investigated using TaqMan SNP Genotyping Assay and GSTM1 and GSTT1 polymorphisms were analyzed using the multiplex PCR assay. Results: The frequency of CC genotype of TP53 rs1042522 polymorphism was 27.1% (26/96) in cases and 12.9% (12/93) in controls. The CC genotype was associated with an increased risk of gallbladder cancer in North Indians (age- and sex-adjusted odds ratio, 2.81; 95% confidence interval, 1.19–6.61; P = 0.02). No significant differences in genotypic and allelic frequencies of the metabolic pathway gene polymorphisms were found between cases and controls. Conclusions: Our data provide preliminary evidence that the CC genotype of the TP53 rs1042522 polymorphism may be associated with an increased risk of gallbladder cancer in North Indians.
Social anxiety changes the way we move—A social approach-avoidance task in a virtual reality CAVE system

Investigating approach-avoidance behavior regarding affective stimuli is important in broadening the understanding of one of the most common psychiatric disorders, social anxiety disorder. Many studies in this field rely on approach-avoidance tasks, which mainly assess hand movements, or interpersonal distance measures, which return inconsistent results and lack ecological validity. Therefore, the present study introduces a virtual reality task, looking at avoidance parameters (movement time and speed, distance to social stimulus, gaze behavior) during whole-body movements. These complex movements represent the most ecologically valid form of approach and avoidance behavior. These are at the core of complex and natural social behavior. With this newly developed task, the present study examined whether high socially anxious individuals differ in avoidance behavior when bypassing another person, here virtual humans with neutral and angry facial expressions. Results showed that virtual bystanders displaying angry facial expressions were generally avoided by all participants. In addition, high socially anxious participants generally displayed enhanced avoidance behavior towards virtual people, but no specifically exaggerated avoidance behavior towards virtual people with a negative facial expression. The newly developed virtual reality task proved to be an ecological valid tool for research on complex approach-avoidance behavior in social situations. The first results revealed that whole body approach-avoidance behavior relative to passive bystanders is modulated by their emotional facial expressions and that social anxiety generally amplifies such avoidance.
The contribution of nonhuman primate research to the understanding of emotion and cognition and its clinical relevance

Psychiatric disorders are often conceptualized as arising from dysfunctional interactions between neural systems mediating cognitive and emotional processes. Mechanistic insights into these interactions have been lacking in part because most work in emotions has occurred in rodents, often without concurrent manipulations of cognitive variables. Nonhuman primate (NHP) model systems provide a powerful platform for investigating interactions between cognitive operations and emotions due to NHPs’ strong homology with humans in behavioral repertoire and brain anatomy. Recent electrophysiological studies in NHPs have delineated how neural signals in the amygdala, a brain structure linked to emotion, predict impending appetitive and aversive stimuli. In addition, abstract conceptual information has also been shown to be represented in the amygdala and in interconnected brain structures such as the hippocampus and prefrontal cortex. Flexible adjustments of emotional behavior require the ability to apply conceptual knowledge and generalize to different, often novel, situations, a hallmark example of interactions between cognitive and emotional processes. Elucidating the neural mechanisms that explain how the brain processes conceptual information in relation to emotional variables promises to provide important insights into the pathophysiology accounting for symptoms in neuropsychiatric disorders.
The structural bases for agonist diversity in an Arabidopsis thaliana glutamate receptor-like channel

Significance Glutamate receptor-like (GLR) channels are plant homologs of glutamate receptors in vertebrate synapses; they are calcium-permeable channels involved in root and pollen tube growth, stomatal regulation, and wound signaling. This study presents crystal structures of a plant GLR ligand-binding domain (LBD) in complex with 4 different amino acid ligands and identifies the protein residues responsible for amino acid binding. Binding assays show that the amino acids that trigger GLR-mediated calcium influx in Arabidopsis thaliana root tip cells bind the GLR LBD with micromolar affinities. Arabidopsis thaliana glutamate receptor-like (GLR) channels are amino acid-gated ion channels involved in physiological processes including wound signaling, stomatal regulation, and pollen tube growth. Here, fluorescence microscopy and genetics were used to confirm the central role of GLR3.3 in the amino acid-elicited cytosolic Ca2+ increase in Arabidopsis seedling roots. To elucidate the binding properties of the receptor, we biochemically reconstituted the GLR3.3 ligand-binding domain (LBD) and analyzed its selectivity profile; our binding experiments revealed the LBD preference for l-Glu but also for sulfur-containing amino acids. Furthermore, we solved the crystal structures of the GLR3.3 LBD in complex with 4 different amino acid ligands, providing a rationale for how the LBD binding site evolved to accommodate diverse amino acids, thus laying the grounds for rational mutagenesis. Last, we inspected the structures of LBDs from nonplant species and generated homology models for other GLR isoforms. Our results establish that GLR3.3 is a receptor endowed with a unique amino acid ligand profile and provide a structural framework for engineering this and other GLR isoforms to investigate their physiology.
Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- and reward-elicited responses

The ventromedial prefrontal cortex (vmPFC) is consistently implicated in the cognitive and emotional symptoms of many psychiatric disorders, but the causal mechanisms of its involvement remain unknown. In part, this is because of the poor characterization of the disorders and their symptoms, and the focus of experimental studies in animals on subcortical (rather than cortical) dysregulation. Moreover, even in those experimental studies that have focused on the vmPFC, the preferred animal model for such research has been the rodent, in which there are marked differences in the organization of this region to that seen in humans, and thus the extent of functional homology is unclear. There is also a paucity of well-defined behavioral paradigms suitable for translating disorder-relevant findings across species. With these considerations in mind, we discuss the value of nonhuman primates (NHPs) in bridging the translational gap between human and rodent studies. We focus on recent investigations into the involvement in reward and threat processing of 2 major regions of the vmPFC, areas 25 and 32 in NHPs and their anatomical homologs, the infralimbic and prelimbic cortex, in rodents. We highlight potential similarities, but also differences between species, and consider them in light of the extent to which anatomical homology reflects functional homology, the expansion of the PFC in human and NHPs, and most importantly how they can guide future studies to improve the translatability of findings from preclinical animal studies into the clinic.
Soil nitrogen cycling is determined by the competition between mycorrhiza and ammonia-oxidizing prokaryotes.

Mycorrhizal fungi have considerable effects on soil carbon (C) storage, as they control the decomposition of soil organic matter (SOM), by modifying the amount of soil nitrogen (N) available for free-living microbes. Through their access to organic N, ectomycorrhizal (ECM) fungi compete with free-living soil microbes; this competition is thought to slow down SOM decomposition. However, arbuscular mycorrhizal (AM) fungi cannot decompose SOM, and therefore must wait for N to first be processed by free-living microbes. It is unclear what form of N the ECM fungi and free-living microbes compete for, or which microbial groups compete for N with ECM fungi. To investigate this, we focused on the N transformation steps (i.e., the degradation of high-molecular-weight organic matter, mineralization, and nitrification) and the microbes driving each step. Simple comparisons between AM forests and ECM forests are not sufficient to assert that mycorrhizal types would determine the N transformation steps in soil, because soil physiochemistry, which strongly affects N transformation steps, differs between the forests. We used an aridity gradient with large differences in soil moisture, pH, and SOM quantity and quality, to distinguish the mycorrhizal and physicochemical effects on N transformation. Soil samples (0-10 cm depth) were collected from AM-symbiotic black locust forests under three aridity levels, and from ECM-symbiotic oak forests under two aridity levels. Soil physicochemical properties, extractable N dynamics and abundance, composition, and function of soil microbial communities were measured. In ECM forests, the ammonia-oxidizing prokaryotic abundance was low, whereas that of ECM fungi was high, resulting in lower nitrate N content than in AM forests. Since ECM forests did not have lower saprotrophic fungal abundance and prokaryotic decompositional activity than the AM forests, the hypothesis that ECM fungi could reduce SOM decay and ammonification by free-living microbes, might not hold in ECM forests. However, the limitation of ECM fungi on nitrate N production would result in a feedback that will accelerate plant dependence on these fungi, thereby raising soil C storage through an increase in the ECM biomass and plant C investment in soils.
Progesterone exerts antidepressant-like effect in a mouse model of maternal separation stress through mitigation of neuroinflammatory response and oxidative stress

Abstract Context Experiencing early-life adversity plays a key role in the development of mood disorders in adulthood. Experiencing adversities during early life period negatively affects brain development. Sex steroids such as progesterone affect the brain structure and functions and subsequently affects behaviour. Objective We assess the antidepressant-like effect of progesterone in a mouse model of maternal separation (MS) stress, focussing on its anti-neuroinflammatory and antioxidative effects. Materials and methods NMRI mice were treated with progesterone (10, 50, and 100 mg/kg, i.p., respectively) for 14 days. Valid behavioural tests including forced swimming test (FST), splash test and open field test (OFT) were used. Quantitative reverse transcription-PCR (qRT-PCR) was used for evaluation of genetic expression in the hippocampus. Antioxidant capacity was assessed by the FRAP method and the level of malondialdehide by TBA. Results MS provoked depressive-like behaviour in mice. Treatment of MS mice with progesterone increased the grooming activity time in the splash test and decreased the immobility time in the FST. In addition, progesterone decreased the expression of inflammatory genes related to neuroinflammation (IL-1β, TNF-α, TLR4 and NLRP3) as well as increased the antioxidant capacity and decreased the lipid peroxidation (MDA) in the hippocampus. Discussion and Conclusion Administration of progesterone significantly mitigated the negative effects of MS on behaviours relevant to depressive-like behaviour as well as attenuated neuro-immune response and oxidative stress in the hippocampus of MS mice. In this context, we conclude that progesterone, at least partially, via attenuation of oxidative stress and neuroinflammation, exerts antidepressant-like effects.
Cell wall‐anchored 5′‐nucleotidases in Gram‐positive cocci

5′‐nucleotidases (5′‐NTs) are enzymes that catalyze the hydrolysis of nucleoside monophosphates to produce nucleosides and phosphate. Since the identification of adenosine synthase A (AdsA) in Staphylococcus aureus in 2009, several other 5′‐NTs have been discovered in Gram‐positive cocci, mainly in streptococci. Despite some differences in substrate specificity, pH range and metal ion requirements, all characterized 5′‐NTs use AMP and ADP, and in some cases ATP, to produce the immunosuppressive adenosine, which dampens pro‐inflammatory immune responses. Several 5′‐NTs are also able to use dAMP as substrate to generate deoxy‐adenosine which is cytotoxic for macrophages. A synergy between 5′‐NTs and exonucleases which are commonly expressed in Gram‐positive cocci has been described, where the nucleases provide dAMP as a cleavage product from DNA. Some of these nucleases produce dAMP by degrading the DNA backbone of neutrophil extracellular traps (NETs) resulting in a “double hit” strategy of immune evasion. This Micro Review provides an overview of the biochemical properties of Gram‐positive cell wall‐anchored 5′‐NTs and their role as virulence factors. A potential use of 5′‐NTs for vaccine development is also briefly discussed.
The effect of an active transcutaneous bone conduction device on spatial release from masking

Abstract Objective: The aim was to quantify the effect of the experimental active transcutaneous Bone Conduction Implant (BCI) on spatial release from masking (SRM) in subjects with bilateral or unilateral conductive and mixed hearing loss. Design: Measurements were performed in a sound booth with five loudspeakers at 0°, +/−30° and +/−150° azimuth. Target speech was presented frontally, and interfering speech from either the front (co-located) or surrounding (separated) loudspeakers. SRM was calculated as the difference between the separated and the co-located speech recognition threshold (SRT). Study Sample: Twelve patients (aged 22–76 years) unilaterally implanted with the BCI were included. Results: A positive SRM, reflecting a benefit of spatially separating interferers from target speech, existed for all subjects in unaided condition, and for nine subjects (75%) in aided condition. Aided SRM was lower compared to unaided in nine of the subjects. There was no difference in SRM between patients with bilateral and unilateral hearing loss. In aided situation, SRT improved only for patients with bilateral hearing loss. Conclusions: The BCI fitted unilaterally in patients with bilateral or unilateral conductive/mixed hearing loss seems to reduce SRM. However, data indicates that SRT is improved or maintained for patients with bilateral and unilateral hearing loss, respectively.
Multiscale porous elastomer substrates for multifunctional on-skin electronics with passive-cooling capabilities

Significance Point-of-care thermal management (e.g., joule heating, passive cooling) shows promising applications in body temperature regulations, which can improve human comfort and reduce energy consumption. On-skin electronics with joule-heating elements have been reported. However, the research of making on-skin electronics with passive-cooling functionalities is still rare. By using multiscale porous polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene as supporting substrates, we have developed multifunctional on-skin electronics with outstanding passive-cooling capabilities, delivering around 6 °C cooling effects under a solar intensity of 840 W⋅m−2. Other desired properties, rooted in porous SEBS substrates, include high breathability and outstanding waterproofing. In addition, a variety of bioelectronic devices are made on porous SEBS substrates via spray printing of silver nanowires (Ag NWs). The enabled devices demonstrate high performance and are recyclable. In addition to mechanical compliance, achieving the full potential of on-skin electronics needs the introduction of other features. For example, substantial progress has been achieved in creating biodegradable, self-healing, or breathable, on-skin electronics. However, the research of making on-skin electronics with passive-cooling capabilities, which can reduce energy consumption and improve user comfort, is still rare. Herein, we report the development of multifunctional on-skin electronics, which can passively cool human bodies without needing any energy consumption. This property is inherited from multiscale porous polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS) supporting substrates. The multiscale pores of SEBS substrates, with characteristic sizes ranging from around 0.2 to 7 µm, can effectively backscatter sunlight to minimize heat absorption but are too small to reflect human-body midinfrared radiation to retain heat dissipation, thereby delivering around 6 °C cooling effects under a solar intensity of 840 W⋅m−2. Other desired properties, rooted in multiscale porous SEBS substrates, include high breathability and outstanding waterproofing. The proof-of-concept bioelectronic devices include electrophysiological sensors, temperature sensors, hydration sensors, pressure sensors, and electrical stimulators, which are made via spray printing of silver nanowires on multiscale porous SEBS substrates. The devices show comparable electrical performances with conventional, rigid, nonporous ones. Also, their applications in cuffless blood pressure measurement, interactive virtual reality, and human–machine interface are demonstrated. Notably, the enabled on-skin devices are dissolvable in several organic solvents and can be recycled to reduce electronic waste and manufacturing cost. Such on-skin electronics can serve as the basis for future multifunctional smart textiles with passive-cooling functionalities.
Three years dermoscopic follow‐up of atypical nevi

Atypical nevi are dynamic lesions and may progressively transform into more or less atypical lesions. We aimed to investigate the dermoscopic features of atypical nevi and dynamic changes in these lesions over a period of 3‐years. Patients with 3‐year dermoscopic follow‐up records were enrolled in the study. We compared the dermatoscopic features of the nevus recorded in the first dermoscopic examination and at the end of the third year. Changes in size (mm), pattern, and color were investigated. The most common dermoscopic patterns were reticular (18 patients; 34%), reticular‐homogeneous (17 patients; 32.1%), and reticular‐globular (7 patients; 13.2%). The most common pigmentation patterns were central hyperpigmentation (28 patients; 52.8%), regular pigmentation (nine patients; 17.0%), and multifocal hypo/hyperpigmentation (eight patients; 15.1%). Twenty‐one (39.6%) patients showed changes in pattern. The transformation from reticular‐homogeneous pattern to the homogeneous pattern was the most frequent change in pattern (7 of 21 patients; 33.3%). The transformation from reticular pattern to reticular‐homogeneous pattern was the second most common change in pattern (5 of 21 patients; 23.8%). Fourteen (26.4%) patients experienced symmetrical enlargement. Symmetrical enlargement was statistically more frequent in patients who showed dermoscopic changes in pattern than in those who did not show any changes in the pattern (p: .038). In this study, we did not observe any new dermoscopic clues for the diagnosis of melanoma during the follow‐up. The nevi tended to turn into a homogeneous (structureless) pattern. We observed that the most common dermoscopic change in pattern was the transformation from reticular‐homogeneous pattern to homogeneous pattern, and the lesions had symmetrical enlargement during this transformation. In conclusion, despite the known association between atypical nevi and the risk of developing melanoma, most atypical nevi do not transform into melanoma. Therefore, our study suggests that the excision of atypical nevi is not necessary and dermatoscopic follow‐up can reduce the number of unnecessary excisions.
Human Pharmacokinetic Parameters of Orally Administered Δ9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences.

Background: There is variability in the reported Δ9-tetrahydrocannabinol (THC) and 11-hydroxy-tetrahydrocannabinol (11-OH-THC) pharmacokinetic (PK) and pharmacodynamic (PD) parameters between studies and there is limited investigation into how the presence of food or sex affect these parameters. In this study, we examined the PK and PD parameters of an encapsulated THC extract and its major active metabolite, 11-OH-THC, under different fed states. Methods: The study was a single-dose, randomized, double-blinded, four-way crossover investigation. THC capsules (1 or 2×5 mg) were administered to 28 healthy adults (13 females: 15 males) under a fasted condition or after a high-fat meal. Blood samples were collected and PK parameters were determined through noncompartmental analysis. Adverse events (AEs), cognitive function (through completion of digit symbol substitution tests), blood pressure, and heart rate were also recorded. Results: The presence of high-fat food significantly enhanced time to peak plasma concentration (T max) and area under the curve (AUC0-24) for both THC and 11-OH-THC and reduced THC's apparent volume of distribution (V z/F) and apparent clearance (Cl/F). Females had a significantly greater peak plasma concentration (C max) compared with males after 5 mg THC in a fasted state. No cardiovascular or cognitive effects and only mild AEs (somnolence, fatigue, and euphoric mood) were reported. Conclusion: These findings may help to inform the guidelines provided by governing health bodies on the effects of cannabis, such as time to onset and duration of action, and aid health care practitioners in their prescribing practices. Furthermore, the doses used in this study are safe to consider for future interventional studies in disease conditions where THC has been shown to have therapeutic efficacy.