Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered DNA Methylation in the Developing Brains of Rats Genetically Prone to High versus Low Anxiety

There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report altered DNA methylation markers (altered DNA methyltransferase protein levels and increased global DNA methylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylation profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior. SIGNIFICANCE STATEMENT Epigenetic changes are biological mechanisms that regulate the expression and function of genes throughout the brain and body. DNA methylation, one type of epigenetic mechanism, is known to be altered in brains of psychiatric patients, which suggests a role for DNA methylation in the pathogenesis of psychiatric disorders, such as depression and anxiety. The present study examines brains of rats that display high versus low levels of anxiety- and depression-like behavior to investigate how neural DNA methylation levels differ in these animals and how such differences shape their emotional behavioral differences. Studying how epigenetic processes affect emotional behavior may improve our understanding of the neurobiology of psychiatric disorders and lead to improved treatments.
Rapid adjustment of pecking trajectory to prism-induced visual shifts in crows as compared with pigeons

ABSTRACT Pecking in birds is analogous to reaching and grasping movements in primates. Earlier studies on visuomotor control in birds, which were conducted mostly in pigeons, suggested that avian pecking is controlled feedforwardly, and is out of the control of visual guidance during movement. However, recent studies using crows suggested a role of vision in pecking control during movement. To unveil what visuomotor mechanisms underlie the flexibility of pecking in crows, we examined whether pigeons and crows adjust their pecking to the visual distortion induced by prisms. Because prisms induce visual shifts of object positions, birds were required to adjust their movements. Pecking kinematics were examined before and after attaching prisms in front of the birds' eyes. Analysis of lateral deviation caused by the prisms showed that crows rapidly adjusted their pecking trajectories, but pigeons did so slowly. Angular displacement also increased in pigeons after attachment of the prism, but decreased in crows. These responses to prisms were consistent among individuals in pigeons but varied in crows, though the adjustment of pecking commonly succeeded in crows. These results suggest that pecking in pigeons predominantly involves feedforward control and that the movement is determined depending on the visual information available before the initiation of pecking. In contrast, the results from crows suggest that their pecking trajectories are corrected during the movement, supporting on-line visual control. Our findings provide the first evidence to suggest the on-line visual control of pecking in birds. Highlighted Article: The visuomotor control of avian pecking is poorly understood. Visual distortion caused by prisms indicates that vision plays a role in pecking adjustments only before movement initiation in pigeons, whereas crows may use vison during movement.
Web-Based Stress Management Program for University Students in Indonesia: Systematic Cultural Adaptation and Protocol for a Feasibility Study

Background The number of university students experiencing stress is increasing, which often leads to adverse effects such as poor grades, academic probation, and emotional problems. Unfortunately, most of these problems remain untreated because of limited professional resources and fear of stigma. Several Web-based stress management interventions are now available for student populations, but these treatments are not yet available in Indonesia. To make treatment for stress more acceptable in Indonesia, a cultural adaptation process is needed, and part of the process is assessing the feasibility of the adapted intervention. Objective This paper describes the first two stages of a cultural adaptation process and the protocol of a feasibility study that will assess the acceptability of a culturally adapted stress management intervention for university students in Indonesia. Methods Focus group discussions with Indonesian university students were held, and input from Indonesian psychologists was gathered for developing the adapted intervention. A single-group feasibility study with a pre-post design will be conducted. We will recruit at minimum 50 university students who have an elevated level of stress (Depression, Anxiety, and Stress Scales–42 stress subscale score ≥15), identify themselves as being of Indonesian culture (eg, able to speak Bahasa Indonesia fluently), and are studying at a university in Indonesia. The primary endpoints of this study will be rates of participant satisfaction, system usability, dropout rates, and level of adherence. We will also use qualitative data to assess the adapted intervention more thoroughly. Secondary study endpoints will be quality of life, stress, anxiety, and depression levels. Feasibility parameters (eg, participant satisfaction, system usability, and level of adherence) will be summarized with descriptive statistics. Two-tailed paired within-group t tests will be used to analyze stress, anxiety, depression, and quality of life. Results The enrollment of pilot study is currently ongoing. First results are expected to be ready for analysis in the second half of 2019. The project was funded as part of a PhD trajectory in 2015 by the Indonesian Endowment Fund for Education. Conclusions This is one of the first studies to assess the feasibility of a culturally adapted Web-based stress management intervention for university students in Indonesia. Strengths and limitations of the study are discussed. International Registered Report Identifier (IRRID) DERR1-10.2196/11493
The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients

Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. Methods: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen. We describe the first report of an anti-AChR Ab-seropositive lung cancer patient achieving a durable complete response (CR) to an anti-PD-1 antibody therapy. To further explore this case, we performed multiplex immunofluorescence analysis on a pretreatment tumor. Results: The patient achieved a durable CR without developing MG. However, the levels of anti-AChR Abs were elevated during two years of anti-PD-1 antibody therapy. The tumor of the subclinical MG patient had high PD-L1 expression and an infiltrated–inflamed tumor immune microenvironment. Conclusions: This study suggests that immune checkpoint inhibitors can be safely used and provide the benefits for advanced cancer patients with immunologically ‘hot’ tumor even if anti-AChR Abs are positive. Although careful monitoring clinical manifestation in consultation with neurologist is needed, immune checkpoint inhibitors should be considered as a treatment option for asymptomatic anti-AChR Ab-seropositive cancer patients.
Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds

Significance The RAS family of oncogenic proteins is important as therapy targets because of the frequency of activating mutations in almost all major cancers. An important approach is development of small molecules with drug-like properties that can inhibit RAS-effector protein interactions inside cells. We present a strategy for identification of such compounds, and their development as RAS-effector interaction inhibitors, utilizing a structure-based design approach and cell-based assays. By combining moieties from two distinct sets of RAS-binding molecules, we generated cross-over compounds that showed improved efficacy in vitro and in cell-based assays. The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein–protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein–protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein–protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
ApoE-associated modulation of neuroprotection from Aβ-mediated neurodegeneration in transgenic Caenorhabditis elegans

ABSTRACT Allele-specific distinctions in the human apolipoprotein E (APOE) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform APOEε2 is associated with reduced risk, while APOEε3 is neutral and APOEε4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (Aβ) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOEε2 with Aβ attenuated Aβ-induced neurodegeneration, whereas expression of the APOEε4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOEε3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three APOE isoforms in the absence of Aβ co-expression. Pharmacological treatment that examined neuroprotective effects of APOE alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the Aβ background. Additionally, Aβ suppressed survival, an effect that was rescued by APOEε2 and APOEε3, but not APOEε4. Expression of the APOE alleles in neurons, independent of Aβ, exerted no impact on survival. Taken together, these results illustrate that C. elegans provides a powerful in vivo platform with which to explore how AD-associated neuronal pathways are modulated by distinct APOE gene products in the context of Aβ-associated neurotoxicity. The significance of both ApoE and Aβ to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship. This article has an associated First Person interview with the first author of the paper. Summary: We report new humanized nematode models of amyloid-beta and apolipoprotein E gene expression, examining readouts for neurodegeneration, behavior, cellular function and survival, to elucidate the relative contributions of the proteins to the underlying pathology of Alzheimer's disease.
Oral Selumetinib Does Not Negatively Impact Photoreceptor Survival in Murine Experimental Retinal Detachment

Purpose Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling is neuroprotective in some retinal damage models but its role in neuronal survival during retinal detachment (RD) is unclear. In addition, serous RDs are a prevalent side effect of MEK inhibitors (MEKi), blocking MAPK/ERK signaling for treatment of certain cancers. We tested the hypothesis that MEKi treatment in experimental RD would increase photoreceptor death. Methods The MEKi selumetinib was delivered daily to C57BL/6 mice at a clinically relevant dose (10 mg/mL) starting 1 day prior to creating RD with subretinal hyaluronic acid injection. Photoreceptor TUNEL and outer nuclear layer (ONL) thickness were analyzed. Phospho-ERK1/2 (pERK) distribution, glial fibrillary acidic protein (GFAP) accumulation, and Iba-1 (microglia/macrophages) were evaluated with immunofluorescence. Results pERK accumulated in the Müller glia in detached retinas, but this was effectively blocked by selumetinib. Selumetinib did not induce serous RDs at day 1 and did not increase TUNEL positive photoreceptors or further decrease ONL thickness compared to controls. Retinal gliosis was not altered, but selumetinib did block the increase in intraretinal microglia/macrophage Iba-1 fluorescence intensity and acquisition of amoeboid morphology. Conclusions MAPK/ERK is neuroprotective in some retinal damage models; in RD, selumetinib blocked Müller pERK accumulation and changed the retinal microglia/macrophage phenotype but did not alter photoreceptor survival. This is consistent with the relatively good visual acuity seen in patients developing transient retinal detachments on MEK inhibitor therapy. Compensation by other neuroprotective pathways in the retina during retinal detachment may occur in the presence of MEK inhibition.
The Quest for Novel Antimicrobial Compounds: Emerging Trends in Research, Development, and Technologies

Pathogenic antibiotic resistant bacteria pose one of the most important health challenges of the 21st century. The overuse and abuse of antibiotics coupled with the natural evolutionary processes of bacteria has led to this crisis. Only incremental advances in antibiotic development have occurred over the last 30 years. Novel classes of molecules, such as engineered antibodies, antibiotic enhancers, siderophore conjugates, engineered phages, photo-switchable antibiotics, and genome editing facilitated by the CRISPR/Cas system, are providing new avenues to facilitate the development of antimicrobial therapies. The informatics revolution is transforming research and development efforts to discover novel antibiotics. The explosion of nanotechnology and micro-engineering is driving the invention of antimicrobial materials, enabling the cultivation of “uncultivable” microbes and creating specific and rapid diagnostic technologies. Finally, a revival in the ecological aspects of microbial disease management, the growth of prebiotics, and integrated management based on the “One Health” model, provide additional avenues to manage this health crisis. These, and future scientific and technological developments, must be coupled and aligned with sound policy and public awareness to address the risks posed by rising antibiotic resistance.
Impact of a youth-led social marketing intervention run by adolescents to encourage healthy lifestyles among younger school peers (EYTO-Kids project): a parallel-cluster randomised controlled pilot study

Background Encouraging healthy lifestyles in children is a challenge. This project aimed to improve lifestyles of younger peers by engaging adolescent creators (ACs) to design and implement peer-led and social marketing (SM) health-promoting activities. Methods A 10-month parallel-cluster randomised controlled school-based pilot study was performed in disadvantaged neighbourhoods in Reus (Spain) spanning two academic years (2015–2016/2016–2017). Eight primary schools (n=375 children) and four high schools (n=94ACs) were randomly placed in the intervention group. The 94 ACs (12–14 years) designed and implemented four SM activities for their younger peers (9–11 years). Eight primary schools (n=327 children) and three high schools (n=98 adolescents) served as the control group and received no intervention. Primary (physical activity and fruit consumption) and secondary outcomes (screen time, vegetables, soft drinks, sweets and fast food consumptions) were assessed with validated questionnaires at baseline and at the end of the study. Results After 10 months, fruit consumption and physical activity were maintained in the children who consumed ≥1 fruit/day and spent ≥6 hours/week physical activity. However, compared with the controls, the intervention significantly increased the physical activity of girls to 15.6 min/week, whereas the percentage of girls who consumed sweets, soft drinks and fast food decreased significantly by 8.4%, 14.5% and 5.9%, respectively. Additionally, the percentage of ≥2 hour/weekday of screen time by boys decreased significantly by 8.2%. Conclusion The European Youth Tackling Obesity-Kids, SM and peer-led intervention, effectively increased physical activity hours/week in girls, but was not effective in improving the percentage of children who consumed the recommended fruit. Moreover, the percentages of girls who consumed sweets, soft drinks and fast food and boys screen time decreased. Trial registration number NCT02702336; Pre-results.
Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy

Blood-brain barrier (BBB) disruption is associated with hypoxia-ischemia (HI) induced brain injury and life-long neurological pathologies. Treatment options are limited. Recently, we found that mesenchymal stem/stromal cell derived extracellular vesicles (MSC-EVs) protected the brain in ovine fetuses exposed to HI. We hypothesized that Annexin A1 (ANXA1), present in MSC-EVs, contributed to their therapeutic potential by targeting the ANXA1/Formyl peptide receptor (FPR), thereby preventing loss of the BBB integrity. Cerebral ANXA1 expression and leakage of albumin into the fetal ovine brain parenchyma after HI were analyzed by immunohistochemistry. For mechanistic insights, barrier integrity of primary fetal endothelial cells was assessed after oxygen-glucose deprivation (OGD) followed by treatment with MSC-EVs or human recombinant ANXA1 in the presence or absence of FPR inhibitors. Our study revealed that BBB integrity was compromised after HI which was improved by MSC-EVs containing ANXA1. Treatment with these MSC-EVs or ANXA1 improved BBB integrity after OGD, an effect abolished by FPR inhibitors. Furthermore, endogenous ANXA1 was depleted within 24 h after induction of HI in cerebovasculature and ependyma and upregulated 72 h after HI in microglia. Targeting ANXA1/FPR with ANXA1 in the immature brain has great potential in preventing BBB loss and concomitant brain injury following HI.
Coupled influence of precipitation and vegetation on millennial-scale erosion rates derived from 10Be

Water is one of the main agent of erosion in many environmental settings, but erosion rates derived from beryllium-10 (10Be) suggests that a relationship between precipitation and erosion rate is statistically non-significant on a global scale. This might be because of the strong influence of other variables on erosion rate. In this global 10Be compilation, we examine if mean annual precipitation has a statistically significant secondary control on erosion rate. Our secondary variable assessment suggests a significant secondary influence of precipitation on erosion rate. This is the first time that the influence of precipitation on 10Be-derived erosion rate is recognized on global scale. In fact, in areas where slope is <200m/km (~11°), precipitation influences erosion rate as much as mean basin slope, which has been recognized as the most important variable in previous 10Be compilations. In areas where elevation is <1000m and slope is <11°, the correlation between precipitation and erosion rate improves considerably. These results also suggest that erosion rate responds to change in mean annual precipitation nonlinearly and in three regimes: 1) it increases with an increase in precipitation until ~1000 mm/yr; 2) erosion rate stabilizes at ~1000 mm/yr and decreases slightly with increased precipitation until ~2200 mm/yr; and 3) it increases again with further increases in precipitation. This complex relationship between erosion rate and mean annual precipitation is best explained by the interrelationship between mean annual precipitation and vegetation. Increased vegetation, particularly the presence of trees, is widely recognized to lower erosion rate. Our results suggest that tree cover of 40% or more reduces erosion rate enough to outweigh the direct erosive effects of increased rainfall. Thus, precipitation emerges as a stronger secondary control on erosion rate in hyper-arid areas, as well as in hyper-wet areas. In contrast, the regime between ~1000 and ~2200 mm/yr is dominated by opposing relationships where higher rainfall acts to increase erosion rate, but more water also increases vegetation/tree cover, which slows erosion. These results suggest that when interpreting the sedimentological record, high sediment fluxes are expected to occur when forests transition to grasslands/savannahs; however, aridification of grasslands or savannahs into deserts will result in lower sediment fluxes. This study also implies that anthropogenic deforestation, particularly in regions with high rainfall, can greatly increase erosion.