Miracle-dz/UniFAR-FTUs huggingface dataset:
Adolescent Binge-Type Ethanol Exposure in Rats Mirrors Age-Related Cognitive Decline by Suppressing Cholinergic Tone and Hippocampal Neurogenesis

Heavy alcohol consumption followed by periods of abstinence (i.e., binge drinking) during adolescence is a concern for both acute and chronic health issues. Persistent brain damage after adolescent intermittent ethanol exposure in rodents, a model of binge drinking, includes reduced hippocampal neurogenesis and a loss of neurons in the basal forebrain that express the cholinergic phenotype. The circuit formed between those regions, the septohippocampal pathway, is critical for learning and memory. Furthermore, this circuit is also altered during the aging process. Thus, we examined whether pathology in septohippocampal circuit and impairments in spatial behaviors are amplified during aging following adolescent intermittent ethanol exposure. Female and male rats were exposed to intermittent intragastric gavage of water (control) or 20% ethanol (dose of 5 g/kg) for a 2 days on/off cycle from postnatal days 25–55. Either 2 (young adult) or 12–14 (middle-age) months post exposure, rats were tested on two spatial tasks: spontaneous alternation and novel object in place. Acetylcholine efflux was assessed in the hippocampus during both tasks. There was no adolescent ethanol-induced deficit on spontaneous alternation, but middle-aged male rats displayed lower alternation rates. Male rats exposed to ethanol during adolescence had blunted behavioral evoked acetylcholine during spontaneous alternation testing. All ethanol-exposed rats displayed suppression of the cholinergic neuronal phenotype. On the novel object in place task, regardless of sex, ethanol-exposed rats performed significantly worse than control-treated rats, and middle aged-rats, regardless of sex or ethanol exposure, were significantly impaired relative to young adult rats. These results indicate that male rats display earlier age-related cognitive impairment on a working memory task. Furthermore, male rats exposed to ethanol during adolescence have blunted behavior-evoked hippocampal acetylcholine efflux. In addition, middle-aged and ethanol-exposed rats, regardless of sex, are impaired at determining discrete spatial relationship between objects. This type of pattern separation impairment was associated with a loss of neurogenesis. Thus, binge-type adolescent ethanol exposure does affect the septohippocampal circuit, and can accelerate age-related cognitive impairment on select spatial tasks.
Computational Analysis of Alternative Photosynthetic Electron Flows Linked With Oxidative Stress

During photosynthesis, organisms respond to their energy demand and ensure the supply of energy and redox equivalents that sustain metabolism. Hence, the photosynthetic apparatus can, and in fact should, be treated as an integrated supply-demand system. Any imbalance in the energy produced and consumed can lead to adverse reactions, such as the production of reactive oxygen species (ROS). Reaction centres of both photosystems are known sites of ROS production. Here, we investigate in particular the central role of Photosystem I (PSI) in this tightly regulated system. Using a computational approach we have expanded a previously published mechanistic model of C3 photosynthesis by including ROS producing and scavenging reactions around PSI. These include two water to water reactions mediated by Plastid terminal oxidase (PTOX) and Mehler and the ascorbate-glutathione (ASC-GSH) cycle, as a main non-enzymatic antioxidant. We have used this model to predict flux distributions through alternative electron pathways under various environmental stress conditions by systematically varying light intensity and enzymatic activity of key reactions. In particular, we studied the link between ROS formation and activation of pathways around PSI as potential scavenging mechanisms. This work shines light on the role of alternative electron pathways in photosynthetic acclimation and investigates the effect of environmental perturbations on PSI activity in the context of metabolic productivity.
Lack of Parkinsonian Pathology and Neurodegeneration in Mice After Long-Term Injections of a Proteasome Inhibitor in Olfactory Bulb and Amygdala

Proteinaceous inclusions, called Lewy bodies (LBs), are used as a pathological hallmark for Parkinson’s disease (PD). Recent studies suggested a prion-like spreading mechanism for α-synucleinopathy where early neuropathological deposits occur, among others, in the olfactory bulb (OB) and amygdala. LBs contain insoluble α-synuclein and many other ubiquitinated proteins, suggesting a role of protein degradation system failure in PD pathogenesis. Therefore, we wanted to study the effects of a proteasomal inhibitor, lactacystin, on the aggregability and transmissibility of α-synuclein in the OB and amygdala. We performed injections of lactacystin in the OB and amygdala of wild-type mice. Motor behavior, markers of neuroinflammation, α-synuclein, and dopaminergic integrity were assessed by immunohistochemistry. Overall, there were no differences in the number of neurons and α-synuclein expression in these regions following injection of lactacystin into either the OB or amygdala. Microglial and astroglial labeling appeared to be correlated with surgery-induced inflammation or local effects of lactacystin. Consistent with the behavior and pathological findings, there was no loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. Our data showed that long-term lactacystin injections in extra nigrostriatal regions may not mimic spreading aspects of PD and reinforce the special vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc).
Effects of the Pars Plana Vitrectomy on the Chronic Total Rhegmatogenous Retinal Detachment in the Young Adults

Objective: To observe the characteristics and evaluate the efficacy and safety of the chronic total rhegmatogenous retinal detachment (RRD) treatment by the 23-gauge pars plana vitrectomy (PPV) in young adults and to analyze the related factors. Methods: A retrospective chart review was performed for the young adults who underwent the 23-gauge PPV for the chronic total RRD at the Tianjin Medical University General Hospital from 2011 to 2018. A total of 54 eyes of 48 patients were included in this study. The preoperative vision ranged from 2.00 to 1.00. The mean duration of RRD was 9 ± 0.6 months with a range from 4 to 18 months. The proliferative vitreoretinopathy (PVR) grade D1 and grade D2 was diagnosed in 48 eyes and 6 eyes, respectively. About 37 eyes were filled with C3F8 and 17 eyes were filled with silicone oil tamponade. The follow-up ranged from 9 to 78 months with a mean of 23 ± 2.2 months. Results: The postoperative visual acuity increased in all the eyes at the final observation. The retinal attachment was achieved in 49 eyes (90.7%) in the primary PPV. Five eyes (9.3%) with the failed retinal attachment finally achieved the attachment after the second procedure. The postoperative complications mainly included temporary intraocular pressure (IOP) elevation, hyphema, and retinal redetachment. Conclusion: Chronic total RRD can be treated via the 23-gauge PPV with a great anatomical and visual prognosis in the young adult. The successful treatment of the chronic total RRD in young adults is mainly associated with the complete dissection of the severe vitreoretinopathy, especially for the epiretinal membrane at the retinal breaks and degenerations and the subretinal proliferation during surgery.
Towards a Program Theory for Family-Focused Practice in Adult Mental Health Care Settings: An International Interview Study With Program Leaders

Objectives: In several high-income countries, family-focused practice programs have been introduced in adult mental health care settings to identify and support children whose parents live with mental health problems. Whilst their common goal is to reduce the impact of parental mental illness on children, the mechanisms by which they improve outcomes in different systems and settings are less well known. This kind of knowledge can importantly contribute to ensuring that practice programs achieve pre-defined impacts. Methods: The aim of this study was to develop knowledge about relationships between contextual factors, mechanisms and impact that could inform a program theory for developing, implementing, and evaluating family-focused practice. Principles of a realist evaluation approach and complex system thinking were used to conceptualize the design of semi-structured in-depth interviews with individuals who led the implementation of programs. Seventeen individuals from eight countries participated in the study. Results: Interviewees provided rich accounts of the components that programs should include, contextual factors in which they operated, as well as the behavior changes in practitioners that programs needed to achieve. Together with information from the literature, we developed an initial program theory, which illustrates the interconnectedness between changes that need to co-occur in practitioners, parents, and children, many of which related to a more open communication about parental mental health problems. Stigma, risk-focused and fragmented health systems, and a lack of management commitment were the root causes explaining, for example, why conversations about parents' mental illness did not take place, or not in a way that they could help children. Enabling practitioners to focus on parents' strengths was assumed to trigger changes in knowledge, emotions and behaviors in parents that would subsequently benefit children, by reducing feelings of guilt and improving self-esteem. Conclusion: To our knowledge, this is the first research, which synthesizes knowledge about how family-focused practice programs works in a way that it can inform the design, implementation, and evaluation of programs. Stakeholder, who fund, design, implement or evaluate programs should start co-developing and using program theories like the one presented in this paper to strengthen the design and delivery of family-focused practice.
When and Why Did Human Brains Decrease in Size? A New Change-Point Analysis and Insights From Brain Evolution in Ants

Human brain size nearly quadrupled in the six million years since Homo last shared a common ancestor with chimpanzees, but human brains are thought to have decreased in volume since the end of the last Ice Age. The timing and reason for this decrease is enigmatic. Here we use change-point analysis to estimate the timing of changes in the rate of hominin brain evolution. We find that hominin brains experienced positive rate changes at 2.1 and 1.5 million years ago, coincident with the early evolution of Homo and technological innovations evident in the archeological record. But we also find that human brain size reduction was surprisingly recent, occurring in the last 3,000 years. Our dating does not support hypotheses concerning brain size reduction as a by-product of body size reduction, a result of a shift to an agricultural diet, or a consequence of self-domestication. We suggest our analysis supports the hypothesis that the recent decrease in brain size may instead result from the externalization of knowledge and advantages of group-level decision-making due in part to the advent of social systems of distributed cognition and the storage and sharing of information. Humans live in social groups in which multiple brains contribute to the emergence of collective intelligence. Although difficult to study in the deep history of Homo, the impacts of group size, social organization, collective intelligence and other potential selective forces on brain evolution can be elucidated using ants as models. The remarkable ecological diversity of ants and their species richness encompasses forms convergent in aspects of human sociality, including large group size, agrarian life histories, division of labor, and collective cognition. Ants provide a wide range of social systems to generate and test hypotheses concerning brain size enlargement or reduction and aid in interpreting patterns of brain evolution identified in humans. Although humans and ants represent very different routes in social and cognitive evolution, the insights ants offer can broadly inform us of the selective forces that influence brain size.
Plasma and CSF Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Cross-Sectional and Longitudinal Study

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course. Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit. Results: ALS patients (n = 171) showed significantly higher pNfL (p < 0.0001) and cNfL (p < 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course. Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.
Editorial: Intracranial Atherosclerotic Disease: Epidemiology, Imaging, Treatment and Prognosis

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong SAR, China, Department of Neurology, University of Chicago, Chicago, IL, United States, Department of Neurology, Ajou University School of Medicine, Ajou University Medical Center, Suwon-si, South Korea, Department of Neurology, Henry Ford Health System, Detroit, MI, United States, Department of Neurology, Neurovascular Imaging Research Core and
Emerging Role of microRNAs in Stroke Protection Elicited by Remote Postconditioning

Remote ischemic conditioning (RIC) represents an innovative and attractive neuroprotective approach in brain ischemia. The purpose of this intervention is to activate endogenous tolerance mechanisms by inflicting a subliminal ischemia injury to the limbs, or to another “remote” region, leading to a protective systemic response against ischemic brain injury. Among the multiple candidates that have been proposed as putative mediators of the protective effect generated by the subthreshold peripheral ischemic insult, it has been hypothesized that microRNAs may play a vital role in the infarct-sparing effect of RIC. The effect of miRNAs can be exploited at different levels: (1) as transducers of protective messages to the brain or (2) as effectors of brain protection. The purpose of the present review is to summarize the most recent evidence supporting the involvement of microRNAs in brain protection elicited by remote conditioning, highlighting potential and pitfalls in their exploitation as diagnostic and therapeutic tools. The understanding of these processes could help provide light on the molecular pathways involved in brain protection for the future development of miRNA-based theranostic agents in stroke.
Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda

Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation – denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.
Predicting Fusarium Head Blight Resistance for Advanced Trials in a Soft Red Winter Wheat Breeding Program With Genomic Selection

Many studies have evaluated the effectiveness of genomic selection (GS) using cross-validation within training populations; however, few have looked at its performance for forward prediction within a breeding program. The objectives for this study were to compare the performance of naïve GS (NGS) models without covariates and multi-trait GS (MTGS) models by predicting two years of F4:7 advanced breeding lines for three Fusarium head blight (FHB) resistance traits, deoxynivalenol (DON) accumulation, Fusarium damaged kernels (FDK), and severity (SEV) in soft red winter wheat and comparing predictions with phenotypic performance over two years of selection based on selection accuracy and response to selection. On average, for DON, the NGS model correctly selected 69.2% of elite genotypes, while the MTGS model correctly selected 70.1% of elite genotypes compared with 33.0% based on phenotypic selection from the advanced generation. During the 2018 breeding cycle, GS models had the greatest response to selection for DON, FDK, and SEV compared with phenotypic selection. The MTGS model performed better than NGS during the 2019 breeding cycle for all three traits, whereas NGS outperformed MTGS during the 2018 breeding cycle for all traits except for SEV. Overall, GS models were comparable, if not better than phenotypic selection for FHB resistance traits. This is particularly helpful when adverse environmental conditions prohibit accurate phenotyping. This study also shows that MTGS models can be effective for forward prediction when there are strong correlations between traits of interest and covariates in both training and validation populations.
CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis

Store-operated Ca2+ release-activated Ca2+ (CRAC) channel is the main Ca2+ influx pathway in lymphocytes and is essential for immune response. Lupus nephritis (LN) is an autoimmune disease characterized by the production of autoantibodies due to widespread loss of immune tolerance. In this study, RNA-seq analysis revealed that calcium transmembrane transport and calcium channel activity were enhanced in naive B cells from patients with LN. The increased expression of ORAI1, ORAI2, and STIM2 in naive B cells from patients with LN was confirmed by flow cytometry and Western blot, implying a role of CRAC channel in B-cell dysregulation in LN. For in vitro study, CRAC channel inhibition by YM-58483 or downregulation by ORAI1-specific small-interfering RNA (siRNA) decreased the phosphorylation of Ca2+/calmodulin-dependent protein kinase2 (CaMK2) and suppressed Blimp-1 expression in primary human B cells, resulting in decreased B-cell differentiation and immunoglobulin G (IgG) production. B cells treated with CaMK2-specific siRNA showed defects in plasma cell differentiation and IgG production. For in vivo study, YM-58483 not only ameliorated the progression of LN but also prevented the development of LN. MRL/lpr lupus mice treated with YM-58483 showed lower percentage of plasma cells in the spleen and reduced concentration of anti-double-stranded DNA antibodies in the sera significantly. Importantly, mice treated with YM-58483 showed decreased immune deposition in the glomeruli and alleviated kidney damage, which was further confirmed in NZM2328 lupus mice. Collectively, CRAC channel controlled the differentiation of pathogenic B cells and promoted the progression of LN. This study provides insights into the pathogenic mechanisms of LN and that CRAC channel could serve as a potential therapeutic target for LN.
Ethnic and Sociocultural Differences in Ovarian Reserve: Age-Specific Anti-Müllerian Hormone Values and Antral Follicle Count for Women of the Arabian Peninsula

Background Anti-Müllerian hormone (AMH) and antral follicle count (AFC) age-specific reference values form the basis of infertility treatments, yet they were based upon studies performed primarily on Caucasian populations. However, they may vary across different age-matched ethnic populations. This study aimed to describe age-specific serum AMH and AFC for women native to the Arabian Peninsula. Methods A retrospective large-scale study was performed including 2,495 women, aged 19 to 50 years, native to the Arabian Peninsula. AMH and AFC were measured as part of their fertility assessment at tertiary-care fertility centres. Age-specific values and nomograms were calculated. Results 2,495 women were evaluated. Mean, standard deviation and median values were calculated for AMH and AFC by 1-year and 5-years intervals. Median age was 34.81 years, median AMH was 1.76ng/ml and median AFC was 11. From the total group, 40.60% presented with AMH levels below 1.3ng/mL. For women <45 years old, the decrease in AFC was between -0.6/-0.8 per year. Up to 36 years old, the decrease of AMH was 0.1ng/ml. However, from 36 to 40 years old, an accelerated decline of 0.23ng/ml yearly was noted. In keeping with local customs, 71.23% of women wore the hijab and 25.76% the niqab. AMH and AFC were significantly lower for niqab group compared with hijab group (p=0.02 and p=0.04, respectively). Conclusion This is to-date the largest data set on age-specific AMH and AFC values in women from the Arabian Peninsula aiming to increase clinical awareness of the ovarian reserve in this population.