Miracle-dz/UniFAR-FTUs huggingface dataset:
Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice

Background: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. Aims: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. Methods: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. Results: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. Conclusions: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.
Non-microtubule tubulin-based backbone and subordinate components of postsynaptic density lattices

This study proposes a postsynaptic density (PSD) lattice model comprising a non-microtubule tubulin-based backbone structure and its associated proteins, including various PSD scaffold/adaptor proteins and other PSD proteins. A purification protocol was developed to identify and analyze the component proteins of a postsynaptic density (PSD) lattice, a core structure of the PSD of excitatory synapses in the central nervous system. “Enriched”- and “lean”-type PSD lattices were purified by synaptic plasma membrane treatment to identify the protein components by comprehensive shotgun mass spectrometry and group them into minimum essential cytoskeleton (MEC) and non-MEC components. Tubulin was found to be a major component of the MEC, with non-microtubule tubulin widely distributed on the purified PSD lattice. The presence of tubulin in and around PSDs was verified by post-embedding immunogold labeling EM of cerebral cortex. Non-MEC proteins included various typical scaffold/adaptor PSD proteins and other class PSD proteins. Thus, this study provides a new PSD lattice model consisting of non-microtubule tubulin-based backbone and various non-MEC proteins. Our findings suggest that tubulin is a key component constructing the backbone and that the associated components are essential for the versatile functions of the PSD.
PIF4 negatively modulates cold tolerance in tomato anthers via temperature-dependent regulation of tapetal cell death.

Extreme temperature conditions seriously impair male reproductive development in plants; however, the molecular mechanisms underlying the response of anthers to extreme temperatures remain poorly described. The transcription factor PHYTOCHROME-INTERACTING FACTOR4 (PIF4) acts as a hub that integrates multiple signaling pathways to regulate thermosensory growth and architectural adaptation in plants. Here, we report that SlPIF4 in tomato (Solanum lycopersicum) plays a pivotal role in regulating cold tolerance in anthers. CRISPR/Cas9-generated SlPIF4 knockout mutants showed enhanced cold tolerance in pollen due to reduced temperature sensitivity of the tapetum, while overexpressing SlPIF4 conferred pollen abortion by delaying tapetal programmed cell death (PCD). SlPIF4 directly interacts with SlDYT1, a direct upstream regulator of SlTDF1, both of which (SlDYT1 and SlTDF1) play important roles in regulating tapetum development and tapetal PCD. Moderately low temperature (MLT) promotes the transcriptional activation of SlTDF1 by the SlPIF4-SlDYT1 complex, resulting in pollen abortion, while knocking out SlPIF4 blocked the MLT-induced activation of SlTDF1. Furthermore, SlPIF4 directly bind to the canonical E-box sequence in the SlDYT1 promoter. Collectively, these findings suggest that SlPIF4 negatively regulates cold tolerance in anthers by directly interacting with the tapetal regulatory module in a temperature-dependent manner. Our results shed light on the molecular mechanisms underlying the adaptation of anthers to low temperatures.
Comprehensive assessment of the impact of horticultural activities on salivary stress biomarkers, psychological status, and the autonomic nervous system response visualized using a wearable biosensor.

OBJECTIVES This study aims to comprehensively investigate the changes of salivary stress biomarkers, psychological status, and autonomic nervous system (ANS) response due to horticultural activities (HAs). DESIGN AND METHODS A prospective observational study was conducted in twenty Japanese healthy adults (mean age, 58.4 years). Flower appreciation, flower arrangement, and farm work experience were performed as three HAs with different working concepts. Five salivary stress biomarkers (cortisol, α-amylase, S-IgA, chromogranin A, and oxytocin) were measured to quantify the stress levels before and after each HA. The Profile of Mood Status 2nd edition (POMS2) was used as a subjective psychological evaluation. Wearable biosensors were used to visualize the continuous ANS response throughout the process. RESULTS In the POMS2 investigation, the negative factors, which included Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Tension-Anxiety, and Total Mood Disturbance, were significantly decreased (p=0.0135, p=0.0004, p=0.0024, p=0.0015, p=0.0063, respectively). In the measurement of salivary stress biomarkers, flower appreciation decreased cortisol (p=0.0134), and farm work experience not only decreased cortisol but also increased oxytocin (p=0.0041, p=0.0128 respectively). In the visualization results of the ANS response, a graph demonstrated that the difference in activity between the sympathetic nerve and the parasympathetic nerve was narrowed by a series of HAs. CONCLUSIONS In healthy adults, HAs had a stress-reducing effect, which was evidenced by neuroendocrinological and psychological evaluations, a study of POMS2, salivary stress biomarkers, and visualization of the ANS response.
The effect of socially supportive church ministry on children’s prosocial behavior: An experimental study of Latin American Protestant Congregations

Abstract The church is commonly assumed to scaffold individuals’ socially supportive relationships and prosocial behavior. If true, that would make the church an important support for individual development and community change, facilitating and fostering healthy relationships and positive interactions with others. In this study, we analyzed experimental data collected from 30 churches in three Latin American countries to assess the impact of an intervention targeting relational ministry practices on 6- to 14-year-old children’s perceived support and prosocial behavior. Data were collected from children before (n = 710) and after (n = 612) the intervention in treatment (n = 25 churches) and control (n = 5 churches) conditions. Results indicated that the introduction of socially supportive practices in church children’s ministries increased children’s prosocial behavior, an effect mediated by changes in perceived support. Implications for children’s development and the church as a means of community change are discussed.
Associations between Lower-Order Anxiety Sensitivity Facets and PTSD Symptomatology among Trauma-Exposed Firefighters

Firefighters are chronically exposed to potentially traumatic events, augmenting their risk of developing posttraumatic stress disorder (PTSD). The current study aimed to examine the incremental associations of lower-order dimensions of anxiety sensitivity (AS), examined concurrently, and PTSD symptom severity among a sample of trauma-exposed firefighters. We hypothesized that AS physical and cognitive concerns would be strongly associated with all PTSD symptom clusters and overall symptom severity, after controlling for theoretically relevant covariates (trauma load; years in fire service; alcohol use severity; depressive symptom severity). Participants were comprised of firefighters (N = 657) who completed an online questionnaire battery and endorsed PTSD Criterion A trauma exposure. Results revealed that the AS cognitive concerns, but not AS physical concerns, was significantly and robustly associated with overall PTSD symptom severity, intrusion symptoms, and negative alterations in cognitions and mood (∆R2’s = .028–.042; p’s < .01); AS social concerns was incrementally associated with PTSD avoidance (∆R2 = .03, p < .01). Implications for firefighter-informed, evidence-based interventions are discussed.
Cutaneous microRNA expression in healthy Labrador and Golden retrievers and retrievers with allergic and inflammatory skin diseases.

BACKGROUND MicroRNAs (miRNA) are short, single-stranded RNA molecules that regulate gene expression in a post-transcriptional manner. Their expression is proposed to be tissue-specific and alterations in miRNA expression have been detected in many diseases. OBJECTIVE To compare miRNA expression in the skin of healthy Labrador and golden retrievers, and those with allergic and nonallergic dermatitis. METHODS AND MATERIALS Formalin-fixed and paraffin-embedded (FFPE) skin specimens from seven healthy Labrador and golden retrievers, and seven dogs with allergic skin disease were collected. A further mixed nonallergic inflammation group consisted of samples from five dogs with fungal infection, demodicosis and mast cell tumours. Total RNA was extracted and miRNA primer assays for 18 target miRNAs (miR-142, miR-363, miR-18b, miR-451, miR-146a, miR-124, miR-409, miR-193b, miR-223, miR-215, miR-155, miR-423a, miR-143, miR-1839, miR-21, miR-34b, miR-146b and miR-202) were performed, with RNU6-2 and SNORD95 as miRNAs for normalisation. The selection of miRNAs for investigation was based on reported data and a pilot study evaluating miRNA extraction from FFPE tissue specimens. RESULTS In the two dogs with mast cell tumours, miRNA expression was undetermined for most miRNAs, so both were excluded from analysis. Although there were differences in the miRNA expression between healthy and inflamed skin, allergic and nonallergic inflammation showed similar expression patterns. CONCLUSION AND CLINICAL RELEVANCE Although the number of included dogs was small, based on this study, none of the evaluated miRNAs allowed differentiation of allergic dermatitis from other inflammatory skin diseases in retriever dogs.
Methane Oxidation to Methanol in Water.

ConspectusMethane represents one of the most abundant carbon sources for fuel or chemical production. However, remote geographical locations and high transportation costs result in a substantial proportion being flared at the source. The selective oxidation of methane to methanol remains a grand challenge for catalytic chemistry due to the large energy barrier for the initial C-H activation and prevention of overoxidation to CO2. Indirect methods such as steam reforming produce CO and H2 chemical building blocks, but they consume large amounts of energy over multistage processes. This makes the development of the low-temperature selective oxidation of methane to methanol highly desirable and explains why it has remained an active area of research over the last 50 years.The thermodynamically favorable oxidation of methane to methanol would ideally use only molecular oxygen. Nature effects this transformation with the enzyme methane monooxygenase (MMO) in aqueous solution at ambient temperature with the addition of 2 equiv of a reducing cofactor. MMO active sites are Fe and Cu oxoclusters, and the incorporation of these metals into zeolitic frameworks can result in biomimetic activity. Most approaches to methane oxidation using metal-doped zeolites use high temperature with oxygen or N2O; however, demonstrations of catalytic cycles without catalyst regeneration cycles are limited. Over the last 10 years, we have developed Fe-Cu-ZSM-5 materials for the selective oxidation of methane to methanol under aqueous conditions at 50 °C using H2O2 as an oxidant (effectively O2 + 2 reducing equiv), which compete with MMO in terms of activity. To date, these materials are among the most active and selective catalysts for methane oxidation under this mild condition, but industrially, H2O2 is an expensive oxidant to use in the production of methanol.This observation of activity under mild conditions led to new approaches to utilize O2 as the oxidant. Supported precious metal nanoparticles have been shown to be active for a range of C-H activation reactions using O2 and H2O2, but the rapid decomposition of H2O2 over metal surfaces limits efficiency. We identified that this decomposition could be minimized by removing the support material and carrying out the reaction with colloidal AuPd nanoparticles. The efficiency of methanol production with H2O2 consumption was increased by 4 orders of magnitude, and crucially it was demonstrated for the first time that molecular O2 could be incorporated into the methanol produced with 91% selectivity. The understanding gained from these two approaches provides valuable insight into possible new routes to selective methane oxidation which will be presented here in the context of our own research in this area.
Regenerative responses following DNA damage – β-catenin mediates head regrowth in the planarian Schmidtea mediterranea

ABSTRACT Pluripotent stem cells hold great potential for regenerative medicine. Increased replication and division, such is the case during regeneration, concomitantly increases the risk of adverse outcomes through the acquisition of mutations. Seeking for driving mechanisms of such outcomes, we challenged a pluripotent stem cell system during the tightly controlled regeneration process in the planarian Schmidtea mediterranea. Exposure to the genotoxic compound methyl methanesulfonate (MMS) revealed that despite a similar DNA-damaging effect along the anteroposterior axis of intact animals, responses differed between anterior and posterior fragments after amputation. Stem cell proliferation and differentiation proceeded successfully in the amputated heads, leading to regeneration of missing tissues. Stem cells in the amputated tails showed decreased proliferation and differentiation capacity. As a result, tails could not regenerate. Interference with the body-axis-associated component β-catenin-1 increased regenerative success in tail fragments by stimulating proliferation at an early time point. Our results suggest that differences in the Wnt signalling gradient along the body axis modulate stem cell responses to MMS. Highlighted Article: Planarian stem cells respond differently to the genotoxic agent MMS in anterior versus posterior fragments, which could be linked with differential β-catenin activity along the body axis.
The use of local and nonlocal priors in Bayesian test‐based monitoring for single‐arm phase II clinical trials

Bayesian sequential monitoring is widely used in adaptive phase II studies where the objective is to examine whether an experimental drug is efficacious. Common approaches for Bayesian sequential monitoring are based on posterior or predictive probabilities and Bayesian hypothesis testing procedures using Bayes factors. In the first part of the paper, we briefly show the connections between test‐based (TB) and posterior probability‐based (PB) sequential monitoring approaches. Next, we extensively investigate the choice of local and nonlocal priors for the TB monitoring procedure. We describe the pros and cons of different priors in terms of operating characteristics. We also develop a user‐friendly Shiny application to implement the TB design.
Effect of age and care organization on sources of variation in kidney transplant waiting list registration

Despite national guidelines, medical practices and kidney transplant waiting list registration policies may differ from one dialysis/transplant unit to another. Benefit risk assessment variations, especially for elderly patients, have also been described. The aim of this study was to identify sources of variation in early kidney transplant waiting list registration in France. Among 16 842 incident patients during the period 2016–2017, 4386 were registered on the kidney transplant waiting list at the start of, or during the first year after starting, dialysis (26%). We developed various log‐linear mixed effect regression models on three levels: patients, dialysis networks, and transplant centers. Variability was expressed as variance from the random intercepts (± standard error). Although patient characteristics have an important impact on the likelihood of registration, the overall magnitude of variability in registration was low and shared by dialysis networks and transplant centers. Between‐transplant center variability (0.23 ± 0.08) was 1.8 higher than between‐dialysis network variability (0.13 ± 0.004). Older age was associated with a lower probability of registration and greater variability between networks (0.04, 0.20, & 0.93 in the 18–64, 65–74, and 75–84 age groups). Targeted interventions should focus on elderly patients and/or certain regions with greater variability in waiting list access.
TDP-43 a protein central to amyotrophic lateral sclerosis is destabilized by Tankyrase-1/2.

In >95% of amyotrophic lateral sclerosis (ALS) and ∼45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes Tankyrase 1 and Tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined Tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.
Oral and Palmitate Paliperidone Long-Acting Injectable Formulations’ Use in Schizophrenia Spectrum Disorders: A Retrospective Cohort Study from the First Episode Psychosis Intervention Program (CRUPEP)

Abstract Background Long-acting injectable antipsychotics (LAIs) may be a suitable therapeutic option for those patients in earlier stages of psychosis to avoid relapses and disease progression. Despite that, there is a lack of evidence in the literature regarding the use of LAIs in this profile of patients. Methods This is a retrospective cohort analysis to assess the efficacy, tolerability, and pattern of use of palmitate paliperidone long-acting injectable (PPLAI) formulations (1- and 3-month doses) compared to oral paliperidone/risperidone in patients with a nonaffective first episode of psychosis (FEP) over 12 months of follow-up. Relevant sociodemographic and clinical information were assessed, as well as main clinical scales: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, and Clinical Global Impression Scale Improvement and Severity measures. Results The study included 48 patients, 16 per arm, who were aged 20–50 years and had an FEP. Significant improvements were registered for all treatment groups. Despite that, patients receiving PPLAI 1- and 3-month formulations obtained greater improvements than those in the oral group in the main domains assessed (P < .001). We found no statistically significant differences in hospitalizations between groups. Side effects were presented in 24% of patients. A trend towards reducing antipsychotic doses was observed in 43.8% of patients to achieve the minimum effective dose and avoid the occurrence of side effects. Conclusions To our knowledge, this is the first study assessing the use of palmitate paliperidone long-acting formulations versus oral risperidone or paliperidone in FEP. Treatment with PPLAI formulations seems to be an effective therapeutic choice at earlier stages of the disease.
Yoga and Bone Health

Osteoporosis is a public health problem affecting individuals globally. Yoga has been found to prevent and reverse bone loss. Yoga may result in better balance, improved posture, and greater range of motion, strength, and coordination, all factors that also mitigate the risk of falls and fractures. A 12-minute, 12-pose yoga regimen is discussed in detail. Once learned, the ongoing use of yoga is safe, without cost, and may be done lifelong.
Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism‐like phenotype

The key role of APP for Alzheimer pathogenesis is well established. However, perinatal lethality of germline knockout mice lacking the entire APP family has so far precluded the analysis of its physiological functions for the developing and adult brain. Here, we generated conditional APP/APLP1/APLP2 triple KO (cTKO) mice lacking the APP family in excitatory forebrain neurons from embryonic day 11.5 onwards. NexCre cTKO mice showed altered brain morphology with agenesis of the corpus callosum and disrupted hippocampal lamination. Further, NexCre cTKOs revealed reduced basal synaptic transmission and drastically reduced long‐term potentiation that was associated with reduced dendritic length and reduced spine density of pyramidal cells. With regard to behavior, lack of the APP family leads not only to severe impairments in a panel of tests for learning and memory, but also to an autism‐like phenotype including repetitive rearing and climbing, impaired social communication, and deficits in social interaction. Together, our study identifies essential functions of the APP family during development, for normal hippocampal function and circuits important for learning and social behavior.