Miracle-dz/UniFAR-FTUs huggingface dataset:
Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice

Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25−0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug–drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.
Chemokines in COPD: From Implication to Therapeutic Use

Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chemokine receptors. Here, we provide an overview of the evidence regarding chemokines involvement in COPD, and we hypothesize that a dysregulation of this tightly regulated system is critical in COPD evolution, both at a stable state and during exacerbations. Targeting chemokines and chemokine receptors could be highly attractive as a mean to control both chronic inflammation and bronchial remodeling. We present a special focus on the CXCL8-CXCR1/2, CXCL9/10/11-CXCR3, CCL2-CCR2, and CXCL12-CXCR4 axes that seem particularly involved in the disease pathophysiology.
Socioeconomic status and the structure of the self-concept.

Individuals have a myriad of potential identities that they can use to define who they are, yet little research has investigated which types of identities people tend to prioritize within their self-concepts, and how this may vary across individuals. We analyse data from two large UK social surveys (Ns = 16,966 and 44,903) that assessed the importance respondents attached to various identities within their self-concepts, and find that social class plays a crucial role. Our results show that respondents attached high importance to identities that are indicative of their social class (income, education, and professional), and at least as much importance as they gave to identities more commonly studied by psychologists (such as ethnicity, nationality, or gender). Furthermore, respondents' objective social class was one of the strongest predictors of the importance they attached to different types of identities: Higher class respondents placed greater importance on identities that are indicative of their social class, but less importance on identities based on basic demographics, chosen communities, or their sociocultural orientation. Our results suggest that social class plays an important role in structuring the self-concept, and that researchers should pay more attention to the importance of social class to self and identity processes.
The influence of landscape, climate and history on spatial genetic patterns in keystone plants (Azorella) on sub‐Antarctic islands

The distribution of genetic variation in species is governed by factors that act differently across spatial scales. To tease apart the contribution of different processes, especially at intermediate spatial scales, it is useful to study simple ecosystems such as those on sub‐Antarctic oceanic islands. In this study, we characterize spatial genetic patterns of two keystone plant species, Azorella selago on sub‐Antarctic Marion Island and Azorella macquariensis on sub‐Antarctic Macquarie Island. Although both islands experience a similar climate and have a similar vegetation structure, they differ significantly in topography and geological history. We genotyped six microsatellites for 1,149 individuals from 123 sites across Marion Island and 372 individuals from 42 sites across Macquarie Island. We tested for spatial patterns in genetic diversity, including correlation with elevation and vegetation type, and clines in different directional bearings. We also examined genetic differentiation within islands, isolation‐by‐distance with and without accounting for direction, and signals of demographic change. Marion Island was found to have a distinct northwest–southeast divide, with lower genetic diversity and more sites with a signal of population expansion in the northwest. We attribute this to asymmetric seed dispersal by the dominant northwesterly winds, and to population persistence in a southwestern refugium during the Last Glacial Maximum. No apparent spatial pattern, but greater genetic diversity and differentiation between sites, was found on Macquarie Island, which may be due to the narrow length of the island in the direction of the dominant winds and longer population persistence permitted by the lack of extensive glaciation on the island. Together, our results clearly illustrate the implications of island shape and geography, and the importance of direction‐dependent drivers, in shaping spatial genetic structure.
Long‐Term Fine Motor Capability on the Staircase Test Correlates with the Absolute Number, but Not the Density, of DARPP‐Positive Neurons in the Caudate‐Putamen

Measurement of long‐term functional and anatomical outcomes in the same animal is considered a powerful strategy for correlating structure with function. In a neonatal animal model of hypoxic–ischemic brain injury that is relevant to cerebral palsy, long‐term functional deficits on the staircase test and long‐term anatomical deficits in the absolute number of medium‐spiny projection neurons in the caudate‐putamen were reported in different animals due to logistical constraints. Here, we investigated if these functional and anatomical measures were correlated when measured in the same animals. The medium‐spiny projection neurons were investigated because (1) they comprise the vast majority (>97%) of all neurons in the caudate‐putamen and (2) motor deficits observed during staircase testing are likely to involve these striatal medium‐spiny projection neurons through their connections. We found that long‐term skilled forepaw capability on the staircase test was correlated with the absolute number of DARPP‐32‐positive medium‐spiny projection neurons in the caudate‐putamen. Specifically, deficits in skilled forepaw ability for the number of sugar pellets eaten and retrieved, and for the maximum staircase level reached, were significantly correlated with a lower absolute neuronal number. We also found that skilled forepaw ability on the staircase test was not correlated with the neuronal density (i.e., number per unit volume) of DARPP‐32‐positive medium‐spiny projection neurons. Since neuronal density is an indirect measure of neuronal survival that is used in the literature, and absolute neuronal number is a direct measure, the results also highlight the scientific value of measuring absolute neuronal number. Anat Rec, 302:2040–2048, 2019. © 2019 American Association for Anatomy
Cell death assays for neurodegenerative disease drug discovery

ABSTRACT Introduction: Neurodegenerative diseases affect millions of people worldwide. Neurodegeneration is gradual over time, characterized by neuronal death that causes deterioration of cognitive or motor functions, ultimately leading to the patient’s death. Currently, there are no treatments that effectively slow the progression of any neurodegenerative disease, but improved microscopy assays and models for neurodegeneration could lead the way to the discovery of disease-modifying therapeutics. Areas covered: Herein, the authors describe cell-based assays used to discover drugs with the potential to slow neurodegeneration, and their associated disease models. They focus on microscopy technologies that can be adapted to a high-throughput screening format that both detect cell death and monitor early signs of neurodegeneration and functional changes to identify drugs that the block early stages of neurodegeneration. Expert opinion: Many different phenotypes have been used in screens for the development of therapeutics towards neurodegenerative disease. The context of each phenotype in relation to neurodegeneration must be established to identify therapeutics likely to successfully target and treat disease. The use of improved models of neurodegeneration, statistical analyses, computational models, and improved markers of neuronal death will help in this pursuit and lead to better screening methods to identify therapeutic compounds against neurodegenerative disease.
A systematic review of vital events tracking by community health agents

ABSTRACT Background: Efforts to improve national civil registration and vital statistics (CRVS) systems are focusing on transforming traditionally passive systems into active systems that have the ability to reach the household level. While community health agents remain at the core of many birth and death reporting efforts, previous literature has not explored elements for their successful integration into CRVS efforts. Objective: To inform future efforts to improve CRVS systems, we conducted a systematic review of literature to understand and describe the design features, resulting data quality, and factors impacting the performance of community health agents involved in tracking vital events. Methods: We reviewed 393 articles; reviewers extracted key information from 58 articles meeting the eligibility criteria: collection of birth and/or death information outside of a clinic environment by a community agent. Reviewers recorded information in an Excel database on various program aspects, and results were summarized into key themes and topic areas. Results: The majority of articles described work in rural areas of Africa or South-East Asia. Nearly all articles (86%) cited some form of household visitation by community health agents. Only one article described a process in which vital events tracking activities were linked to official vital events registers. Other factors commonly described included program costs, relationship of community agents to community, and use of mobile devices. About 1/3 of articles reported quantitative information on performance and quality of vital events data tracked; various methods were described for measuring completeness of reporting, which varied greatly across articles. Conclusions: The multitude of articles on this topic attests to the availability of community health agents to track vital events. Creating a programmatic norm of integrating with CRVS systems the vital events information collected from existing community health programs has the potential to provide governments with information essential for public health decision-making.
3D printing in the design of pharmaceutical dosage forms

Abstract Three-dimensional (3D) printing technologies are manufacturing approaches with widespread use in industry (e.g. automotive, automobile, pharmaceutical industries). With regard to its use in pharmaceutical industry, 3D printing is demonstrating to be of added value attributed to the possibility of printing tailored pharmaceutical products, namely personalized medical devices, such as implants and other dosage forms. However, with the approval of the first 3D-printed drug-product in 2015, a new perspective has arisen, i.e. the use of this technology to produce solid oral dosage forms exhibiting complex drug release profiles and allowing for individual dosing. Technological hurdles and regulatory issues still have to be overcome before this technology can truly find its place in the healthcare sector, where it can certainly contribute to a personalized and patient-centered healthcare. This manuscript offers a comprehensive analysis of the most extensively used methods of 3D printing in the pharmaceutical field, with examples of solid oral dosage forms and other medical devices currently under development or already marketed.
Microneedle Coating Methods: A Review with a Perspective

A coated microneedle array comprises sharp micrometer-sized needle shafts attached to a base substrate and coated with a drug on their surfaces. Coated microneedles are under investigation for drug delivery into the skin and other tissues, and a broad assortment of active materials, including small molecules, peptides, proteins, deoxyribonucleic acids, and viruses, have been coated onto microneedles. To coat the microneedles, different methods have been developed. Some coating methods achieve selective coating of just the microneedle shafts, whereas other methods coat not only microneedle shafts but also the array base substrate. Selective coating of just the microneedle shafts is more desirable since it provides control over drug dosage, prevents drug waste, and offers high delivery efficiency. Different excipients are added to the coating liquid to modulate its viscosity and surface tension in order to achieve uniform coatings on microneedles. Coated microneedles have been used in a broad range of biomedical applications. To highlight these different applications, a table summarizing the different active materials and the amounts coated on microneedles is provided. We also discuss factors that should be considered when deciding suitability of coated microneedles for new-drug delivery applications. In recent years, many coated microneedles have been investigated in human clinical trials, and there is now a strong effort to bring the first coated microneedle-based product to market.
Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared with Common β-Chain Cytokines IL-5 and GM-CSF

Key Points β-Chain receptor cytokines produce a proinflammatory and survival phenotype. IL-3 stimulation yields a distinct eosinophil gene expression program. IL-3–upregulated hub genes may have implications in future asthma therapeutics. Despite recent advances in asthma management with anti–IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit–specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3–upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti–IL-5 therapies.
2‐ and N6‐functionalized adenosine‐5′‐diphosphate analogs for the inhibition of mortalin

Our early efforts to find a covalent inhibitor of mortalin, a member of the 70 kD heat shock protein (Hsp70) family, led us to solve the structure of the mortalin nucleotide‐binding domain (NBD) in complex with N6‐propargyladenosine‐5′‐diphosphate. The acquired structure emphasizes the ability of the nucleotide‐binding pocket to accommodate modified ADP compounds. A library of ADP analogs modified at either the 2‐ or N6‐positions of adenosine was screened against the mortalin‐NBD. Competitive inhibition and binding assays of the analogs demonstrate that modifications at the 2‐ or N6‐positions have potential to bind and inhibit mortalin uniquely compared to other Hsp70 homologs, and that modifications at the 2‐position confer the greatest selectivity in binding and inhibition of the mortalin‐NBD.
Diurnal properties of voltage‐gated Ca2+ currents in suprachiasmatic nucleus and roles in action potential firing

Circadian oscillations in spontaneous action potential firing in the suprachiasmatic nucleus (SCN) translate time‐of‐day throughout the mammalian brain. The ion channels that regulate the circadian pattern of SCN firing have not been comprehensively identified. Ca2+ channels regulate action potential activity across many types of excitable cells, and the activity of L‐, N‐, P/Q‐ and R‐type channels are required for normal daytime firing frequency in SCN neurons and circuit rhythms. Only the L‐type Ca2+ current exhibits a day versus night difference in current magnitude, providing insight into the mechanism that produces rhythmic action potential firing in SCN.
ECF σ factors with regulatory extensions: the one‐component systems of the σ universe

The σ subunit of the bacterial RNA polymerase determines promoter specificity. The extracytoplasmic function σ factors (ECFs) represent the most abundant and diverse group of alternative σ factors and are present in the vast majority of bacterial genomes. Typically, ECFs are regulated by anti‐σ factors that sequester their cognate ECFs, thereby preventing their interaction with the RNA polymerase. Beyond these ECF paradigms, a number of distinct modes of regulation have been proposed and experimentally investigated. Regulatory extensions represent one such alternative mechanism of ECF regulation that can be found in 18 phylogenetically distinct ECF groups. Here, the σ factors contain additional domains that are fused to the ECF core domains and are involved in stimulus perception and modulation of σ factor activity. We will summarize the current state of knowledge on regulating ECF activity by C‐terminal extensions. We will also discuss newly identified ECF groups containing either N‐ or C‐terminal extensions and propose possible mechanisms by which these extensions have been generated and affect ECF σ factor activity. Based on their modular architecture and the resulting physical connection between stimulus perception and transcriptional output, these ECFs are analogous to one‐component systems, the primary mechanism of bacterial signal transduction.
Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairments (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. OBJECTIVE We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. METHODS PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no difference in hyper- versus hypo-connectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. RESULTS Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. CONCLUSIONS The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.