bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychosocial interventions for people with a first episode psychosis: between tradition and innovation
Authors: Singh Swaran P. , Mohan Mohapradeep , Giacco Domenico 
Published: July 2021

Purpose of review
Assessing recent evidence on psychosocial interventions for people with first episode psychosis (FEP).

Recent findings
Family interventions (FI) reduce relapse rates, whilst cognitive behavioural therapy (CBT) shows a moderate effect in improving positive psychotic symptoms. Vocational interventions (VI) appear to be worthy of implementation within early intervention for psychosis (EIP) teams, but it is still unclear what is the most cost-effective strategy for their delivery. Promising interventions, which need more careful evaluation, focus on substance misuse, physical health comorbidities, improvement of social participation, peer support and the potential of new technologies.

Summary
The first five years after the onset of psychotic symptoms are a ‘critical period’ in which psychosocial interventions can be particularly influential in determining prognosis. Traditional EIP interventions have different effectiveness profiles, i.e., FI reduce relapse rates, CBT has a moderate effectiveness on overall and positive symptoms and VI can improve educational and employment-related functioning. Newer interventions show promise on important targets for FEP treatment but require higher-quality evaluations. Decisions on which interventions to implement within EIP teams should be informed by high-quality evidence, but difficult choices will have to be made based on costs, professionals and technologies available, and local priorities.
Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods
Authors: Gasparini P , Philot EA , Magro AJ , Mattos JC , Torres-Bonfim NESM , Kliousoff A , Quiroz RCN , Perahia D , Scott AL 
Published: July 2021

AbstractThe main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. Integrated methods combining the lowest-frequency movements obtained by Normal Mode Analysis (NMA), and the faster movements from Molecular Dynamics (MD), and data from biophysical techniques, are necessary to establish the correlation between complex structural dynamics of macromolecules and their function. In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.HighlightsSingle surface mutations lead to changes in Mpro structural dynamics.Mutants can be more stable than WT according to the structural dynamics properties.Mpromutants can present a distinct functionality in relation to the wild-type.Potential viral markers for more pathogenic or transmissible SARS-CoV-2 variants.
Rapid visual CRISPR assay: a naked-eye colorimetric detection method for nucleic acids based on CRISPR/Cas12a and convolutional neural network
Authors: Xie Shengsong , Tao Dagang , Fu Yuhua , Xu Bingrong , Tang You , Steinaa Lucilla , Hemmink Johanneke D , Pan Wenya , Huang Xin , Nie Xiongwei , Zhao Changzhi , Ruan Jinxue , Zhang Yi , Han Jianlin , Fu Liangliang , Ma Yunlong , Li Xinyun , Liu Xiaolei , Zhao Shuhong 
Published: July 2021

AbstractRapid diagnosis based on naked-eye colorimetric detection remains challenging, but it could build new capacities for molecular point-of-care testing (POCT). In this study, we evaluated the performance of 16 types of single-stranded DNA-fluorophore-quencher (ssDNA-FQ) reporters for use with CRISPR/Cas12a based visual colorimetric assays. Among them, 9 ssDNA-FQ reporters were found to be suitable for direct visual colorimetric detection, with especially very strong performance using ROX-labeled reporters. We optimized the reaction concentrations of these ssDNA-FQ reporters for naked-eye read-out of assay results (no transducing component required for visualization). Subsequently, we developed a convolutional neural network algorithm standardize and to automate the analytical colorimetric assessment of images and integrated this into the MagicEye mobile phone software. A field-deployable assay platform named RApid VIsual CRISPR (RAVI-CRISPR) based on a ROX-labeled reporter with isothermal amplification and CRISPR/Cas12a targeting was established. We deployed RAVI-CRISPR in a single tube towards an instrument-less colorimetric POCT format that requires only a portable rechargeable hand warmer for incubation. The RAVI-CRISPR was successfully used for the single-copy detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and African swine fever virus (ASFV). Our study demonstrates this novel RAVI-CRISPR system for distinguishing different pathogenic nucleic acid targets with high specificity and sensitivity as the simplest-to-date platform for rapid pen-side testing.
Dique Filipeia: A rehabilitation protocol for non-intubated COVID-19 in-hospital patients
Authors: Frazão Murillo , de Brito Marinho Paiva Kamila Januária , da Nova Sá Rossana Maria , Santos Menezes Fábio dos , dos Santos Alves Laís Ailenny , de Souza Rocha Anderson Igor Silva , de França Eduardo Eriko Tenório , Cruz Santos Amilton da , Brasileiro-Santos Maria do Socorro 
Published: July 2021

AbstractObjectiveThe aim of this study was to evaluate the effectiveness of the “Dique Filipeia” rehabilitation protocol in patients with COVID-19 admitted to reference hospitals.MethodsThis is an experimental study with COVID-19 patients admitted to the hospitals wards being considered eligible. The study outcomes were assessed between patients undergoing the rehabilitation protocol (Dique Filipeia group) and patients who did not receive the protocol (control group). The rehabilitation protocol consisted in classifying patients daily into four levels of severity through peripheral oxygen saturation. Severity was classified by the oxygen flow needed to maintain a saturation greater than or equal to the cut-off point of 93%. A standardized ventilatory support and functional rehabilitation exercises were performed for each severity level patient, followed by an attempt to wean oxygen.ResultsA total of 727 patients were analyzed in the study. The Dique Filipeia group presented a lower total (132.7 ± 35.3 vs 307.0 ± 114.3 m3/patient; effect size 1.73) and daily (2.9 ± 1.0 vs 6.8 ± 3.1 m3/day/patient; effect size 1.46) oxygen expenditure than the control group. The Dique Filipeia patients presented higher hospital discharge (64.9 ± 9.3 vs 35.4 ± 7.5%; effect size 3.46) and lower length of stay (15.8 ± 4.2 vs 29.1 ± 3.4 days; effect size 3.47) than the control group. The Dique Filipeia group patients, who were demanding oxygen therapy, were using 6.2 ± 4.3 L/min of oxygen at day 1. There was a statistically significant reduction from day 2 (p = 0.0001) and oxygen flow was reduced below 1L/min after day 7.ConclusionsThe implementation of a standardized rehabilitation protocol reduced oxygen expenditure, increased hospital discharge and reduced the length of hospital stay. Dique Filipeia is a practical, feasible and safe protocol.
Loss of the H4 lysine methyltransferase KMT5B drives tumorigenic phenotypes by depleting H3K27me3 at loci otherwise retained in H3K27M mutant DIPG cells
Authors: Kessler Ketty , Mackay Alan , Grabovska Yura , Molinari Valeria , Burford Anna , Temelso Sara , Tari Haider , Yara-Romero Erika , Liu Ilon , Yu Lu , Castel David , Choudhary Jyoti , Sottoriva Andrea , Filbin Mariella , Vinci Mara , Jones Chris 
Published: July 2021

SUMMARYDIPG are characterised by histone H3K27M mutations, resulting in global loss of the repressive mark H3K27me3, although certain key loci are retained. We recently identified subclonal loss-of-function mutations in the H4 lysine methyltransferase KMT5B to be associated with enhanced invasion/migration, but the mechanism by which this occurred was unclear. Here we use integrated ChIP-seq, ATAC-seq and RNA-seq on patient-derived, subclonal and CRISPR-Cas9-KD DIPG cells to show that loss of KMT5B/C causes depletion of these retained H3K27me3 loci via changes in chromatin accessibility, causing a raft of transcriptional changes which promote tumorigenesis. De-repression occurred at bivalent loci marked by H3K4me3, driving increased transcriptional heterogeneity and elevated gene expression associated with increased invasion, abrogated DNA repair and mesenchymal transition, along with a markedly altered secretome. These data suggest a previously unrecognised trans-histone (H4/H3) interaction in DIPG cells with a potentially profound effect on their diffusely infiltrating phenotype.
Cardiac adenylyl cyclase type 8 overexpression increases locomotor activity in mice by modulating EEG-gamma oscillations
Authors: Agrimi Jacopo , Menicucci Danilo , Qu Jia-Hua , Laurino Marco , Mackey Chelsea D , Hasnain Laila , Tarasova Yelena S , Tarasov Kirill V , McDevitt Ross A , Hoover Donald B , Gemignani Angelo , Paolocci Nazareno , Lakatta Edward G 
Published: July 2021

AbstractThe central nervous system modulates heart function on a beat-to-beat basis via increasingly understood mechanisms. Conversely, whether and how humoral/functional cardiac variations shape brain activity and adaptive behavior remains unclear. This study shows that mice overexpressing adenylyl cyclase type 8 in myocytes (TGAC8), characterized by persistently elevated heart rate/contractility, also display increased locomotion. This effect is sustained by enhanced gamma rhythms, as evidenced by simultaneous behavioral and EEG/ECG monitoring. These changes are specific because they are not paralleled by other modifications, such as heightened anxiety-like behavior. In unison, TGAC8 mice hippocampus exhibits upregulated GABA-A receptors, whose activation chiefly accounts for gamma activity generation. Moreover, the Granger causality analysis between ECG and EEG attests to the causal involvement of the autonomic component of the heartbeat in shaping EEG gamma oscillations in a bottom-up modality. Mechanistically, TGAC8 harbors elevated circulating dopamine/DOPA levels of cardiac origin and upregulated hippocampal D5 dopamine receptor levels. In synergy with the GABA-A receptor, D5 activation favors hippocampal inhibitory currents that drive EEG gamma oscillations. These studies, therefore, inform how heart-initiated functional and/or humoral modifications reverberate back to the brain to modulate specific primary adaptive responses, such as locomotion.SignificanceThe brain is continuously aware of the functional status of many bodily organs, modulating, for instance, the heart’s activity beat-by-beat. Conversely, how cardiac activity modifications impact brain function and behavior is less understood. We disclose that augmenting myocyte adenyl cyclase 8 (AC8) activity in mice increases their locomotion. Elevated cardiac AC8 levels lead to higher circulating dopamine and DOPA, hormones crucially involved in movement control, and increased expression of the hippocampus’s GABA-A and D5 receptors; the activation of the latter modifies hippocampal gamma oscillations shaping locomotor activity. Thus, the brain interprets changes in myocardial AC8 activity as a “sustained exercise-like” situation and responds by activating areas commanding to increase locomotion.
Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy
Authors: Eapen Vinay V. , Swarup Sharan , Hoyer Melissa J. , Paulo Joao A. , Harper J. Wade 
Published: July 2021

ABSTRACTRemoval of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. Damaged organelles are recognized by a dedicated surveillance machinery, leading to the assembly of an autophagosome around the damaged organelle, prior to fusion with the degradative lysosomal compartment. Lysosomes themselves are also prone to damage and are degraded through the process of lysophagy. While early steps involve recognition of ruptured lysosomal membranes by glycan-binding Galectins and ubiquitylation of transmembrane lysosomal proteins, many steps in the process, and their inter-relationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. Here, we employ quantitative organelle capture and proximity biotinylation proteomics of autophagy adaptors, cargo receptors, and Galectins in response to acute lysosomal damage, thereby revealing the landscape of lysosomal proteome remodeling during lysophagy. Among proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. Using newly developed lysophagic flux reporters including Lyso-Keima, we demonstrate that TAX1BP1, together with its associated kinase TBK1, are both necessary and sufficient to promote lysophagic flux in both Hela cells and induced neurons (iNeurons). While the related receptor OPTN can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. Mechanistically, TAX1BP1-driven lysophagy requires its N-terminal SKICH domain, which binds both TBK1 and the autophagy regulatory factor RB1CC1, and requires upstream ubiquitylation events for efficient recruitment and lysophagic flux. These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process.
Connectivity and dynamics in the olfactory bulb
Authors: Kersen David E. Chen , Tavoni Gaia , Balasubramanian Vijay 
Published: July 2021

AbstractDendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the probability of synapse between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. It in turn predicts testable relations between network structure, lateral inhibition, and odor pattern decorrelation; between the density of granule cell activity and LFP oscillation frequency; how cortical feedback to granule cells affects mitral cell activity; and how cortical feedback to mitral cells is modulated by the network embedding. Additionally, the methodology we describe here provides a tractable tool for other researchers.Author summaryThe function of the olfactory bulb (OB) critically depends on connectivity patterns between its excitatory and inhibitory cells. Here, we develop an anatomically grounded algorithm for efficiently determining the probability of synapses between mitral cells and granule cells in the OB. We use this algorithm to generate a large-scale network model of the OB with characteristic connectivity distributions between cell types, as well as between sister mitral cells. We simulate the network using the dynamical systems approach of Izhikevich for describing neurons, and show how network structure affects GC-mediated processes, including LFP oscillation frequency, lateral inhibition, odor decorrelation, and cortical feedback. Our results suggest how alterations to the OB network through processes like neurogenesis, or via injury or disease, can have significant effects on function.
Diet modifies allele-specific phenotypes inDrosophilacarrying epilepsy-associatedPNPOvariants
Authors: Chi Wanhao , Iyengar Atulya SR , Fu Wenqin , Liu Wei , Berg Abigayle E , Wu Chun-Fang , Zhuang Xiaoxi 
Published: July 2021

AbstractPyridox(am)ine 5’-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5’-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters GABA and monoamines. Pathogenic variants inPNPOhave been repeatedly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities, including developmental impairment and intellectual disability. It is unclear how seizure types and associated comorbidities are linked to specificPNPOalleles and to what degree diet can modify their expression. Furthermore, the molecular characteristics ofPNPOvariants have not been examined in model systems. Using CRISPR/Cas9, we generated four knock-inDrosophilaalleles,hWT, hR116Q, hD33V, andhR95H, in which the endogenousDrosophila PNPO(sugarlethal) was replaced by wild-type humanPNPOcDNA and epilepsy-associated variants corresponding to R116Q, D33V, and R95H, respectively. We examined these knock-in flies at the molecular, circuitry, and behavioral levels. Collectively, we found a wide range of phenotypes in an allele- and diet-dependent manner. Specifically, the D33V mutation reduces the mRNA level, R95H reduces the protein stability, and R116Q alters the protein localization of PNPO in the brain. D33V and R95H mutations lead to partial and complete lethality during development, respectively and R116Q and D33V mutations shorten lifespan. At the behavioral level,hD33V/hR95Htrans-heterozygous flies are hypoactive on all tested diets whereashR116Qflies show diet-dependent locomotor activities. At the circuitry level,hD33Vhomozygotes show rhythmic burst firing andhD33V/hR95Htrans-heterozygotes exhibit spontaneous seizure discharges. InhR95Hhomozygotes rescued with PLP supplementation, we uncovered that PLP deficiency abolishes development and causes extreme seizures in adults. Lastly, genetic and electrophysiological analyses demonstrate thathWT/hR95Hheterozygous flies are prone to seizures due to a dominant-negative effect of hR95Hon hWT, highlighting the possibility that human R95H carriers may also be susceptible to epilepsy. Together, this study demonstrates that humanPNPOvariants interact with diet to contribute to phenotypic variations; and that the knock-inDrosophilamodel offers a powerful approach to systematically examine clinical manifestations and the underlying mechanisms of human PNPO deficiency.
Gata2a maintains cebpa and npm1a in haematopoietic stem cells to sustain lineage differentiation and genome stability
Authors: Mahony Christopher B. , Noyvert Boris , Vrljicak Pavle , Ott Sascha , Higgs Martin , Monteiro Rui 
Published: July 2021

AbstractThe transcription factor Gata2 is required to produce and maintain haematopoietic stem and progenitor cells (HSPCs) in development and adult haematopoiesis. Mutations in GATA2 lead to GATA2 deficiency syndrome and predispose patients to acquire leukaemia. Here we use zebrafish gata2a enhancer deletion mutants and single cell transcriptomics to understand how GATA2 mediates survival and differentiation of haematopoietic stem cells in GATA2 deficiency. Gata2a mutants show marrow failure, neutropenia, B-lymphopenia and erythrocytosis from 6 months post-fertilization (mpf). Single cell transcriptional profiling of the adult kidney marrow demonstrated that HSPCs express elevated expression of erythroid- and decreased expression of myeloid genes, including cebpa. This is associated with a lineage skewing towards the erythroid fate at the expense of the myeloid fate. Thus, Gata2a is required to initiate and maintain lineage priming in HSPCs, favouring myeloid differentiation. Gata2a regulates expression of multiple targets associated with replication and DNA damage repair (DDR), including npm1a, a zebrafish NPM1 orthologue. Accordingly, mutant marrow cells show increased DNA damage associated with progressive loss of npm1a expression with age. This effect was replicated by inhibiting NPM1 activity in murine HPC7 progenitor cells. We propose that the impaired DDR leads to marrow failure in GATA2 deficiency. This leads to increased genomic instability in the surviving HSPCs, favouring acquisition of secondary leukaemogenic mutations.
Construction of functional biliary epithelial branched networks with predefined geometry using digital light stereolithography
Authors: Mazari-Arrighi Elsa , Ayollo Dmitry , Farhat Wissam , Marret Auriane , Gontran Emilie , Dupuis-Williams Pascale , Larghero Jerome , Chatelain Francois , Fuchs Alexandra 
Published: July 2021

AbstractCholangiocytes, biliary epithelial cells, are known to spontaneously self-organize into spherical cysts with a central lumen. In this work, we explore a promising biocompatible stereolithographic approach to encapsulate cholangiocytes into geometrically-controlled 3D hydrogel structures to guide them towards the formation of branched tubular networks. We demonstrate that within the appropriate mix of hydrogels, normal rat cholangiocytes can proliferate, migrate and organize into branched tubular structures, form walls consisting of a cell monolayer, transport fluorescent dyes into the luminal space and show markers of epithelial maturation such as primary cilia. The resulting structures have dimensions typically found in the intralobular and intrahepatic bile ducts and are stable for weeks, without any requirement of bulk supporting material, thereby offering total access to the basal side of these biliary epithelial constructs.
Global distribution and diversity of alien Ponto-Caspian amphipods
Authors: Copilaș-Ciocianu Denis , Sidorov Dmitry , Šidagytė-Copilas Eglė 
Published: July 2021

AbstractThe Ponto-Caspian region is an important donor of aquatic alien species throughout the Northern Hemisphere, many of which are amphipod crustaceans. Despite decades of ongoing spread and negative effects on native biota, a complete picture of the global diversity and distribution of these amphipods has yet to emerge, hampering efficient monitoring and predictions of future invasions. Herein, we provide a comprehensive summary of alien species taxonomic and ecomorphological diversity, as well as high-resolution distribution maps and biogeographical patterns based on >8000 global records. We find that up to 39 species in 19 genera and five families, belonging to all four currently recognized ecomorphs, are potentially alien, their diversity gradually decreasing with distance from the native region. Most species (62%) have limited distributions, 15% are widespread, and 23% exhibit intermediate ranges. We also find that regions adjacent to the native areal are comparatively less well-sampled than more distant regions. Biogeographical clustering revealed three faunal provinces that largely correspond with the Southern, Central and Northern invasion corridors. We conclude that 1) alien amphipods are a representative subsample of the native Ponto-Caspian phylogenetic and ecomorphological diversity, and 2) that their biogeographical patterns are driven by anthropogenic factors acting on distinct native regional species pools.