The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in smarca5 mutants. Together, our study using zebrafish smarca5 mutants characterizes a novel role for smarca5 in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.

The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

Although thrombosis has been extensively studied using various animal models, however, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus that mimics venous thrombosis. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the venous thrombosis-like phenotypes in smarca5 mutants. Together, our study using zebrafish smarca5 mutants not only characterizes a novel role for smarca5 in blood clot formation, but also provides a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.

Rehabilitation assessments conducted via telerehabilitation for neurological populations: a scoping review protocol (Preprint)

BACKGROUND The COVID-19 global pandemic pushed many rehabilitation practitioners to pivot their in-person practice to adopt telerehabilitation as their main method of delivery. In addition to documenting information on interventions used with clients, it is best practice for therapists to use reliable and validated outcome measures to inform their interventions. OBJECTIVE Through this scoping review, we aim to identify: 1) which outcomes are being used remotely to assess balance, mobility, and gait in patients with neurological conditions, and 2) what psychometric data (validity, reliability, etc.) for remotely-administered outcomes are available. METHODS Three main concepts will be included in our search: 1) neurological conditions, 2) administration by telerehabilitation and 3) outcome measures for balance, mobility and gait. Studies reporting remote assessment of neurological conditions published since 1990 will be included. The database search will be completed in Medline (Ovid), CINAHL, Pubmed, PSychINFO, EMBASE, and Cochrane. Grey literature including dissertations, conference papers and protocol papers will also be sourced. Two reviewers will independently screen each title and abstract using pre-established inclusion and exclusion criteria. Manuscripts which appear to meet the criteria will be subject to further review, and full text extraction using a pre-piloted extraction sheet if all criteria are met. The data will be categorized by assessment types describing impairments (such as balance, strength and mobility) or activity limitations or participation restriction (such as functional mobility, ambulatory functions, and activity of daily living). RESULTS The optimal use of telerehabilitation as a mode to deliver rehabilitation intervention should be coupled with the completion of validated outcome measures. Therefore, it is crucial to further our knowledge on remote outcome measures and therapeutic assessments. CONCLUSIONS This scoping review will document outcome measures currently used in the remote assessment of neurological conditions.

Viroinformatics-Based Analysis of SARS-CoV-2 Core Proteins for Potential Therapeutic Targets

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus for which no known effective antiviral drugs are available. In the present study, to accelerate the discovery of potential drug candidates, bioinformatics-based in silico drug discovery approaches are utilized. We performed multiple sequence alignments of the Spike (S) protein with 75 sequences of different viruses from the Orthocoronavirinae subfamily. This provided us with insights into the evolutionarily conserved domains that can be targeted using drugs or specific antibodies. Further, we analyzed the mechanism of SARS-CoV-2 core proteins, i.e., S and RdRp (RNA-dependent RNA polymerase), to elucidate how the virus infection can utilize hemoglobin to decrease the blood oxygen level. Moreover, after a comprehensive literature survey, more than 60 antiviral drugs were chosen. The candidate drugs were then ranked based on their potential to interact with the Spike and RdRp proteins of SARS-CoV-2. The present multidimensional study further advances our understanding of the novel viral molecular targets and potential of computational approaches for therapeutic assessments. The present study can be a steppingstone in the selection of potential drug candidates to be used either as a treatment or as a reference point when designing a new drug/antibody/inhibitory peptide/vaccine against SARS-CoV-2.

In vivo visualization of propagating α-synuclein pathologies in mouse and marmoset models by a bimodal imaging probe, C05-05

SUMMARYDeposition of intracellular α-synuclein fibrils is implicated in neurodegenerative parkinsonian disorders, while high-contrast in vivo detection of α-synuclein depositions has been unsuccessful in animal models and humans. Here, we have developed a bimodal imaging probe, C05-05, for visualizing α-synuclein inclusions in the brains of living animals modeling α-synuclein propagation. In vivo optical and PET imaging of a mouse model demonstrated sensitive detection of α-synuclein aggregates by C05-05, revealing a dynamic propagation of fibrillogenesis along neural pathways followed by disruptions of these structures. Moreover, longitudinal 18F-C05-05-PET of a marmoset model captured widespread dissemination of fibrillary pathologies accompanied by neurodegeneration detected by dopamine transporter PET. In addition, in vitro assays demonstrated the high-affinity binding of 18F-C05-05 to α-synuclein versus other protein pathologies in human brain tissues. Collectively, we propose a new imaging technology enabling etiological and therapeutic assessments of α-synuclein pathogenesis at nonclinical levels, highlighting the applicability of C05-05 to clinical PET.

The Rorschach As a Window Into Past Traumas During Therapeutic Assessment

In this article, the authors discuss how the Rorschach can be useful in certain Therapeutic Assessments (TAs) by creating an opening for clients to report and discuss past traumatic events that have not previously been resolved. Two case examples are presented. In the first, a 31-year-old woman sought psychological help to understand why she was so afraid all the time, why she did not know what was best for her, and why she was so influenced by others’ opinions. The client saw many disturbing percepts in the Rorschach and was very unsettled afterward. During an extended inquiry she revealed an extensive history of physical and sexual abuse that she had put out of her mind and never told anyone about previously. Talking about her trauma with the assessor helped her understand why she was struggling. In the second case, a 35-year-old woman experienced a flashback when presented with Card X to finding her father after his suicide when she was 8 years old. The client had not previously recalled the details of this event, which were verified by family members. Retrieving this memory helped the client understand her family better and resolve problems she had in her adult romantic relationships. We believe there are essential elements that permit such therapeutic events to occur: (1) the power of the Rorschach to access split-off affects and memories, (2) the secure relationship created in TA that allows for traumatic material to emerge safely, (3) the technique of scaffolding in TA that helps locate clients’ growing edge, and (4) how client–assessor collaboration creates an intersubjective field in which nonlinear healing events may occur.

Self-cartography within migrants and refugees: a tool for resilience?

Purpose Meta-analyses indicate that migrants and refugees develop more mental health problems than the general population as a result of their exposure to armed conflict, violence and torture together with their experiences prior to, during and after resettlement. The purpose of this paper is to experience a tool that allows analysing how migrants and refugees represent the world and how they self-represent in the world. Design/methodology/approach The aim is to design a projective tool called “Self Cartography” to facilitate the production of migration stories, based on narratives. Findings The self-cartography tool revealed the psychological suffering generated by the brutality and violence of exile. The narratives about the pre-migratory phase appear to be more complex and more painful than the migratory and post-migratory phases. Research limitations/implications The preliminary interviews in the exploratory phase have raised certain methodological biases, such as the size of the map, which is currently in A2 format. It was described by some participants as being too large and a source of anxiety. Practical implications The purpose of this work is to conceptualise a standardised projective tool that can be used by researchers and professionals responsible for making therapeutic assessments and supporting individuals in migration situations. Social implications This tool aims to facilitate better social integration for migrants and refugees. Originality/value The self-cartography tool opens up the boundaries of narrativity in a geo-temporal space shared with the clinician. Using the world as a means to self-narrate can be thought of as an attempt to rewrite the collective and individual traumatic histories of our humanity.

A multi-site survey of forensic nursing assessment

Purpose A major difficulty identified many years ago in psychiatric care is the shortage of appropriate instruments with which to carry out valid and reliable therapeutic assessments which are behaviourally based and therefore appropriate for use in a variety of contexts. The aim of this project was to ascertain the utility of a forensic nursing risk assessment tool - Behavioural Status Index (BEST-Index). The paper aims to discuss these issues. Design/methodology/approach A multi-site cross-sectional survey was undertaken using mixed method design. Quantitative data was generated using BEST-Index to allow comparisons across three different levels of security (high, medium and low) in Scotland and Ireland. Qualitative data were gathered from patients and multi-disciplinary team (MDT) members using semi-structured interviews and questionnaire. Findings Measured over an 18-month period, there was a statistically significant improvement in behaviour, when comparing patients in high and medium secure hospitals. Two key themes emerged from patient and staff perspectives: “acceptance of the process” and “production and delivery of information”, respectively. The wider MDT acknowledge the value of nursing risk assessment, but require adequate information to enable them to interpret findings. Collaborating with patients to undertake risk assessments can enhance future care planning. Research limitations/implications Studies using cross-section can only provide information at fixed points in time. Practical implications The BEST-Index assessment tool is well established in clinical practice and has demonstrated good utility. Originality/value This project has served to highlight the unique contribution of BEST-Index to both staff and patients alike and confirm its robustness and versatility across differing levels of security in Scottish and Irish forensic mental health services.