Glial progenitor heterogeneity and key regulators revealed by single-cell RNA sequencing provide insight to regeneration in spinal cord injury.

Recent studies have revealed the heterogeneous nature of astrocytes; however, how diverse constituents of astrocyte-lineage cells are regulated in adult spinal cord after injury and contribute to regeneration remains elusive. We perform single-cell RNA sequencing of GFAP-expressing cells from sub-chronic spinal cord injury models and identify and compare with the subpopulations in acute-stage data. We find subpopulations with distinct functional enrichment and their identities defined by subpopulation-specific transcription factors and regulons.

Low cost circulatory pressure acquisition and fluid infusion rate measurement system for clinical research.

Acquiring patient physiological waveforms is useful for studying hemodynamic management and developing medical monitoring systems. A low cost, Arduino controlled data acquisition system acquires arterial pressure waveforms (Edwards Lifesciences TruWave compatible) and measures fluid infusion rate using hanging scales. This system can be used at the same time as a clinical monitor, enabling recording of patient arterial pressure and fluid delivery for clinical research.

A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer's Disease Transgenic Mice.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns.

Why having a voice is important to children who are involved in family support services.

Background: Having a voice in family matters is considered a protective factor from harm, and key to promoting children's wellbeing. However, since the adoption of the United Nations Convention on the Rights of the Child (1989) and specifically Article 12 pertaining to children's participation, research reveals that children's voices often remain invisible in child protection and family welfare services.

Objective: While there is renewed interest in hearing children's voices about their experiences in out-of-home care, there remains little awareness and knowledge of children's voices in family support services.

Traumatic brain injury modifies synaptic plasticity in newly-generated granule cells of the adult hippocampus.

The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent studies have found that TBI induces enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus, and this cellular response is related to innate cognitive recovery. However, cellular mechanisms of the role of DG neurogenesis in post-TBI recovery remain unclear.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies.

Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.

Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1.

Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.

Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1.

Discussing sudden unexpected death in epilepsy with children and young people with epilepsy and their parents/carers: A mixed methods systematic review.

Purpose: To synthesise the quantitative and qualitative evidence on the views and experiences of children and young people with epilepsy (CYPwE), their family members/caregivers and healthcare professionals on conversations between healthcare professionals and CYPwE/caregivers about the possibility of sudden unexplained death in epilepsy (SUDEP).

Methods: Mixed methods systematic review in accordance with Joanna Briggs Institute methodology, PRISMA guidelines and guided by an a-priori protocol.

Results: 656 potentially relevant studies were identified, 11 of which fulfilled the inclusion criteria for the review: 6 quantitative studies, 4 qualitative studies and 1 opinion/text article.

The R882H DNMT3A hot spot mutation stabilizes the formation of large DNMT3A oligomers with low DNA methyltransferase activity.

DNMT3A (DNA methyltransferase 3A) is a DNA methyltransferase responsible for establishing CpG methylation patterns within the genome. DNMT3A activity is essential for normal development, and its dysfunction has been linked to developmental disorders and cancer. DNMT3A is frequently mutated in myeloid malignancies with the majority of mutations occurring at Arg-882, where R882H mutations are most frequent.

A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury.

Background: Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1β and IL-18, and induction of cell death (pyroptosis).

Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury.

The clearance of damaged myelin sheaths is critical to ensure functional recovery from neural injury. Here we show a previously unidentified role for microvessels and their lining endothelial cells in engulfing myelin debris in spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). We demonstrate that IgG opsonization of myelin debris is required for its effective engulfment by endothelial cells and that the autophagy-lysosome pathway is crucial for degradation of engulfed myelin debris.

Chronic Kidney Disease, Queensland (CKD.QLD) Registry: Management of CKD With Telenephrology.

Introduction: Enabled by the Chronic Kidney Disease, Queensland (CKD.QLD) Registry, we aim to outline the structure, implementation, and outcomes of telenephrology clinics for the management of patients with chronic kidney disease (CKD) in rural, regional, and remote areas of the Darling Downs region in Queensland, Australia.

Methods: This is an observational registry-based study involving adult patients with CKD, attending specialist clinics, and residing ≥50 km away from Toowoomba Hospital.

Genetic screen in myeloid cells identifies TNF-α autocrine secretion as a factor increasing MDSC suppressive activity via Nos2 up-regulation.

The suppressive microenvironment of tumors remains one of the limiting factors for immunotherapies. In tumors, the function of effector T cells can be inhibited by cancer cells as well as myeloid cells including tumor associated macrophages and myeloid-derived suppressor cells (MDSC). A better understanding of how myeloid cells inhibit T cell function will guide the design of therapeutic strategies to increase anti-tumor responses.

An hPSC-Derived Tissue-Resident Macrophage Model Reveals Differential Responses of Macrophages to ZIKV and DENV Infection.

Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses that lead to different clinical outcomes. The mechanism for the distinct pathogenesis of ZIKV and DENV is poorly understood. Here, we investigate ZIKV and DENV infection of macrophages using a human pluripotent stem cell (hPSC)-derived macrophage model and discover key virus-specific responses.

Structural Insights of Benzenesulfonamide Analogues as NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

NLRP3 inflammasome plays critical roles in a variety of human diseases and represents a promising drug target. In this study, we established the in vivo functional activities of JC124, a previously identified NLRP3 inflammasome inhibitor from our group, in mouse models of Alzheimer's disease and acute myocardial infarction. To understand the chemical space of this lead structure, a series of analogues were designed, synthesized, and biologically characterized.

In Vitro Phagocytosis of Myelin Debris by Bone Marrow-Derived Macrophages.

Bone marrow-derived macrophages (BMDMs) are mature leukocytes that serve a critical physiological role as professional phagocytes capable of clearing a variety of particles. Normally, BMDMs are restricted from the central nervous system (CNS), but following an injury, they can readily infiltrate. Once within the injured CNS tissue, BMDMs are the primary cell type responsible for the clearance of injury-derived cellular debris, including large quantities of lipid rich myelin debris.

Patient and Provider Perspectives on a Mind-Body Program for Grieving Older Adults.

Background: Spousal bereavement in older age is a major stressor associated with an increase in both mental and physical problems. The Stress Management and Resiliency Training: Relaxation Response Resiliency Program (SMART-3RP) is an 8-week multimodal mind-body program that targets stress and has been found efficacious in decreasing the mental and physical manifestations of stress in varied populations. This qualitative study sought to investigate the relevance, credibility, and feasibility of the SMART-3RP in the community.

Synthesis of High-Load, Hybrid Silica-Immobilized Heterocyclic Benzyl Phosphate (Si-OHBP) and Triazolyl Phosphate (Si-OHTP) Alkylating Reagents.

The development of new ROMP-derived silica-immobilized heterocyclic phosphate reagents and their application in purification-free protocols is reported. Grafting of norbornenyl norbornenyl-functionalized (Nb-tagged) silica particles with functionalized Nb-tagged heterocyclic phosphate monomers efficiently yield high-load, hybrid silica-immobilized oligomeric heterobenzyl phosphates (Si-OHBP) and heterotriazolyl phosphates (Si-OHTP) as efficient alkylation agents. Applications of these reagents for the diversification of N-, O-, and S-nucleophilic species, for efficient heterobenzylation and hetero(triazolyl)methylation have been validated.

Bioinformatic analysis reveals the expression of unique transcriptomic signatures in Zika virus infected human neural stem cells.

Background: The single-stranded RNA Flavivirus, Zika virus (ZIKV), has recently re-emerged and spread rapidly across the western hemisphere's equatorial countries, primarily through Aedes mosquito transmission. While symptoms in adult infections appear to be self-limiting and mild, severe birth defects, such as microcephaly, have been linked to infection during early pregnancy. Recently, Tang et al.

Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media.

Background: Macrophages play an important role in the inflammatory responses involved with spinal cord injury (SCI). We have previously demonstrated that infiltrated bone marrow-derived macrophages (BMDMs) engulf myelin debris, forming myelin-laden macrophages (mye-Mϕ). These mye-Mϕ promote disease progression through their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells.