Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function mutations in the DYSTROPHIN gene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of TGFß family of cytokines. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation of Smad8 transcription. However, the role of BMP4 in severely affected DMD skeletal muscle is unknown. We hypothesized that transcriptomic signatures in severely affected human DMD skeletal muscle are driven by BMP4 signaling. Transcriptomes from skeletal muscle biopsies of late-stage DMD vs. non-DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated by RNA-Seq and analyzed for single transcript differential expression as well as by Ingenuity Pathway Analysis and weighted gene co-expression network analyses. A total of 2,328 and 5,291 transcripts in the human muscle and C2C12 muscle cells, respectively, were differentially expressed. We identified an overlapping molecular signature of 1,027 genes dysregulated in DMD muscle that were induced in BMP4-stimulated C2C12 muscle cells. Highly upregulated DMD transcripts that overlapped with BMP4-stimulated C2C12 muscle cells included ADAMTS3, HCAR2, SERPING1, SMAD8 , and UNC13C. The DMD transcriptome was characterized by dysregulation of pathways involving immune function, extracellular matrix remodeling, and metabolic/mitochondrial function. In summary, we define a late-stage DMD skeletal muscle transcriptome that substantially overlaps with the BMP4-induced molecular signature in C2C12 muscle cells. This supports BMP4 as a disease-driving regulator of transcriptomic changes in late-stage DMD skeletal muscle and expands our understanding of the evolution of dystrophic signaling pathways and their associated gene networks that could be explored for therapeutic development.

Poly(ADP-ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation.

PARP-1 over-activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP-1 over-activation can bind hexokinase-1 (HK-1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK-1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose-6-phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK-1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR-mediated inhibition of HK-1 results in bioenergetics defects and redox imbalance is not known. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP-1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP-1 and adenoviral-mediated overexpression of wild-type HK-1 (wtHK-1) and PAR-binding mutant HK-1 (pbmHK-1). Our data show that PAR inhibition or overexpression of HK-1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK-1 during OGD drive bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function.

Association of Posttraumatic Stress Disorder and Race on Readmissions After Stroke.

BACKGROUND: There is limited research on outcomes of patients with posttraumatic stress disorder (PTSD) who also develop stroke, particularly regarding racial disparities. Our goal was to determine whether PTSD is associated with the risk of hospital readmission after stroke and whether racial disparities existed. METHODS: The analytical sample consisted of all veterans receiving care in the Veterans Health Administration who were identified as having a new stroke requiring inpatient admission based on the International Classification of Diseases codes. PTSD and comorbidities were identified using the International Classification of Diseases codes and given the date of first occurrence. The retrospective cohort data were obtained from the Veterans Affairs Corporate Data Warehouse. The main outcome was any readmission to Veterans Health Administration with a stroke diagnosis. The hypothesis that PTSD is associated with readmission after stroke was tested using Cox regression adjusted for patient characteristics including age, sex, race, PTSD, smoking status, alcohol use, and comorbidities treated as time-varying covariates. RESULTS: Our final cohort consisted of 93 651 patients with inpatient stroke diagnosis and no prior Veterans Health Administration codes for stroke starting from 1999 with follow-up through August 6, 2022. Of these patients, 12 916 (13.8%) had comorbid PTSD. Of the final cohort, 16 896 patients (18.0%) with stroke were readmitted. Our fully adjusted model for readmission found an interaction between African American veterans and PTSD with a hazard ratio of 1.09 ([95% CI, 1.00-1.20] P=0.047). In stratified models, PTSD has a significant hazard ratio of 1.10 ([95% CI, 1.02-1.18] P=0.01) for African American but not White veterans (1.05 [95% CI, 0.99-1.11]; P=0.10). CONCLUSIONS: Among African American veterans who experienced stroke, preexisting PTSD was associated with increased risk of readmission, which was not significant among White veterans. This study highlights the need to focus on high-risk groups to reduce readmissions after stroke.

Sensory Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Neglected Immunotherapy-Responsive Sensory Neuropathy.

BACKGROUND AND PURPOSE: To report an improvement with immunotherapy in 34 (85%)/40 patients who required an immunotherapy among 56 patients with sensory chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Sensory CIDP was diagnosed when two inclusion criteria are met: 1) acquired, chronic progressive or relapsing symmetrical or asymmetrical sensory polyneuropathy that had progressed for >2 months; and 2) definite electrophysiological and/or biopsy evidence of demyelinating neuropathy. RESULTS: Fifty-six patients with sensory CIDP were identified. Evidence of demyelination was obtained from by the routine motor nerve conduction study (NCS) in 39 (70%) patients, from a nerve biopsy in 10, and from a near-nerve needle sensory NCS in 7 patients. The most prominent laboratory abnormality was a high protein level in the cerebrospinal fluid in 21 (49%) of 43 tested patients. Immunotherapy was required in 41 (79%) of the 52 followed-up patients. An improvement with immunotherapy was observed in 36 (88%)/41 patients. In three patients, motor weakness developed in 5-8 years' follow-up period and so, their diagnosis was changed to CIDP. CONCLUSIONS: Sensory CIDP is responded to an immunotherapy in 88% of the treated patients. Sensory CIDP was diagnosed by the routine motor NCS in 70% of patients and by a sural nerve biopsy in 18% of patients. Thus, sensory CIDP should be recognized as a treatable CIDP variant among the different types of "idiopathic sensory neuropathy."

Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85-90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of "omics" technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis.

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

Evaluating childsmile, Scotland's National Oral Health Improvement Programme for children.

In the early 2000s, a Scottish Government Oral Health Action Plan identified the need for a national programme to improve child oral health and reduce inequalities. 'Childsmile' aimed to improve child oral health in Scotland, reduce inequalities in outcomes and access to dental services, and to shift the balance of care from treatment to prevention through targeted and universal components in dental practice, community and educational settings. This paper describes how an embedded, theory-based research and evaluation arm with multi-disciplinary input helps determine priorities and provides important strategic direction. Programme theory is articulated in dedicated, dynamic logic models, and evaluation themes are as follows: population-level data linkage; trials and economic evaluations; investigations drawing from behavioural and implementation science; evidence reviews and updates; and applications of systems science. There is also a growing knowledge sharing network internationally. Collaborative working from all stakeholders is necessary to maintain gains and to address areas that may not be working as well, and never more so with the major disruptions to the programme from the COVID-19 pandemic and response. Conclusions are that evaluation and research are synergistic with a complex, dynamic programme like Childsmile. The evidence obtained allows for appraisal of the relative strengths of component interventions and the reach and impact of Childsmile to feed into national policy.

Surface Characteristics and Bone Biocompatibility of Cold-Sprayed Porous Titanium on Polydimethylsiloxane Substrates.

A variant of the cold spray (CS) technique was applied for the functionalization of polymer-based materials such as polydimethylsiloxane (PDMS) to improve the extent of mammalian cell interactions with these substrates. This was demonstrated by the embedment of porous titanium (pTi) into PDMS substrates using a single-step CS technique. CS processing parameters such as gas pressure and temperature were optimized to achieve the mechanical interlocking of pTi in the compressed PDMS to fabricate a unique hierarchical morphology possessing micro-roughness. As evidenced by the preserved porous structure, the pTi particles did not undergo any significant plastic deformation upon impact with the polymer substrate. The thickness of the particle embedment layer was determined, by cross-sectional analysis, ranging from 120 µm to over 200 µm. The behavior of osteoblast-like cells MG63 coming into contact with the pTi-embedded PDMS was examined. The results showed that the pTi-embedded PDMS samples promoted 80-96% of cell adhesion and proliferation during the early stages of incubation. The low cytotoxicity of the pTi-embedded PDMS was confirmed, with cell viability of the MG63 cells being above 90%. Furthermore, the pTi-embedded PDMS facilitated the production of alkaline phosphatase and calcium deposition in the MG63 cells, as demonstrated by the higher amount of alkaline phosphatase (2.6 times) and calcium (10.6 times) on the pTi-embedded PDMS sample fabricated at 250 °C, 3 MPa. Overall, the work demonstrated that the CS process provided flexibility in the parameters used for the production of the modified PDMS substrates and is highly efficient for the fabrication of coated polymer products. The results obtained in this study suggest that a tailorable porous and rough architecture could be achieved that promoted osteoblast function, indicating that the method has promise in the design of titanium-polymer composite materials applied to biomaterials used in musculoskeletal applications.

MicroRNA-183-5p regulates TAR DNA-binding protein 43 neurotoxicity via SQSTM1/p62 in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively attacks motor neurons, and leads to progressive muscle weakness and death. A common pathological feature is the misfolding, aggregation, and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43) proteins in more than 95% of ALS patients, suggesting a universal role TDP-43 proteinopathy in ALS. Mutations in SQSTM1/p62 have been identified in familial and sporadic cases of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate their target genes. Emerging evidence indicates that miRNA dysregulation is associated with neuronal toxicity and mitochondrial dysfunction, and also plays a pivotal role in ALS pathogenesis. Here, we report the first evidence that miR-183-5p is aberrantly upregulated in spinal cords of patients with ALS. Using luciferase reporter assays and miR-183-5p agomirs, we demonstrate that miR-183-5p regulates the SQSTM1/p62 3'-untranslated region to suppress expression. A miR-183-5p agomir attenuated SOSTM1/p62 expression and led to an increase in TDP-43 protein levels in neuronal and non-neuronal cells. In contrast, a miR-183-5p antagomir decreased TDP-43 but increased SQSTM1/p62 protein levels. The antagomir repressed formation of stress granules and aggregated TDP43 protein in neuronal cells under stress-induced conditions and protected against cytotoxicity. Knockdown of SQSTM1/p62 decreased total ubiquitination and increased TDP-43 protein aggregation, indicating that SQSTM1/p62 may play a protective role in cells. In summary, our study reveals a novel mechanism of TDP-43 proteinopathy mediated by the miR-183-5p and provides a molecular link between aberrant RNA processing and protein degradation, two major pillars in ALS pathogenesis.

RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders.

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1ß, TNF-α, iNOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine- and uridine-rich element (ARE) which is present in the 3' untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH- type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs.

Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in many diseases. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS compared to normal individuals. By RT-qPCR analysis, we confirmed that 8 circRNAs were significantly elevated and 10 were significantly reduced in ALS, while the linear mRNA counterparts, arising from shared precursor RNAs, generally did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1G93A). Interestingly, a subset of the circRNAs significantly elevated in ALS muscle biopsies were significantly reduced in the spinal cord samples from ALS patients and ALS (SOD1G93A) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.

Life-Long Steroid Responsive Familial Myopathy With Docking Protein 7 Mutation.

ABSTRACT: Docking protein 7 (DOK7) congenital myasthenic syndrome (CMS) is characterized by limb-girdle weakness and lack of fluctuating fatigability simulating many familial myopathies. Albuterol is the first line of therapy in view of consistent improvement. Two brothers with progressive predominant biceps weakness for 1-3 years responded to prednisone treatment for 40-50 years. Various studies including muscle biopsy and many laboratory studies were unsuccessful for the definite diagnosis. Gene study, 40 years after the initial evaluation, confirmed the diagnosis of DOK7 CMS. These are the first reported cases of DOK7 CMS associated with a sustained benefit from corticosteroids.

Targeting the TREM1-positive myeloid microenvironment in glioblastoma.

Background: Tumor cellular and molecular heterogeneity is a hallmark of glioblastoma and underlies treatment resistance and recurrence. This manuscript investigated the myeloid-derived microenvironment as a driver of glioblastoma heterogeneity and provided a pharmacological pathway for its suppression. Methods: Transcriptomic signatures of glioblastoma infiltrated myeloid-derived cells were assessed using R2: genomic platform, Ivy Glioblastoma Spatial Atlas, and single-cell RNA-seq data of primary and recurrent glioblastomas. Myeloid-derived cell prints were evaluated in five PDX cell lines using RNA-seq data. Two immunocompetent mouse glioblastoma models were utilized to isolate and characterize tumor-infiltrated myeloid-derived cells and glioblastoma/host cell hybrids. The ability of an inhibitor of HuR dimerization SRI42127 to suppress TREM1+-microenvironment and glioblastoma/myeloid-derived cell interaction was assessed in vivo and in vitro. Results: TREM1+-microenvironment is enriched in glioblastoma peri-necrotic zones. TREM1 appearance is enhanced with tumor grade and associated with poor patient outcomes. We confirmed an expression of a variety of myeloid-derived cell markers, including TREM1, in PDX cell lines. In mouse glioblastoma models, we demonstrated a reduction in the TREM1+-microenvironment and glioblastoma/host cell fusion after treatment with SRI42127. In vitro assays confirmed inhibition of cell fusion events and reduction of myeloid-derived cell migration towards glioblastoma cells by SRI42127 and TREM1 decoy peptide (LP17) versus control treatments. Conclusions: TREM1+-myeloid-derived microenvironment promulgates glioblastoma heterogeneity and is a therapeutic target. Pharmacological inhibition of HuR dimerization leads to suppression of the TREM1+-myeloid-derived microenvironment and the neoplastic/non-neoplastic fusogenic cell network.

High fidelity dialectical behaviour therapy online: Learning from experienced practitioners.

Dialectical behaviour therapy (DBT) is an effective treatment for borderline personality disorder and other problems underpinned by difficulties with emotional regulation. The main components of DBT are skills training groups and individual therapy. The COVID-19 outbreak forced a rapid adaptation to online delivery, which largely mirrored face-to-face programmes using videoconferencing technology. This study aimed to elicit and describe the experiences and learning of therapists involved in providing high-fidelity DBT programmes via the Australian DBT Institute, which established an online delivery platform called DBT Assist™ prior to the COVID-19 pandemic. The report conforms with the consolidated criteria for reporting qualitative research (COREQ). Seven therapists were interviewed. Data were transcribed and analysed thematically. Delivering skills training online, either exclusively or in hybrid form (with face-to-face individual therapy), was acceptable and even preferable to therapists and clients. It was considered safe, the programme was associated with few non-completers, and it improved the accessibility of DBT to those who might otherwise not be able to engage in a face-to-face programme. Skills training utilized a 'flipped-learning' approach which improved the efficiency of online delivery. Other unique and helpful features of the online programme were described. The best outcomes associated with online DBT are likely to be achieved through careful adaptation to the online environment in accord with the principles of DBT rather than mirroring face-to-face processes. Further research is required to determine the efficacy of online therapy relative to face-to-face, and who might be best suited to different modes of delivery.

Inhibition of the RNA Regulator HuR by SRI-42127 Attenuates Neuropathic Pain After Nerve Injury Through Suppression of Neuroinflammatory Responses.

Microglial activation with the production of pro-inflammatory mediators such as IL-6, TNF-α, and IL-1ß, is a major driver of neuropathic pain (NP) following peripheral nerve injury. We have previously shown that the RNA binding protein, HuR, is a positive node of regulation for many of these inflammatory mediators in glia and that its chemical inhibition or genetic deletion attenuates their production. In this report, we show that systemic administration of SRI-42127, a novel small molecule HuR inhibitor, attenuates mechanical allodynia, a hallmark of NP, in the early and chronic phases after spared nerve injury in male and female mice. Flow cytometry of lumbar spinal cords in SRI-42127-treated mice shows a reduction in infiltrating macrophages and a concomitant decrease in microglial populations expressing IL-6, TNF-α, IL-1ß, and CCL2. Immunohistochemistry, ELISA, and qPCR of lumbar spinal cord tissue indicate suppression of these cytokines and other inflammatory mediators. ELISA of plasma samples in the acute phase also shows attenuation of inflammatory responses. In summary, inhibition of HuR by SRI-42127 leads to the suppression of neuroinflammatory responses and allodynia after nerve injury and represents a promising new direction in the treatment of NP.

Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by skeletal muscle instability, progressive muscle wasting, and fibrosis. A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor ß (TGFß) signaling. In this report, we investigated the major transducers of TGFß signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 compared to total Smad indicating activation of this pathway. In parallel, we observed a profound diminishment of muscle-enriched microRNAs (myomiRs): miR-1, miR-133a, and miR-133b. The pattern of Smad8 induction and myomiR suppression was recapitulated in C2C12 muscle cells after stimulation with bone morphogenetic protein 4 (BMP4), a signaling factor that we found upregulated in DMD muscle. Silencing Smad8 in C2C12 myoblasts derepressed myomiRs and promoted myoblast differentiation; there was also a concomitant upregulation of myogenic regulatory factors (myogenin and myocyte enhancer factor 2D) and suppression of a pro-inflammatory cytokine (interleukin-6). Our data suggest that Smad8 is a negative regulator of miR-1, miR-133a, and miR-133b in muscle cells and that the BMP4-Smad8 axis is a driver of dystrophic pathology in DMD.

Towards online delivery of Dialectical Behaviour Therapy: A scoping review.

Dialectical Behaviour Therapy (DBT) programmes are often the only available treatment for people diagnosed with borderline personality disorder and were rapidly converted to online delivery during the COVID-19 pandemic. Limited research exists surrounding how the major elements of DBT are delivered in an online environment. This scoping review considered the operationalization of online delivery of DBT and its effectiveness. EBSCO host databases were searched using free text. Of 127 papers, 11 studies from 2010 to 2021 investigating online DBT for any clinical population were included in the review. A narrative synthesis of papers selected was undertaken. Seven articles reported results from five clinical trials (n = 437). Most adaptations mirrored face-to-face programmes although there was considerable variation in how therapy was facilitated. Attendance was reported to be greater online with comparable clinical improvements to face-to-face for those who remained in therapy. Additional challenges included managing risk, therapist preparedness and technology difficulties. Online delivery of DBT programmes is feasible and may be more accessible, acceptable and as safe and effective as face-to-face delivery. However, mirroring face to face delivery in an online environment may not be the most effective and efficient way to adapt DBT to online provision. Research is needed to identify areas which require further adaptation.

A Neuroscience Primer for Integrating Geroscience With the Neurobiology of Aging.

Neuroscience has a rich history of studies focusing on neurobiology of aging. However, much of the aging studies in neuroscience occur outside of the gerosciences. The goal of this primer is 2-fold: first, to briefly highlight some of the history of aging neurobiology and second, to introduce to geroscientists the broad spectrum of methodological approaches neuroscientists use to study the neurobiology of aging. This primer is accompanied by a corresponding geroscience primer, as well as a perspective on the current challenges and triumphs of the current divide across these 2 fields. This series of manuscripts is intended to foster enhanced collaborations between neuroscientists and geroscientists with the intent of strengthening the field of cognitive aging through inclusion of parameters from both areas of expertise.

SRI-42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation.

Glial activation with the production of pro-inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro-inflammatory mediators contain adenine- and uridine-rich elements (ARE) in the 3' untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI-42127, that blocks this process. Here we show that SRI-42127 suppressed HuR translocation in LPS-activated glia in vitro and in vivo and significantly attenuated the production of pro-inflammatory mediators including IL1ß, IL-6, TNF-α, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti-inflammatory effects including TGF-ß1, IL-10, YM1, and Arg1 were either unaffected or minimally affected. SRI-42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI-42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors for treating neurological diseases driven by this activation.

The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack.

Glioblastoma (GBM) is a malignant and aggressive brain tumor with a median survival of ∼15 months. Resistance to treatment arises from the extensive cellular and molecular heterogeneity in the three major components: glioma tumor cells, glioma stem cells, and tumor-associated microglia and macrophages. Within this triad, there is a complex network of intrinsic and secreted factors that promote classic hallmarks of cancer, including angiogenesis, resistance to cell death, proliferation, and immune evasion. A regulatory node connecting these diverse pathways is at the posttranscriptional level as mRNAs encoding many of the key drivers contain adenine- and uridine rich elements (ARE) in the 3' untranslated region. Human antigen R (HuR) binds to ARE-bearing mRNAs and is a major positive regulator at this level. This review focuses on basic concepts of ARE-mediated RNA regulation and how targeting HuR with small molecule inhibitors represents a plausible strategy for a multi-pronged therapeutic attack on GBM.