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Huntington’s disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients’ fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC 50 consistently below 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients’ fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models. Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington’s disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.

Distal radius fractures (DRF) and ulnar neuropathy (UNE) present with reduced motor function, restricted range of motion, pain, and reduced grip strength that may lead to similar treatment approaches. With rapid and insidious onset for DRF and UNE, respectively, the contextual factors impacting an individuals’ experience with the condition can vary. The aim of this secondary analysis is to compare ratings of quality of life (QoL) domains prior to treatment and 3 months post treatment for DRF and UNE. This is a retrospective cohort study conducted at the Roth McFarlane Hand and Upper Limb Centre. 36-Item Short Form Survey (SF-36) data from 781 patients treated nonoperatively for DRF, operatively for DRF, or operatively for UNE was extracted from the Hand and Upper Limb Centre database. Group differences for the eight SF-36 domains were calculated using analysis of covariance (ANCOVA) with sex as a covariate. Differences from prior to treatment to 3 months post were assessed using separate repeated measures ANCOVA (RM-ANCOVA) with sex as a covariate. Nonoperative DRF, operative DRF, and operative UNE groups reported 8%-11% improvements in QoL domains at 3 months follow-up despite some persisting impairments for physical domains. Prior to treatment, the DRF patients report greater impairments for physical domains, while the UNE patients managed operatively reported greater impairments to psychosocial domains. Operatively managed DRF patients report greater physical and psychosocial impairments than those conservatively treated. Males report less severe impairments for physical and psychosocial domains than females. Assessing QoL domains for two upper extremity conditions with different contextual factors provides insight into the implications of those factors on QoL. Incorporating early screening and continual monitoring of QoL domains impacted by upper extremity conditions like DRF and UNE could help identify factors impacting prognosis and direct the focus of treatment to improve outcomes at 3 months. •DRF_op, DRF_c, and UNE_op groups report 8%-11% improvements in quality of life domains at 3 months follow-up despite some persisting impairments for physical domains.•Prior to treatment, the DRF patients report greater impairments for physical domains, while UNE_op patients report greater impairments to psychosocial domains.•Operatively managed DRF patients report greater physical and psychosocial impairments than those conservatively treated DRF.•Males report less severe impairments for physical and psychosocial domains than females for DRF and UNE.

Introduction: Mirror therapy (MT) and neuromuscular electrical stimulation (NMES) are interventions that mitigate impairments in pain, strength, range of motion (ROM), and function. Immobilization to treat distal radius fractures (DRF) can result in similar impairments. MT and NMES can be applied during immobilization for DRF as they do not require active movement of the affected extremity. This is the study to investigate the feasibility of in-home MT, NMES, MT+NMES interventions during the immobilization period for DRF. Methods: Literature reviews were conducted to determine how NMES and MT have been used with musculoskeletal conditions. In-home MT, NMES, and MT+NMES interventions were developed for application during immobilization for DRF. A feasibility RCT was implemented to assess recruitment, adherence to interventions, retention to on-site visits, and limited efficacy testing. Semi-structured interviews were conducted 6-weeks post-DRF to gain insight into the patients perspective, the practicality and acceptability of the interventions. Pain, ROM, dexterity, function, and strength were measured at 3-, 6-, 8-, and 12- weeks post-DRF at the on-site visits. Electromyographic recordings were collected during contractions for wrist movements at 8- and 12-weeks to investigate potential mechanisms of change. Results: MT and NMES can help reduce pain, improve function and strength for after periods of disuse. In-home MT, NMES, and MT+NMES interventions that are 10-minute sessions, three times a day, five days a week for the last three weeks of immobilization for DRF were developed. The in-home interventions demonstrate adequate feasibility at this interim analysis with an average of 5 participants recruitment per month, >80% adherence, and >80% retention for the intervention group and 75% retention for the control group. Limited efficacy testing demonstrates trends towards improvement for the intervention groups. Patients expressed the practicality and acceptance of the interventions. Participants attributed their recovery and facilitated outcomes to their participation in the study. iii Discussion: Engaging in early interventions for DRF during immobilization appear feasible at this interim analysis. The full feasibility sample is required to determine whether the protocol can be implemented in a full RCT as it is or requiring modifications.

Mirror therapy is an effective intervention for improving outcomes when an affected extremity has severe movement restrictions or pain. To investigate the effects of mirror therapy interventions on musculoskeletal injuries of the hand/wrist. Systematic review. This systematic review was conducted in accordance with Cochrane and PRISMA guidelines and registered with Open Science Framework (DOI:XXX). The search was conducted in EMBASE, PubMed, and Scopus in April 2024. Search terms included hand and wrist injuries, mirror therapy, pain, range of motion, strength, and function. Descriptive synthesis was used to summarize the data for interventions and outcomes. The Cochrane RoB 2 tool was used for quality assessment. Samples ranged from 22 to 40 participants with a total of 220 participants. Five studies combined mirror therapy with active exercise and had comparator groups performing active exercises for the same duration. Mirror therapy intervention ranged from 20 to 75 minutes per session, two to five times a week for 3-8weeks. Mirror therapy interventions reduced pain, improved range of motion, strength, and function in most studies. Greater improvements for the mirror therapy groups than the comparator group were reported for pain, range of motion, and function in 20%-75% of the studies. Risk assessment for the seven studies resulted in one high, four moderate, and two low quality studies. Moderate quality evidence suggests that mirror therapy interventions may be effective at reducing pain, improving range of motion, strength and function for musculoskeletal hand and wrist injuries. Further investigation is warranted with larger trials with more homogenous interventions. •Mirror therapy (MT) may reduce pain after musculoskeletal (MSK) hand/wrist injuries•MT may improve strength and function after MSK hand/wrist injuries.•MT applied during immobilization may facilitate recovery for MSK hand/wrist injuries.

RNA splicing modulators are a new class of small molecules with the potential to modify the expression levels of proteins. A recent clinical trial investigating the splicing modulator branaplam for Huntington’s disease to lower huntingtin levels was terminated due to the development of peripheral neuropathy. Here, we describe how branaplam leads to this adverse effect. On a cellular level, branaplam disrupts neurite integrity reflected by elevated neurofilament light chain levels in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN). Branaplam does not target neuropathy-associated genes. However, transcription factor binding site enrichment analysis indicates p53 activation. P53 activation upon branaplam treatment in iPSC-MN is linked to increased nucleolar stress, thereby enhanced expression of the neurotoxic p53-target gene BBC3. These findings illustrate that RNA splicing modulators may have clinically relevant off-target effects, implying the necessity of comprehensive pre-screening in human models prior to executing clinical trials. Predicting side effects of RNA splicing modulator branaplam leading to neurotoxicity via nucleolar stress, p53 activation, and axonal degeneration.

Abstract Objective Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. Research Design and Methods We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial. Results In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin. Conclusions This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.

For years we have investigated the presence and molecular evolution of tuberculosis in Pre Dynastic and Early Dynastic Egyptian mummy material from Abydos (c. 3500-2800 BC), Middle and New Kingdom until the Late Period in Thebes-West (c. 2050 – 500 BC). We have analysed 160 bone and soft tissue samples from different time periods and populations for the occurrence of M. tuberculosis complex DNA. All positive specimens were genetically characterised by spoligotyping and mutation analysis. Molecular analyses revealed excellent state of preservation of the specimens. Research showed a high incidence of M. tuberculosis during all time periods. We further detected specific MTB strain differences with M. africanum in some of the Middle Kingdom samples and “modern” M. tuberculosis strains in the New Kingdom to Late Period material. These results demonstrate that aDNA is excellently preserved in ancient Egyptian mummies allowing the reconstruction of occurrence, frequency, molecular evolution and spread of tuberculosis in Pharaonic populations.