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Abstract: Up to a third of patients with hemato-oncologic conditions who have received multiply transfusions develop immune-mediated platelet transfusion refractoriness. Yet factors that influence posttransfusion platelet corrected count increments (CCI) in patients with HLA-alloimmune platelet transfusion refractoriness remain less well elucidated. Recent advances in HLA antibody characterization using fluorescent bead-based platforms enable the study of donor-specific antibody (DSA) avidity (as measured by mean fluorescence intensity [MFI]) and its impact on HLA-alloimmune platelet transfusion refractoriness. In this large retrospective study of 2012 platelet transfusions among 73 HLA-alloimmunized patients, we evaluated the impact of cumulative HLA DSA-MFI alongside other donor, platelet component, and patient characteristics on CCI at 2 and 24 hours after transfusion. As part of a quality improvement initiative, we also developed and tested a computerized algorithm to optimize donor-recipient histocompatibility based on cumulative DSA-MFI and sought other actionable predictors of CCI. In multivariate analyses, cumulative HLA DSA-MFI of ≥10 000, major/bidirectional ABO-mismatch, splenomegaly, transfusion reactions, and platelet storage in additive solution negatively affected 2-hour but not 24-hour posttransfusion CCI. The DSA-MFI threshold of 10 000 was corroborated by greater antibody-mediated complement activation and significantly more CCI failures above this threshold, suggesting the usefulness of this value to inform "permissive platelet mismatching" and to optimize CCI. Furthermore, DSA-MFI decreases were deemed feasible by the computer-based algorithm for HLA-platelet selection in a pilot cohort of 8 patients (122 transfusions) evaluated before and after algorithm implementation. When HLA-selected platelets are unavailable, ABO-identical/minor-mismatched platelet concentrates may enhance 2-hour CCI in heavily HLA-alloimmunized patients with platelet transfusion refractoriness., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABA A /GABA B receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic's early stages severely impacted global fisheries, particularly areas heavily reliant on imported food and tourism like the Galapagos Islands, Ecuador. To contain the spread of the virus, a full lockdown was implemented. However, the collapse of the tourism industry precipitated the worst economic crisis in the history of this multiple-use marine protected area. This paper examines the impact of the pandemic's early stages on consumption patterns and seafood security in the Galapagos from consumers' perspective, drawing on online surveys conducted during the lockdown. Our findings revealed pre-existing seafood insecurity across the archipelago, further exacerbated by the pandemic on the least-populated island. Nevertheless, the seafood system displayed moderated resilience to the pandemic's socioeconomic disruptions. A variety of adaptive responses were adopted by Galapagos residents to cope with the lockdown. Consumers modified their seafood consumption habits, while fishers adapted their harvesting and marketing strategies. Such adaptive responses were shaped by the unique socioeconomic characteristics of each inhabited island and the ability of seafood suppliers to shift from a tourism- and export-oriented to a resident- and domestic-oriented market. This transition has created novel opportunities to foster a systemic transformation of the Galapagos seafood system to enhance its resilience against future crises caused by new pandemics, climate change, or other natural and anthropogenic drivers of change., (© 2024. The Author(s).)

Prior physical activity reduces the risk of future stress-related mental health disorders including depression, anxiety, and post-traumatic stress disorder. Rodents allowed to engage in voluntary wheel running are similarly protected from behavioral consequences of stress. The present review summarizes current knowledge on mechanisms underlying exercise-induced stress resistance. A conceptual framework involving the development (during exercise) and expression (during stress) of stress resistance from exercise is proposed. During the development of stress resistance, adaptations involving multiple exercise signals and molecular mediators occur within neural circuits orchestrating various components of the stress response, which then respond differently to stress during the expression of stress resistance. Recent data indicate that the development and expression of stress resistance from exercise involve multiple independent mechanisms that depend on sex, stressor severity, and behavioral outcome. Recent insight into the role of the prefrontal cortex in exercise-induced stress resistance illustrates these multiple mechanisms. This knowledge has important implications for the design of future experiments aimed at identifying the mechanisms underlying exercise-induced stress resistance., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Common stress-related mental health disorders affect women more than men. Physical activity can provide protection against the development of future stress-related mental health disorders (i.e. stress resistance) in both sexes, but whether there are sex differences in exercise-induced stress resistance is unknown. We have previously observed that voluntary wheel running (VWR) protects both female and male rats against the anxiety- and exaggerated fear-like behavioral effects of inescapable stress, but the time-course and magnitude of VWR-induced stress resilience has not been compared between sexes. The goal of the current study was to determine whether there are sex differences in the time-course and magnitude of exercise-induced stress resistance. In adult female and male Sprague Dawley rats, 6 weeks of VWR produced robust protection against stress-induced social avoidance and exaggerated fear. The magnitude of stress protection was similar between the sexes and was independent of reactivity to shock, general locomotor activity, and circulating corticosterone. Interestingly, 3 weeks of VWR prevented both stress-induced social avoidance and exaggerated fear in females but only prevented stress-induced social avoidance in males. Ovariectomy altered wheel-running behavior in females such that it resembled that of males, however; 3 weeks of VWR still protected females against behavioral consequences of stress regardless of the absence of ovaries. These data indicate that female Sprague Dawley rats are more responsive to exercise-induced stress resistance than are males.

Background: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA., Methods: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete., Findings: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose., Interpretation: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed., Funding: Ionis Pharmaceuticals, Biogen., Competing Interests: Declaration of interests CFB, LM, DAN, and SX are employees of Ionis Pharmaceuticals, which funded the trial, and own stock options in Ionis Pharmaceuticals. CAT received support from Ionis Pharmaceuticals for consultation and sponsored research and carried out collaborative research with CFB under National Institutes of Health (NIH) grant U01NS072323; provides consulting to Biogen, Vertex, Entrada, and Avidity Biosciences; received honoraria from Sanofi; served on scientific advisory boards for Dyne and Pepgen; and serves on the Myotonic Dystrophy Foundation Board. KE received consulting fees from Ionis Pharmaceuticals, Avidity, and Dyne Therapeutics; and received honoraria from the Myotonic Dystrophy Foundation and the Muscular Dystrophy Association. CH receives royalties for the use of multiple disease specific instruments; provided consultation to Biogen, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation; and receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Neurocrine Biosciences, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. WDA received a consulting fee and grant funding from Avidity Biosciences and a consulting fee from Dyne Therapeutics. TA received a grant or contract from the Myotonic Dystrophy Foundation and was on the Myotonic Dystrophy Foundation scientific advisory board. JWD received consulting fees from Affinia Therapeutics and Shift Therapeutics; honoraria from Biogen and Roche Pharmaceuticals; participated in advisory boards for AMO Pharmaceuticals, Avidity Biosciences, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, and Vertex Pharmaceuticals; has leadership roles for Muscular Dystrophy Association, Myotonic Dystrophy Foundation, and Cure Congenital Muscular Dystrophy. GD is an employee of Biogen and owns stock options in Biogen. TD received consulting fees from Dyne, Roche/Genentech Pharmaceuticals, Biogen, Trinds, and ATOM; speaking honoraria for Genentech, Biogen, Roche, and Sarepta; has served on Advisory boards for Novartis, Pfizer, Actigraph, Scholar Rock, Sarepta, Sanofi Genzyme, and Cytokinetics; has unpaid leadership roles for myotonic dystrophy exercise recommendations and physical therapy guidance and the CureSMA Medical Advisory Council. NEJ received royalties or licenses from University of Rochester; received consulting fees from AMO Pharma Fulcrum Therapeutics, Avidity Biosciences, Dyne, Vertex, Arthex, and Entrada; participated in a Data Safety Monitoring Board for Biogen; and owns stock or stock options in ML Bio Solutions. DJL received funding from the DuchenneXchange Advisory Council, Cure Duchenne. JMS received consulting fees from Dyne Therapeutics, Roche, Avidity, ML Bio, Fulcrum Therapeutics, MT Pharma, Sarepta, and Amylyx; payment or honorarium from MDA; and stock or stock options from Dyne Therapeutics. SHS received consulting fees from Reata Pharmaceuticals, Avidity Biosciences, and Dyne therapeutics. KMB was an employee of Ionis Pharmaceuticals at the time the trial was conducted; is a current employee of and owns stock options in Acadia Pharmaceuticals; is an advisor to non-profit organisations Myotonic Dystrophy Foundation and SMA Foundation; and is a Board Member of DTx Pharma. CFB is a Board member of Flamingo Therapeutics and Hereditary Disease Foundation. RM is the chair of three clinical trials in Duchenne muscular dystrophy funded by TRiNDS. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Rationale: Exercise participation remains low despite clear benefits. Rats engage in voluntary wheel running (VWR) that follows distinct phases of acquisition, during which VWR escalates, and maintenance, during which VWR remains stable. Understanding mechanisms driving acquisition and maintenance of VWR could lead to novel strategies to promote exercise. The two phases of VWR resemble those that occur during operant conditioning and, therefore, might involve similar neural substrates. The dorsomedial (DMS) dorsal striatum (DS) supports the acquisition of operant conditioning, whereas the dorsolateral striatum (DLS) supports its maintenance., Objectives: Here we sought to characterize the roles of DS subregions in VWR. Females escalate VWR and operant conditioning faster than males. Thus, we also assessed for sex differences., Methods: To determine the causal role of DS subregions in VWR, we pharmacologically inactivated the DMS or DLS of adult, male and female, Long-Evans rats during the two phases of VWR. The involvement of DA receptor 1 (D1)-expressing neurons in the DS was investigated by quantifying cfos mRNA within this neuronal population., Results: We observed that, in males, the DMS and DLS are critical for VWR exclusively during acquisition and maintenance, respectively. In females, the DMS is also critical only during acquisition, but the DLS contributes to VWR during both VWR phases. DLS D1 neurons could be an important driver of VWR escalation during acquisition., Conclusions: The acquisition and maintenance of VWR involve unique neural substrates in the DS that vary by sex. Results reveal targets for sex-specific strategies to promote exercise., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The crisis caused by COVID-19 has profoundly affected human activities around the globe, and the Galapagos Islands are no exception. The impacts on this archipelago include the impairment of tourism and the loss of linkages with the Ecuadorian mainland, which has greatly impacted the local economy. The collapse of the local economy jeopardized livelihoods and food security, given that many impacts affected the food supply chain. During the crisis, the artisanal fishers of the Galapagos showed a high capacity to adapt to the diminishing demand for fish caused by the drastic drop in tourism. We observed that fishers developed strategies and initiatives by shifting roles, from being mainly tourism-oriented providers to becoming local-household food suppliers. This new role of fishers has triggered an important shift in the perception of fishers and fisheries in Galapagos by the local community. The community shifted from perceiving fisheries as a sector opposed to conservation and in conflict with the tourism sector to perceiving fisheries as the protagonist sector, which was securing fresh, high-quality protein for the human community. This study explores the socio-economic impacts and adaptations of COVID-19 on Galapagos' artisanal fisheries based on a mixed methods approach, including the analysis of fisheries datasets, interviews, surveys, and participant observation conducted during and after the lockdown. We illustrate the adaptive mechanisms developed by the sector and explore the changes, including societal perceptions regarding small-scale fisheries in the Galapagos. The research proposes strategies to enhance the Galapagos' economic recovery based on behaviors and traits shown by fishers which are considered potential assets to build-up resilience., Supplementary Information: The online version contains supplementary material available at 10.1007/s40152-022-00268-z., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022.)

Biomarker-driven trials hold promise for therapeutic development in chronic diseases, such as muscular dystrophy. Myotonic dystrophy type 1 (DM1) involves RNA toxicity, where transcripts containing expanded CUG-repeats (CUGexp) accumulate in nuclear foci and sequester splicing factors in the Muscleblind-like (Mbnl) family. Oligonucleotide therapies to mitigate RNA toxicity have emerged but reliable measures of target engagement are needed. Here we examined muscle transcriptomes in mouse models of DM1 and found that CUGexp expression or Mbnl gene deletion cause similar dysregulation of alternative splicing. We selected 35 dysregulated exons for further study by targeted RNA sequencing. Across a spectrum of mouse models, the individual splice events and a composite index derived from all events showed a graded response to decrements of Mbnl or increments of CUGexp. Antisense oligonucleotides caused prompt reduction of CUGexp RNA and parallel correction of the splicing index, followed by subsequent elimination of myotonia. These results suggest that targeted splice sequencing may provide a sensitive and reliable way to assess therapeutic impact in DM1., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Impaired fear extinction, combined with the likelihood of fear relapse after exposure therapy, contributes to the persistence of many trauma-related disorders such as anxiety and post-traumatic stress disorder. Identifying mechanisms to aid fear extinction and reduce relapse could provide novel strategies for augmentation of exposure therapy. Exercise can enhance learning and memory and augment fear extinction of traumatic memories in humans and rodents. One factor that could contribute to enhanced fear extinction following exercise is the mammalian target of rapamycin (mTOR). mTOR is a translation regulator involved in synaptic plasticity and is sensitive to many exercise signals such as monoamines, growth factors, and cellular metabolism. Further, mTOR signaling is increased after chronic exercise in brain regions involved in learning and emotional behavior. Therefore, mTOR is a compelling potential facilitator of the memory-enhancing and overall beneficial effects of exercise on mental health.The goal of the current study is to test the hypothesis that mTOR signaling is necessary for the enhancement of fear extinction produced by acute, voluntary exercise. We observed that intracerebral-ventricular administration of the mTOR inhibitor rapamycin reduced immunoreactivity of phosphorylated S6, a downstream target of mTOR, in brain regions involved in fear extinction and eliminated the enhancement of fear extinction memory produced by acute exercise, without reducing voluntary exercise behavior or altering fear extinction in sedentary rats. These results suggest that mTOR signaling contributes to exercise-augmentation of fear extinction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adverse life events can lead to stable changes in brain structure and function and are considered primary sources of risk for post-traumatic stress disorder, depression and other neuropsychiatric disorders. However, most individuals do not develop these conditions following exposure to traumatic experiences, and research efforts have identified a number of experiential factors associated with an individual's ability to withstand, adapt to and facilitate recovery from adversity. While multiple animal models of stress resilience exist, so that the detailed biological mechanisms can be explored, studies have been disproportionately conducted in male subjects even though the prevalence and presentation of stress-linked disorders differ between sexes. This review focuses on (a) the mechanisms by which experiential factors (behavioral control over a stressor, exercise) reduce the impact of adverse events as studied in males; (b) whether other manipulations (ketamine) that buffer against stress-induced sequelae engage the same circuit features; and (c) whether these processes operate similarly in females. We argue that investigation of experiential factors that produce resistance/resilience rather than vulnerability to adversity will generate a unique set of biological mechanisms that potentially underlie sex differences in mood disorders., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Stress-related disorders are more common in females than males. This difference could arise from differential responses to behavioral interventions that enable stress resistance between sexes. In male rats, regular physical activity prevents the behavioral consequences of uncontrollable stress, such as social avoidance and exaggerated fear conditioning. However, it is unknown if these protective effects are also present in females. Here we demonstrate for the first time in female rats that six weeks of voluntary wheel running buffers against the behavioral sequelae of uncontrollable stress. This observation allows for mechanistic investigations of exercise-induced stress resistance in both sexes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear tends to resurface even after successful extinction. Identification of novel strategies to enhance fear extinction and reduce fear relapse is of paramount importance to mental health. Exercise can enhance cognitive function, but it is not yet well understood whether exercise can be an effective augmentation strategy for fear extinction. In the current review, we present the current state of knowledge on the effects of exercise on fear extinction. Effects of exercise duration, explanations for conflicting results, and potential mechanisms, focusing on a hypothesized role for dopamine, are all discussed. We also provide new data suggesting that the timing in which acute exercise occurs relative to fear extinction, is a crucial variable in determining whether exercise can enhance fear extinction. Clinical implications and ideas to guide future research endeavors in this area are provided., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is an inherited disease characterized by the inability to relax contracted muscles. Affected individuals carry large CTG expansions that are toxic when transcribed. One possible treatment approach is to reduce or eliminate transcription of CTG repeats. Actinomycin D (ActD) is a potent transcription inhibitor and FDA-approved chemotherapeutic that binds GC-rich DNA with high affinity. Here, we report that ActD decreased CUG transcript levels in a dose-dependent manner in DM1 cell and mouse models at significantly lower concentrations (nanomolar) compared to its use as a general transcription inhibitor or chemotherapeutic. ActD also significantly reversed DM1-associated splicing defects in a DM1 mouse model, and did so within the currently approved human treatment range. RNA-seq analyses showed that low concentrations of ActD did not globally inhibit transcription in a DM1 mouse model. These results indicate that transcription inhibition of CTG expansions is a promising treatment approach for DM1., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)