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Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age = 32.50, male = 21, female = 13) and 30 subjects with schizophrenia (mean age = 33.07, male = 19, female = 11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60) = 21.19, p < 0.0001). MMP9 levels correlated with negative symptoms in patients (R = 0.39, p = 0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59) = 9.12, p = 0.0040) and right (F(1,59) = 6.49, p = 0.013) hippocampal volumes. Finally, left (R = −0.39, p = 0.034) and right (R = −0.37, p = 0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Mice lacking the mechanically activated ion channel Piezo2 in both sensory neurons and Merkel cells are almost totally incapable of light-touch sensation while other somatosensory functions, such as mechanical nociception, remain intact, implying that other mechanically activated ion channels must now be identified to account for painful touch sensation. Touch and pain sensation are separable Recent decades have seen the mechanisms of sensing photons (vision), chemicals (olfaction, taste) and temperature (thermosensation) elucidated in some detail. The sense of touch, implying the transduction of mechanical forces into electrical signals, is less well understood. Here Ardem Patapoutian and colleagues show that mice lacking the mechanically activated ion channel Piezo2 in both sensory neurons and in Merkel cells, a type of modified skin cell, are almost totally incapable of light-touch sensation. As the mice are intact in other somatosensory functions such as mechanical nociception, the work implies that other mechanically activated ion channels must now be identified to account for painful touch sensation. The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals 1 . It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive 2 . Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell–neurite complexes 3 , 4 . It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron 4 , 5 , 6 ; however, major aspects of touch sensation remain intact without Merkel cell activity 4 , 7 . Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.

This study evaluated the effects of maternal fish oil supplementation rich in n-3 PUFA on the performance and bone health of offspring broilers at embryonic development stage and at market age. Ross 708 broiler breeder hens were fed standard diets containing either 2.3% soybean oil (SO) or fish oil (FO) for 28 days. Their fertilized eggs were collected and hatched. For a pre-hatch study, left tibia samples were collected at 18 days of incubation. For a post-hatch study, a total of 240 male chicks from each maternal treatment were randomly selected and assigned to 12 floor pens and provided with the same broiler diets. At 42 days of age, growth performance, body composition, bone microstructure, and expression of key bone marrow osteogenic and adipogenic genes were evaluated. One-way ANOVA was performed, and means were compared by student’s t-test. Maternal use of FO in breeder hen diet increased bone mineral content ( p < 0.01), bone tissue volume ( p < 0.05), and bone surface area ( p < 0.05), but decreased total porosity volume ( p < 0.01) during the embryonic development period. The FO group showed higher body weight gain and feed intake at the finisher stage than the SO group. Body composition analyses by dual-energy X-ray absorptiometry showed that the FO group had higher fat percentage and higher fat mass at day 1, but higher lean mass and total body mass at market age. The decreased expression of key adipogenic genes in the FO group suggested that prenatal FO supplementation in breeder hen diet suppressed adipogenesis in offspring bone marrow. Furthermore, no major differences were observed in expression of osteogenesis marker genes, microstructure change in trabecular bone, or bone mineral density. However, a significant higher close pores/open pores ratio suggested an improvement on bone health of the FO group. Thus, this study indicates that maternal fish oil diet rich in n-3 PUFA could have a favorable impact on fat mass and skeletal integrity in broiler offspring.

Background The prevalence of chronic illness and multimorbidity rises with population aging, thereby increasing the acuity of care. Consequently, the demand for emergency and critical care services has increased. However, the forecasted requirements for physicians have shown a continued shortage. Among efforts underway to search for innovations to strengthen the workforce, there is a heightened interest to have nurses in advanced practice participate in patient care at a great extent. Therefore, it is of interest to evaluate the impact of increasing the autonomy of nurses assuming advanced practice roles in emergency and critical care settings on patient outcomes. Objectives The objectives of this study are to present, critically appraise, and synthesize the best available evidence on the impact of advanced practice nursing on quality of care, clinical outcomes, patient satisfaction, and cost in emergency and critical care settings. Review methods A comprehensive and systematic search of nine electronic databases and a hand-search of two key journals from 2006 to 2016 were conducted to identify studies evaluating the impact of advanced practice nursing in the emergency and critical care settings. Two authors were involved selecting the studies based on the inclusion criteria. Out of the original search yield of 12,061 studies, 15 studies were chosen for appraisal of methodological quality by two independent authors and subsequently included for analysis. Data was extracted using standardized tools. Results Narrative synthesis was undertaken to summarize and report the findings. This review demonstrates that the involvement of nurses in advanced practice in emergency and critical care improves the length of stay, time to consultation/treatment, mortality, patient satisfaction, and cost savings. Conclusions Capitalizing on nurses in advanced practice to increase patients’ access to emergency and critical care is appealing. This review suggests that the implementation of advanced practice nursing roles in the emergency and critical care settings improves patient outcomes. The transformation of healthcare delivery through effective utilization of the workforce may alleviate the impending rise in demand for health services. Nevertheless, it is necessary to first prepare a receptive context to effect sustainable change.

This paper demonstrates that Pif1 helicase works with polymerase d to promote DNA synthesis through a migrating D-loop, a mechanism used to copy tens of kilobases during repair of chromosome breaks by break-induced replication (BIR). Pif1 helicase promotes BIR-specific DNA synthesis When DNA is repaired by homologous recombination, DNA synthesis is involved in the latter stages. Two papers published in this issue of Nature now define a role for the DNA helicase Pif1 in this reaction. They show that although the initial stages of break-induced replication (BIR) can occur normally in the absence of Pif1, synthesis from a migrating D-loop intermediate is compromised. The mechanism of replication during BIR involves a unique bubble-like replication fork that results in conservative inheritance of the new genetic material, in contrast to the S-phase replication that duplicates the genome before cell division, and is inherently mutagenic. During DNA repair by homologous recombination (HR), DNA synthesis copies information from a template DNA molecule. Multiple DNA polymerases have been implicated in repair-specific DNA synthesis 1 , 2 , 3 , but it has remained unclear whether a DNA helicase is involved in this reaction. A good candidate DNA helicase is Pif1, an evolutionarily conserved helicase in Saccharomyces cerevisiae important for break-induced replication (BIR) 4 as well as HR-dependent telomere maintenance in the absence of telomerase 5 found in 10–15% of all cancers 6 . Pif1 has a role in DNA synthesis across hard-to-replicate sites 7 , 8 and in lagging-strand synthesis with polymerase δ (Polδ) 9 , 10 , 11 . Here we provide evidence that Pif1 stimulates DNA synthesis during BIR and crossover recombination. The initial steps of BIR occur normally in Pif1-deficient cells, but Polδ recruitment and DNA synthesis are decreased, resulting in premature resolution of DNA intermediates into half-crossovers. Purified Pif1 protein strongly stimulates Polδ-mediated DNA synthesis from a D-loop made by the Rad51 recombinase. Notably, Pif1 liberates the newly synthesized strand to prevent the accumulation of topological constraint and to facilitate extensive DNA synthesis via the establishment of a migrating D-loop structure. Our results uncover a novel function of Pif1 and provide insights into the mechanism of HR.

A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research. MATR3 is an ALS-linked gene. Here the authors describe a mutant MATR3 knockin mouse, which mimics some aspects of early-stage ALS.

Gastrointestinal (GI) cancers constitute over 25% of global cancer cases annually, with hepato-pancreato-biliary (HPB) cancers presenting particularly poor prognosis and challenging surgical treatments. While advancements in clinical care have improved post-operative outcomes over time, surgery for HPB cancers remains associated with high morbidity and mortality rates. Patients with HPB cancer are often older, diagnosed at later stages, and have a higher prevalence of co-morbid conditions, leading to reduced life expectancy, suboptimal post-operative recovery, and increased recurrence risk. Exercise and nutrition interventions have emerged as safe non-pharmacological strategies to enhance clinical outcomes among cancer survivors, but their potential in the pre-operative period for patients with HPB cancer remains underexplored. This narrative review evaluates existing evidence on exercise and nutritional interventions during pre-operative prehabilitation for HPB cancer populations, focusing on clinically relevant post-operative outcomes related to frailty and malnutrition. We conducted a literature search in PubMed and Google Scholar databases to identify studies utilizing a prehabilitation intervention in HPB cancer populations with exercise and nutritional components. The currently available evidence suggests that incorporating exercise and nutrition into prehabilitation programs offers a critical opportunity to enhance post-operative outcomes, mitigate the risk of comorbidities, and support overall survivorship among HPB cancer populations. This review underscores the need for further research to optimize the timing, duration, and components of pre-operative prehabilitation programs, emphasizing patient-centered, multidisciplinary approaches in this evolving field.

Cancer-associated cognitive deficits following chemotherapy have received increased attention in clinical research. Exercise has been shown to preserve cognitive function in cancer patients, though the overall effect is mixed. Here we present a scoping review of the published literature summarizing methods used to assess cognitive function in exercise oncology trials. Methods: PubMed, PsycINFO and CINAHL databases were searched using keywords “cognition,” “cancer” OR “neoplasm” OR “tumor,” “chemotherapy” and “exercise” OR “physical activity.” Studies eligible for inclusion include prospective studies that were published in English in peer-reviewed journals that include a method of assessing cognitive function in adult cancer patients, in which an exercise modality or method of quantifying exercise habits was evident. Studies were excluded if they included a pediatric population, patients that were not diagnosed with cancer, or were systematic/narrative/scoping reviews, protocol papers or dissertation/theses. Results: A total of 29 studies met the inclusion criteria. In total, 29 unique assessments were used to evaluate cognitive function, including patient-reported outcomes (PROs; n = 8) and objective (n = 21) methods. More than half (n = 17) of included studies relied on PROs while 12 studies utilized objective measures of cognitive function Cognitive domains of the PROs were limited in scope, focusing on memory and attention/concentration while the objective measures were broader and inclusive of multiple domains. Conclusion: The results of this review indicate that mixed approaches to evaluating cognitive function in cancer patients pose a major limitation to understanding the role of exercise as an integrative approach. The evidence demonstrates a need for more uniform assessment of cognitive function in exercise oncology trials.