Translational Research Research Articles

CRIME-Q—a unifying tool for critical appraisal of methodological (technical) quality, quality of reporting and risk of bias in animal research

BackgroundSystematic reviews within the field of animal research are becoming more common. However, in animal translational research, issues related to methodological quality and quality of reporting continue to arise, potentially leading to underestimation or overestimation of the effects of interventions or prevent studies from being replicated. The various tools and checklists available to ensure good-quality studies and proper reporting include both unique and/or overlapping items and/or simply lack necessary elements or are too situational to certain conditions or diseases. Currently, there is no tool available, which covers all aspects of animal models, from bench-top activities to animal facilities, hence a new tool is needed. This tool should be designed to be able to assess all kinds of animal studies such as old, new, low quality, high quality, interventional and noninterventional on. It should do this on multiple levels through items on quality of reporting, methodological (technical) quality, and risk of bias, for use in assessing the overall quality of studies involving animal research.MethodsDuring a systematic review of meningioma models in animals, we developed a novel unifying tool that can assess all types of animal studies from multiple perspectives. The tool was inspired by the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist, the ARRIVE 2.0 guidelines, and SYRCLE’s risk of bias tool, while also incorporating unique items. We used the interrater agreement percentage and Cohen’s kappa index to test the interrater agreement between two independent reviewers for the items in the tool.ResultsThere was high interrater agreement across all items (92.9%, 95% CI 91.0–94.8). Cohen’s kappa index showed quality of reporting had the best mean index of 0.86 (95%-CI 0.78–0.94), methodological quality had a mean index of 0.83 (95%-CI 0.78–0.94) and finally the items from SYRCLE’s risk of bias had a mean kappa index of 0.68 (95%-CI 0.57–0.79).ConclusionsThe Critical Appraisal of Methodological (technical) Quality, Quality of Reporting and Risk of Bias in Animal Research (CRIME-Q) tool unifies a broad spectrum of information (both unique items and items inspired by other methods) about the quality of reporting and methodological (technical) quality, and contains items from SYRCLE’s risk of bias. The tool is intended for use in assessing overall study quality across multiple domains and items and is not, unlike other tools, restricted to any particular model or study design (whether interventional or noninterventional). It is also easy to apply when designing and conducting animal experiments to ensure proper reporting and design in terms of replicability, transparency, and validity.

Risk-based pricing models and the role they might play in patients' access to new stem cell therapies.

Stem cell research is currently undergoing a promising transformation from primarily basic research to increasing emphasis on translation and clinical trials. To reach patients, however, stem cell treatments need to be not only technically but also economically viable. In this commentry we present insights into emerging pricing models that may help ensure access to advanced and expensive treatments like stem cell therapies. Further, we present some reflections on the practical and ethical challenges that these models involve. We provide this information to allow the field of translational stem cell research to think ahead and to raise awareness of the outstanding social and ethical issues.

Differential somatic coding variant landscapes between laser microdissected luminal epithelial cells from canine mammary invasive ductal solid carcinoma and comedocarcinoma

BackgroundBreast cancer (BC) is the most common cancer in women. Likewise, canine mammary tumors (CMT) represent the most common cancer in intact female dogs and develop in the majority spontaneously. Similarities exist in clinical presentation, histopathology, biomarkers, and treatment. However, CMT subtype-specific genomic background is less investigated. Here, we assess the genetic etiology of two histomorphological (HM) subtypes with BC counterparts, the CMT invasive ductal simple solid carcinoma (SC) and comedocarcinoma (CC), and compare the results with BC data.MethodsGroups of 11–13 transformed ductal luminal epithelial cells were laser-capture microdissected from snap-frozen invasive mammary SC and CC subtypes of one intact female dog. HM unaffected lobular luminal epithelial cells were controls. Single-cell whole genome libraries were generated using PicoPLEX and sequenced to compare the subtypes’ somatic coding variant landscapes with each other and with BC data available in COSMIC-CGC and KEGG. Furthermore, HM and immunohistochemical (IHC) subtype characteristics were compared with the genomic results.ResultsThe CC had six times more variants than the SC. The SC showed variants in adherens junction genes and genes of the MAPK, mTOR and NF-kappa-B signaling pathways. In the CC, the extracellular matrix (ECM) receptor interaction, cell adhesion, PI3K-Akt and cGMP-PKG pathways were enriched, reflecting the higher cellular malignancy. Affected pathways in both CMT subtypes overlapped with BC pathways in KEGG. Additionally, we identified ATP6V1C2, GLYATL3, CARMIL3, GATAD2B, OBSCN, SIX2, CPEB3 and ZNF521 as potential new subtype-distinct driver genes. Furthermore, our results revealed biomarker alterations in IHC in the basal/myoepithelial cell layer without respective genetic mutations, suggesting changes to their complex signaling pathways, disturbed regulative feedback loops or other silencing mechanisms.ConclusionsThis study contributes to understanding the subtype-specific molecular mechanisms in the canine mammary invasive ductal simple SC and CC, and revealed subtype-specific molecular complexity for phenotypically similar characteristics. Several affected genes and signaling pathways overlapped with BC indicating the potential use of CMT as model for BC. Our findings emphasize the need for thorough characterization of cancer specimens with respect to translational cancer research, but also how insight into tumor heterogeneity will be crucial for the development of targeted prognostics and therapeutic interventions.

Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges.

Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.

Bacterial attachment and junctional transport function in induced apical-out polarized and differentiated canine intestinal organoids

Dogs are increasingly recognized as valuable large animal models for understanding human intestinal diseases, as they naturally develop conditions similar to those in humans, such as Enterohemorrhagic E. coli, Clostridium difficile infection, inflammatory bowel disease, and ulcerative colitis. Given the similarity in gut flora between dogs and humans, canine in vitro intestinal models are ideal for translational research. However, conventional extracellular matrix-embedded organoids present challenges in accessing the lumen, which is critical for gut function. This study aimed to investigate the feasibility of inducing polarity reversal and differentiation in canine apical-out colonic organoids (colonoids), evaluate their barrier integrity, and visualize host-pathogen interactions. Our results demonstrated successful polarity reversal and differentiation induction while maintaining barrier integrity. Polarity reversal allowed for enhanced observation of host-pathogen interactions, facilitating visual assessments and membrane integrity evaluations using both pathogenic and nonpathogenic E. coli. This process led to the downregulation of stem cell marker LGR5 and upregulation of intestinal epithelial cell marker ALPI, indicating differentiation. Further differentiation was observed with the use of a differentiation culture medium, resulting in significant upregulation of ALPI and goblet cell marker MUC2. The findings suggest that apical-out canine colonoids can serve as physiologic and valuable models for studying the pathogenic mechanisms and clinical significance of intestinal diseases in dogs. This model has the potential to advance both canine and human gastrointestinal research, enhancing our understanding of gastrointestinal physiology and pathology and aiding in the development of novel therapeutics.

Лингвотопологическое моделирование процесса перевода: к общим основаниям

Cognitive research in translation is currently at its peak. The authors studied L. V. Kushnina’s synergetic concept of translation space in an interaction with the topological fields of translation to develop a linguistic topological model of translation as a process. The analysis yielded graphic constructs represented by topologically structured spaces that illustrate the process of interlingual and intercultural interaction. The research relied on P. A. Florensky’s idea of the language of spatial objects and the provisions of philological and translation topology developed by L. V. Polubichenko, who studied the variant vs. invariant patterns of different philological objects, from words to texts. The current Chinese translation studies show similar ideas (see: Wu Dan, Ding Xiuhei, Zhao Genglin, Jiang Shengnan, etc.). The article visualizes the modern translation paradigm from the perspective of linguistic topology. Translation is a multifunctional verbal and mental activity that unites various objects in the spaces between the sender, the translator, and the recipient. The resulting topological translation model represents the linguistic topology of interlingual communication at the intersection of cognitive topology, linguistics, translation theory and practice, and cognitive translation studies.

Recovery model for minimally invasive central cannulation, cardiopulmonary bypass, and cardioplegic arrest in quadrupeds.

Objectives: Sternotomy is rarely performed for veterinary therapeutic or recovery models in quadrupeds because of difficulties with breathing, ambulation, and pain control. Central cannulation for cardiopulmonary bypass (CPB) is infrequent and typically performed through full thoracotomies. Experienced clinical surgeons and perfusionists should provide guidance for new therapeutic interventions and translational research. We sought to develop, validate, and detail a contemporary model for minimally-invasive central cannulation, CPB, and cardioplegic arrest. Methods: After induction of anesthesia and sterile preparation, a right second-interspace parasternal mini-thoracotomy was performed, the ascending aorta was cannulated using Seldinger technique, and a cardioplegia needle was placed. A dual-stage cannula was introduced through the right atrial appendage and CPB commenced. The aorta was clamped and Buckberg 4:1 induction cardioplegia was administered. Arrest was maintained for 30minutes. CPB was discontinued after 2hours and the great vessels were decannulated. Hemostasis was achieved and the wound was closed. Initial recovery was accomplished in intensive care with subsequent transfer to the vivarium.Results: Ten consecutive Yorkshire swine (45 ± 5kg) were minimally invasively placed on CPB including cardioplegic arrest using central cannulation through a right parasternal mini-thoracotomy. There was no operative or late mortality. Morbidity appeared minimal. Planned euthanasia and scheduled necropsy were performed to exclude clinically-occult major complications. None were identified. Following initial supervision, veterinary and resident surgeons completed the procedures autonomously with excellent results.Conclusion: The described protocols should facilitate safe veterinary cardiac surgical care and humane translational research.

Mapping AI’s Integration into Linguistics- A Bibliometric and Thematic Analysis of ChatGPT’s Influence

This study is a systematic and bibliometric analysis of research on artificial intelligence, ChatGPT, and large language models, focusing on the top fifty publications from high-impact linguistics journals indexed in Web of Science and Scopus. This study aims to identify and analyze the historical significance of ChatGPT’s release and its broader influence on linguistic research as a field. Through scientific mapping we examine research publications from before and after the launch of ChatGPT, analyzing how it presents in choice of topics and methodologies. The study presents a thematic review of articles published up to March 2024, categorizing them into major themes such as editorials, survey studies, translation research, and assessment methodologies. Through the use of Bibliometrix software, the research analyzes the geographical networks of articles, authorship collaborations, citations, and recurring keywords. The findings reveal the growing influence of artificial intelligence, particularly ChatGPT, on various subfields of linguistics, and demonstrate how AI technologies are being integrated into areas such as translation, language assessment, and educational practices. By mapping the trajectory of AI’s integration into linguistics, the study offers insights into future research directions, emphasizing the need to continuously assess AI’s impact on educational and linguistic practices.

The biliary ecosystem: a holistic perspective on critical scientific issues regarding biliary tract surgeries and diseases

The establishment of modern biliary surgery system, alongside pivotal scientific paradigm shifts, has heralded a new era featured by precision, personalization, life-cycle care, and multidisciplinary management in the treatment of both benign and malignant biliary diseases. However, two formidable challenges persist in haunting the treatment of biliary diseases: (1) The refinement of surgical techniques has reached a plateau in reducing the disability associated with benign biliary conditions and in improving survival outcomes in biliary tract cancers; (2) Traditional evidence-based clinical studies have shown limited power in addressing complex dilemmas, such as determining whether to excise or preserve pathological gallbladders or selecting the optimal biliary drainage strategy. Consequently, the authors propose the conceptual framework of "biliary ecosystem". In this model, diverse and abundant cholangiocytes represent forest, while blood vessels, nerves, and lymphatic vessels serve as nurturing soil, biliary stem cells function as seeds, bile flows like river network, and hepatocytes mark the river's origins. Both benign and malignant biliary diseases exhibit significant spatiotemporal dynamics. The bile ducts form the "macro" environment, bile constitutes the "sub-macro" environment, and diverse cellular niches create the microenvironment. Specific pathological biliary conditions are shaped by intricate regulatory mechanisms that operate across these three tiers. Within the biliary ecosystem, cellular subpopulations exist remarkable diversity with states of homeostasis, oscillation, perturbation, or imbalance, underpinned by complex signaling networks. This holistic approach allows us to reframe and critically examine the pressing scientific issues confronting biliary tract diseases. Based on this framework, the authors distill key scientific questions and offer preliminary recommendations for embracing the paradigm shift. The authors anticipate that this conceptual model will promote interdisciplinary integration and accelerate clinical and translational researches.

Review on pathogenesis and treatment of Alzheimer's disease.

The rising incidence of Alzheimer's disease (AD) and the associated economic impacts has prompted a global focus in the field. In recent years, there has been a growing understanding of the pathogenic mechanisms of AD, including the aggregation of β-amyloid, hyperphosphorylated tau, and neuroinflammation. These processes collectively lead to neurodegeneration and cognitive decline, which ultimately results in the loss of autonomy in patients. Currently, there are three main types of AD treatments: clinical tools, pharmacological treatment, and material interventions. This review provides a comprehensive analysis of the underlying etiology and pathogenesis of AD, as well as an overview of the current prevalence of AD treatments. We believe this article can help deepen our understanding of the AD mechanism, and facilitate the clinical translation of scientific research or therapies, to address this global problem of AD.

Leptomeningeal metastatic disease: new frontiers and future directions.

Leptomeningeal metastatic disease (LMD), encompassing entities of 'meningeal carcinomatosis', neoplastic meningitis' and 'leukaemic/lymphomatous meningitis', arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients. Underdiagnosis and misdiagnosis are common, response assessment remains challenging, and the prognosis associated with this disease of whole neuroaxis remains extremely poor. The dearth of effective therapies is further challenged by the difficulties in studying this dynamic disease state. In this Review, a multidisciplinary group of experts describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Drawing upon paradigm-changing advances in mechanistic science, computational approaches, and trial design, the authors discuss domain-specific and cross-disciplinary strategies for optimizing the clinical and translational research landscape for LMD. Advances in diagnostics, multi-agent intrathecal therapies, cell-based therapies, immunotherapies, proton craniospinal irradiation and ongoing clinical trials offer hope for improving outcomes for patients with LMD.

Defining a core set of research and development priorities for virtual care in the post-pandemic environment: a call to action.

To identify research and development priorities for virtual care following the coronavirus disease 2019 pandemic from the perspective of key stakeholders (patients, clinicians, informaticians and academics). Qualitative study using a modified nominal group technique. Online semi-structured interviews and workshops held in November 2022 and February 2023. Health workers involved in delivering virtual care in two metropolitan local health districts and one specialty statewide network, and people who had received care from these sites, were recruited using passive snowball sampling. Research and academic staff from a tertiary institution were also invited to participate. Priorities to support a translational research agenda for virtual care. Twenty-five individuals participated including 18 innovation deliverers, two innovation recipients and five implementation facilitators. Stakeholders identified several key priorities for developing virtual care models and for sustaining and scaling virtual care services. These included demonstrating the economic and societal value of virtual care, developing a common framework to support evaluation and comparison of virtual care services, ensuring virtual care services integrate acute and primary care, and defining which models of care are most appropriate for virtual care delivery. As the health system recalibrates with the return of in-person care, there is a growing need to demonstrate the value of virtual care models to patients, the health system, and society at large. Demonstrating this value while also demonstrating improvements to health outcomes will future-proof virtual care, enabling it to be used to address broader challenges of health care delivery. In addition, sustaining virtual care will depend on robust operational structures and workforce training and education. As services evolve, research and development priorities must be revisited to ensure that translational research aligns with stakeholder interests.

Deepening the participation of neurodivergent youth in qualitative mental health research: Co‐development of a general approach and the evaluation of its implementation in a study on emotion

AbstractBackgroundThere is a growing expectation that neurodivergent young people, such as those with diagnoses of attention‐deficit/hyperactivity disorder (ADHD) and/or autism, should play a central role in shaping research on neurodevelopmental conditions. However, currently, their involvement is typically limited to arms‐length advice. To address this, the Regulating Emotions‐Strengthening Adolescent Resilience (RE‐STAR) programme has co‐developed a framework for deepening the involvement of neurodivergent participants in translational research. Here we apply this to build, implement and evaluate a new approach to participatory qualitative research.MethodsDevelopment – Building on the track record of successful collaboration between RE‐STAR academic researchers (ARs) and its Youth Researcher Panel (Y‐RP), a cycle of meetings was convened to co‐develop a collaborative protocol for the participatory approach. Implementation – ARs and Y‐RPers applied the general protocol to study a specific topic. This involved co‐designing and co‐delivering an interview schedule to study the emotional experiences of 12 adolescents with diagnoses of ADHD and/or autism and then co‐analysing the interviews. Evaluation – ARs, Y‐RPers and interviewees shared their reflections on the participatory approach and its implementation, during interviews (N = 36) and short open‐ended surveys (N = 22).ResultsDevelopment ‐ The protocol for the participatory approach gave detailed advice on how to engage Y‐RP members (or equivalent) in the co‐design, co‐delivery and co‐analysis of interviews. Implementation ‐ The approach was successfully implemented by ARs and Y‐RPers working together to co‐design an interview to study the emotional lives of adolescents with diagnoses of ADHD and/or autism, co‐deliver it and then co‐analyse the interview scripts. Evaluation ‐ The implementation experience of the Y‐RP, ARs and interviewees was characterised by common themes relating to (a) adapting research methods and making practical adjustments; (b) taking on new roles, adding value to research and (c) valuing neurodivergent characteristics.ConclusionsThis new RE‐STAR protocol proved feasible to implement in a way that was generally perceived, from multiple perspectives, to add depth and authenticity to research into the experiences of neurodivergent young people.

Six Month Follow up of the one of the First Patients to Complete MDMA-Assisted Therapy for PTSD Outside of Clinical Trials in Australia: Implications for Translating Clinical Research to Clinical Practice

Purpose: The goal of this case report is to illustrate the implementation of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder (PTSD) and learning points for health professionals in the translation of psychedelic assisted therapy research into clinical practice. We present our key learnings and 6-month follow up data from one of the first patients to complete MDMA-assisted therapy for PTSD outside of clinical trials, in an Australian outpatient clinic setting. Methodology: The patient described in this case report had chronic PTSD, depression and anxiety due to experiencing domestic violence, including sexual, physical, and psychological abuse in her adolescence. Treatment was informed by the Multidisciplinary Association of Psychedelic Studies (MAPS) MDMA-assisted therapy manual. After completing treatment, she enrolled in our weekly integration peer support group, including meditation workshops and family support sessions. Data was gathered using the Australian National University (ANU) Psychedelic-assisted therapy Australian national outcome database (https://medicine-psychology.anu.edu.au/research/research-projects/australian-interventional-pharmacotherapy-psychedelic-assisted-psychotherapy), which collates de-identified questionnaire data and outcomes from MDMA, psilocybin and ketamine assisted psychotherapy. Outcome data was gathered at baseline, the beginning of preparation, in the week after each dosing session, at the end of the program. Follow up data is collected at 3-, 6-, 9- and 12-months post-treatment. At the time of writing, she had completed 3 and 6 month follow up. Tables and figures are used to present the outcome data. Findings: Our patient no longer met DSM-V criteria for PTSD or major depressive disorder at the end of treatment, and at 6-month follow up. Her Impact of Events Scale – Revised (IES-R) score was 61 at intake, reduced to 0 after the second dosing session and remained 0 at 3 and 6-months follow up. There were no adverse events, with the only side effect reported being loss of appetite in the first 24 hours after each dosing session. All scores on depression and anxiety measures reduced to the normal ranges after the second dosing session and remained in the normal ranges at her six month follow up. After the second dosing session reported having greater self-compassion and being less troubled by the trauma memories. After the third dosing session, she began to feel comfortable leaving her children with their father or trusted family member to run errands for the first time, and an increased sense of connectedness with herself and with others. All these gains were maintained at three- and six-months post-treatment, illustrating a case of safe and effective implementation of MDMA-assisted therapy for PTSD in an outpatient mental health service. Unique Contribution to Theory, Practice and Policy: Our case study offers one model of clinical practice, contributing to Australian practitioner’s implementation of safe and effective MDMA-assisted therapy in mental health services. We reflect on learning points for practitioners such as whether MDMA or psilocybin would be the most effective treatment, for a patient with both PTSD and treatment resistant depression. Recommendations for practitioners include the importance of working in a dyad, accessing ongoing supervision in the early stages of implementation, and the benefits of the having had legal experience with psychedelic medicines as part of therapist training.

Denfivontinib activates effector T-cells through NLRP3-inflammasome, yielding potent anticancer effects by combination with pembrolizumab.

Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutical limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances the anti-tumor effects when combined with anti-PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with NSCLC. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating the NLRP3 inflammasome formation. This leads to macrophage activation via the NF-kB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knock-out mice confirmed that AXL inhibition by denfivontinib enhances the anti-tumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk-RNA sequencing data from 21 NSCLC patients undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for NLRP3 inflammasome in activating immune responses during treatment.

Wounds and Vulnerabilities. The Participation of Special Operations Forces in Experimental Brain-Computer Interface Research.

Brain-computer interfaces (BCIs) exemplify a dual-use neurotechnology with significant potential in both civilian and military contexts. While BCIs hold promise for treating neurological conditions such as spinal cord injuries and amyotrophic lateral sclerosis in the future, military decisionmakers in countries such as the United States and China also see their potential to enhance combat capabilities. Some predict that U.S. Special Operations Forces (SOF) will be early adopters of BCI enhancements. This article argues for a shift in focus: the U.S. Special Operations Command (SOCOM) should pursue translational research of medical BCIs for treating severely injured or ill SOF personnel. After two decades of continuous military engagement and on-going high-risk operations, SOF personnel face unique injury patterns, both physical and psychological, which BCI technology could help address. The article identifies six key medical applications of BCIs that could benefit wounded SOF members and discusses the ethical implications of involving SOF personnel in translational research related to these applications. Ultimately, the article challenges the traditional civilian-military divide in neurotechnology, arguing that by collaborating more closely with military stakeholders, scientists can not only help individuals with medical needs, including servicemembers, but also play a role in shaping the future military applications of BCI technology.

ELemur: A cellular-resolution 3D atlas of the mouse lemur brain

The gray mouse lemur (Microcebus murinus), one of the smallest living primates, emerges as a promising model organism for neuroscience research. This is due to its genetic similarity to humans, its evolutionary position between rodents and humans, and its primate-like features encapsulated within a rodent-sized brain. Despite its potential, the absence of a comprehensive reference brain atlas impedes the progress of research endeavors in this species, particularly at the microscopic level. Existing references have largely been confined to the macroscopic scale, lacking detailed anatomical information. Here, we present eLemur, a unique resource, comprising a repository of high-resolution brain-wide images immunostained with multiple cell type and structural markers, elucidating the cyto- and chemoarchitecture of the mouse lemur brain. Additionally, it encompasses a segmented two-dimensional reference and 3D anatomical brain atlas delineated into cortical, subcortical, and other vital regions. Furthermore, eLemur includes a comprehensive 3D cell atlas, providing densities and spatial distributions of non-neuronal and neuronal cells across the mouse lemur brain. Accessible via a web-based viewer (https://eeum-brain.com/#/lemurdatasets), the eLemur resource streamlines data sharing and integration, fostering the exploration of different hypotheses and experimental designs using the mouse lemur as a model organism. Moreover, in conjunction with the growing 3D datasets for rodents, nonhuman primates, and humans, our eLemur 3D digital framework enhances the potential for comparative analysis and translation research, facilitating the integration of extensive rodent study data into human studies.

Preventing epileptogenesis by interaction between inositol isomers and proteins.

Inositols play significant roles in biological systems. Myo-inositol (MI), the most prevalent isomer, functions as an osmolyte and mediates cell signal transduction. Other notable isomers include Scyllo-inositol (SCI) and D-Chiro-inositol (DCHI). Our previous investigations have highlighted MI's potential antiepileptogenic effects, although its exact mechanisms of action during epileptogenesis remain unclear. A critical, unexplored area is how inositols interact with proteins. Additionally, the antiepileptogenic capabilities of SCI and DCHI have yet to be determined. This study seeks to address these gaps. Inositol interacting proteins were identified by cellular thermal shift assay. Status epilepticus (SE) in rats was induced using kainic acid (KA), followed by a 28-day treatment with either MI, SCI, DCHI, or saline. The duration and frequencies of behavioral spontaneous recurrent seizures (SRS) were scored for 8 weeks by 24 h video monitoring system. The effects of inositol treatment on spatial learning and memory deficits associated with epileptogenesis were evaluated by Morris water maze test. The changes in protein amounts were studied by Western immunoblotting. We identified several proteins that interact with inositols, noting both commonalities and isomer-specific associations. For the first time, we demonstrated that the treatment with SCI and DCHI, alongside MI, significantly reduces the frequency and duration of behavioral SRS in a KA-induced post-status epilepsy model in rats. This reduction persisted for 4 weeks post-treatment. Moreover, all three inositol isomers mitigated spatial learning and memory deficits associated with epileptogenesis. Alterations in the inositol interacting proteins: alpha synuclein and 14-3-3 theta were further examined 8 weeks post-SE in the hippocampus and neocortex of rats. Myo-inositol, SCI and DCHI interact with a number of proteins involved in different biological pathways. All studied inositol isomers express long-term beneficial effects on KA-induced SRS and the associated comorbidities. Inositols can be successfully used in the future for translational research. Epilepsy is a common neurological disorder characterized by spontaneous recurrent seizures and a range of associated comorbidities. The process that leads to the development of epilepsy is called epileptogenesis, and currently, no medication can effectively prevent it. Our study investigated the effects of a group of compounds-myo-inositol, scyllo-inositol, and D-chiro-inositol-that have potential antiepileptogenic properties on epilepsy induced by kainic acid. We found that: (i) the three inositol isomers share some common target proteins and also have unique ones and (ii) all of them counteract epileptogenesis and the related cognitive impairments.

TRPC6 is a mechanosensitive channel essential for ultrasound neuromodulation in the mammalian brain

Ultrasound neuromodulation has become an innovative technology that enables noninvasive intervention in mammalian brain circuits with high spatiotemporal precision. Despite the expanding utility of ultrasound neuromodulation in the neuroscience research field and clinical applications, the molecular and cellular mechanisms by which ultrasound impacts neural activity in the brain are still largely unknown. Here, we report that transient receptor potential canonical 6 (TRPC6), a mechanosensitive nonselective cation channel, is essential for ultrasound neuromodulation of mammalian neurons in vitro and in vivo. We first demonstrated that ultrasound irradiation elicited rapid and robust Ca2+ transients mediated via extracellular Ca2+ influx in cultured mouse cortical and hippocampal neurons. Ultrasound-induced neuronal responses were massively diminished by blocking either the generation of action potential or synaptic transmission. Importantly, both pharmacological inhibition and genetic deficiency of TRPC6 almost completely abolished neuronal responses to ultrasound. Furthermore, we found that intracerebroventricular administration of a TRPC6 blocker significantly attenuated the number of neuronal firings in the cerebral cortex evoked by transcranial ultrasound irradiation in mice. Our findings indicate that TRPC6 is an indispensable molecule of ultrasound neuromodulation in intact mammalian brains, providing fundamental understanding of biophysical molecular mechanisms of ultrasound neuromodulation as well as insight into its future feasibility in neuroscience and translational research in humans.

LGBTQ+ Population Well-Being: Health Equity Implementation Science in Action.

Health equity is actualized when all individuals can attain the highest level of health. Youth who identify as LGBTQ+ experience health disparities and scarce access to culturally congruent mental healthcare. Our nurse-led research team recognized evidence-based practice guidance gaps and prioritized a systematic inquiry into the lived experiences of LGBTQ+ identifying youth who needed emergency care for suicidality. Concurrently, we translated new findings into practice. The purpose of this endeavor is to implement a nimble evidence-based practice adoption process for nursing staff to effectively address LGBTQ+ population health needs. Informed by Purnell's Cultural Competence Theory, qualitative findings from a prospective study and available literature, we developed an LGBTQ+ sensitive care curriculum for nursing staff using the American Nurses Credentialing Center's (ANCC) Nursing Continuing Education Professional Development (NCPD) Framework to address the intersectionality of cultural awareness and care provision. The curriculum was delivered and formally evaluated longitudinally with a focus on communication confidence and knowledge. The curriculum was delivered in one session to nursing staff during a 6-month period. Program evaluations indicated curriculum acceptability and effectiveness. Participants reported improved ability to use appropriate language when communicating with patients who identify as LGBTQ+ and their families and a moderate to high change in confidence when providing care to LGBTQ+ identifying patients. Concurrent, evidence-based efforts to uncover and apply new knowledge relevant to nursing communication with youth who identify as LGBTQ+ is possible and yield effective, positive change in nursing knowledge and confidence in providing care for these youth. Implementation science is essential to advance evidence-based nursing practice or the full positive impact of research on patient outcomes is not likely. When the implementation science program is not incorporated early in the research process, research excellence is at risk. Evolving evidence-based practices that enhance individualized holistic patient care delivery for LGBTQ+ individuals are strengthened when primary research, implementation science, and scaling research co-occurrence is achievable. This implementation strategy demonstrates that early translation of health equity research on culturally congruent care for individuals identifying as LGBTQ+ can be done effectively and replicated across practice settings. Further, this work validates the importance of the relationship between nurse scientists, translational scientists, and clinical practice and education experts in the early dissemination and adoption of new knowledge. Evidence-based practice adoption improves healthcare professionals' propensity to positively impact public health patient care outcomes. Nursing staff are equipped with the knowledge and skills to deliver equitable care. Dissemination of early research findings as an implementation science strategy supports concurrent adoption in clinical practice to advance health equity outcomes with urgency. No patient or public contribution.