Specific Activation Research Articles

Brainstem noradrenergic neuronal populations: dual effects on regulating GnRH and LH secretion.

Noradrenergic neurons are a brain network that integrate viscero-sensorial signals to modulate neural and neuroendocrine function. Although it has been known for decades that noradrenergic neural circuits influence neuroendocrine and reproductive function, the cellular and molecular players involved remain largely unknown. The objective of this review is to summarize past and current knowledge regarding the influence of brainstem noradrenergic systems on gonadotrophin-releasing hormone (GnRH) and gonadotrophin secretion. The main noradrenergic cell groups A1, A2 and A6, known as the ventrolateral medulla, nucleus of the solitary tract and locus coeruleus, respectively, are involved in the control of reproductive neuroendocrine secretion. Current evidence suggests that brainstem noradrenergic circuits promote the generation and maintenance of the luteinizing hormone (LH) surge in both spontaneous (rats, sheep) or induced ovulators (rabbit, ferret). In contrast, recent studies have established that LH pulsatile secretion is suppressed by specific activation of brainstem noradrenergic cell groups. The duality of the GnRH/LH response to noradrenaline reflects the inherent complexity of hindbrain noradrenaline neurons, which are responsive to stressors and gonadal steroids (i.e. estradiol) and co-express a variety of neurotransmitters and neuropeptides. Therefore, elucidating the organization and functionality of brainstem noradrenergic systems will provide targets for controlling reproduction and understanding the interconnection with stress.

Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.

Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.

Role of aquaporins in brain water transport and edema

Water serves as the primary substance in all living cells and is an essential molecule involved in numerous biological processes critical for maintaining homeostasis in the central nervous system (CNS). Disruptions in water balance can occur in conditions such as cerebral edema, where fluid accumulation results in increased intracranial pressure (ICP). Aquaporins (AQPs) are transmembrane proteins that play a vital role in the rapid transport of water across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, and AQP11) have been identified in brain tissue. This review summarizes the latest advancements in our understanding of the critical role of AQPs in regulating water transport in brain edema. Abundant evidence indicates that AQP4, the most prevalent AQP in the CNS, regulates brain water transport and contributes to both cytotoxic and vasogenic edema, suggesting that AQP4 may serve as a potential therapeutic target for brain edema. Additionally, some studies have indicated that AQP1 plays a significant role in the formation of cerebrospinal fluid (CSF) and the maintenance of steady-state ICP. However, to date, these findings have not been translated into clinical practice. There is an urgent need to develop specific AQP inhibitors and activators to explore the potential benefits of modulating the functions of AQP1 and AQP4 in the context of brain edema.

CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease

The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.

Impact of Brain Lesion Characteristics on Motor Function and Cortical Reorganization in Hemiplegic Cerebral Palsy

Background and Objectives: Hemiplegic or unilateral cerebral palsy (UCP) is primarily characterized by motor impairment, mainly affecting the upper limb. Research has centered on factors influencing the varying degrees of motor deficit in UCP, using neuroscience advancements for in vivo exploration of brain structure (morphometry) and cortical reorganization (functional magnetic resonance imaging (fMRI)). This study aims to evaluate functional activation in the motor cortex in UCP and to explore how lesion characteristics and timing affect neuroplasticity and motor function. Materials and Methods: Between 2017 and 2021, structural and functional MRIs were performed on 44 UCP patients (mean age 15.5 years, 24 males, 20 females), all with Manual Ability Classification System (MACS) levels I-III and Intelligence Quotient (IQ) ≥ 50. The lesion characteristics of size, type, and time of occurrence (ante-, peri-, or early postnatal) were analyzed. An association was sought between the characteristics of the lesion and the degree of motor deficit of the upper limb, as determined by the MACS level. fMRI assessed cortical activation during a finger-tapping task for the paretic hand and compared activation patterns based on lesion characteristics. Results: Six lesion types were identified, with arterial ischemic stroke being the most common and largest in volume. Lesion size strongly correlated with patients’ MACS levels, while lesion type and timing showed no association with the severity of motor impairment classified by MACS. Motor reorganization varied, with activation occurring ipsi-, contra-, or bilaterally to the affected hand, depending on lesion size and type. Smaller, subcortical lesions primarily showed ipsilesional activation, while larger, cortical lesions did not exhibit a specific group activation, possibly due to varying individual reorganization. No association was found between the lesion timing and the reorganization model. Conclusions: Motor functional reorganization in UCP is closely linked to lesion characteristics, with smaller, subcortical lesions favoring typical organization in the contralateral motor cortex. The timing of the lesion does not significantly affect cortical reorganization. Lesion size was a key determinant of motor function, whereas lesion type (e.g., ischemic stroke) and timing (early vs. late occurrence) were less critical for predicting functional outcome.

Neural mechanisms of behavioral addiction: AnALE meta-analysis and MACM analysis.

Behavioral addictions (BAs) represent complex and multifaceted disorders often associated with maladaptive neural alteration. To deepen our understanding of the essence of BAs, this study focuses on the neural mechanisms underlying its three stages: reward seeking, self-control, and decision-making. The aim of the current meta-analysis is to investigate the brain regions and neural networks involved in BAs. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched for relevant articles published before September 1, 2024, in the Web of Science and PubMed databases, and supplemented our search with Google Scholar. We conducted analyses using activation likelihood estimation (ALE) meta-analysis and meta-analytic connectivity modeling (MACM) analyses. A total of 50 functional magnetic resonance imaging studies involving 906 participants were included. The findings showed that individuals with BAs exhibited hyperactivation in the right inferior frontal gyrus (IFG), bilateral caudate and left middle frontal gyrus (MFG), and a high degree of connectivity was found between the right caudate, left caudate, and right IFG. These findings indicated that BAs were associated with the fronto-striatal circuits. Individuals with BAs demonstrate specific neural activation patterns in the reward seeking, self-control, and decision-making stages, characterized by differences in activation and functional connectivity of brain regions associated with these stages. This study verifies the pivotal role of the fronto-striatal circuits in BAs and highlights the specific patterns of brain activity in different stages of addictive behavior. These findings expand our understanding of neural mechanisms underlying BAs and supports and provide partial support for the I-PACE model.

Distribution and role of peripheral arterial chemoreceptors in cardio-respiratory control of the south american rattlesnake (Crotalus durissus).

Peripheral arterial chemoreceptors monitor the levels of arterial blood gases and adjust ventilation and perfusion to meet metabolic demands. These chemoreceptors are present in all vertebrates studied to date but have not been described fully in reptiles other than turtles. The goals of this study were to 1) identify functional chemosensory areas in the South American rattlesnake (Crotalus durissus) 2) determine the neurochemical content of putative chemosensory cells in these areas and 3) determine the role each area plays in ventilatory and cardiovascular control. To this end, rattlesnakes were instrumented with transonic flow probes, arterial catheters, and subcutaneous impedance electrodes to measure shunt fraction, heart rate, blood pressure and ventilation, respectively. The catheters were placed at three putative chemosensory sites, the bases of the aortic arch, pulmonary artery, as well as at the carotid bifurcation, for site specific activation with sodium cyanide (NaCN, 0.5mg/0.1ml). These same sites were subsequently examined using immunohistochemical markers for acetylcholine, tyrosine hydroxylase (TH, the rate limiting enzyme in catecholamine synthesis) and serotonin, to identify putative oxygen-sensing cells. All three sites were chemosensory and stimulating each led to cardiovascular (shunt fraction and heart rate) and respiratory adjustments although not in an identical fashion. All three chemosensory areas contained cells positive for serotonin (5-HT), however, cells positive for vesicular acetylcholine transporter (VAChT) were found only in the aorta and pulmonary artery. We found no labeling for TH at any site.

Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia.

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR+) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR+ neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABAA receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR+ neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.

Deep topic modeling of spatial transcriptomics in the rheumatoid arthritis synovium identifies distinct classes of ectopic lymphoid structures.

Single-cell RNA sequencing studies have revealed the heterogeneity of cell states present in the rheumatoid arthritis (RA) synovium. However, it remains unclear how these cell types interact with one another in situ and how synovial microenvironments shape observed cell states. Here, we use spatial transcriptomics (ST) to define stable microenvironments across eight synovial tissue samples from six RA patients and characterize the cellular composition of ectopic lymphoid structures (ELS). To identify disease-relevant cellular communities, we developed DeepTopics, a scalable reference-free deconvolution method based on a Dirichlet variational autoencoder architecture. DeepTopics identified 22 topics across tissue samples that were defined by specific cell types, activation states, and/or biological processes. Some topics were defined by multiple colocalizing cell types, such as CD34 + fibroblasts and LYVE1 + macrophages, suggesting functional interactions. Within ELS, we discovered two divergent cellular patterns that were stable across ELS in each patient and typified by the presence or absence of a "germinal-center-like" topic. DeepTopics is a versatile and computationally efficient method for identifying disease-relevant microenvironments from ST data, and our results highlight divergent cellular architectures in histologically similar RA synovial samples that have implications for disease pathogenesis.

Nanostructured lipid carriers based mRNA vaccine leads to a Tcell-inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour model.

mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) invitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Our vaccine activates DCs invitro through the TLR4/8 and ROS signalling pathways and induces specific Tcell activation while exhibits significant preventive and therapeutic antitumour efficacy invivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. This work was supported by Inserm Transfert, la Région Auvergne Rhône Alpes, FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411).

Application Strategies of Super-Enhancer RNA in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are a leading cause of death worldwide, and new therapeutic strategies are urgently needed. In recent years, enhancer RNAs (eRNAs) have gradually attracted attention because they offer new directions for the treatment of CVDs. Super-enhancer RNAs (seRNAs) are a subset of non-coding RNAs that are transcribed from regions of the genome known as super enhancers, which are large clusters of enhancers with a high density of transcription factors and cofactors. These regions play a pivotal role in regulating genes involved in cell identity and disease progression. This article reviews the characteristics of seRNAs, their expression patterns, and regulatory mechanisms in the cardiovascular system. We also explore their role in the occurrence and development of CVDs, as well as their potential as diagnostic biomarkers and therapeutic targets. Currently, therapies targeting seRNAs are a research hotspot. The development of specific inhibitors or activators is expected to facilitate precise interventions for CVDs. In addition, the use of gene editing techniques to modify relevant eRNA introduces new possibilities for disease treatment. This review aims to provide a comprehensive overview of seRNAs in CVDs and discusses their potential as a novel class of therapeutic targets.

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery.

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors' signaling capabilities. Targeting more variable allosteric sites, which are spatially different from the highly conserved orthosteric sites, represents a novel approach in biased GPCR drug discovery, leading to innovative strategies for targeting GPCRs. Notably, the emergence of cryptic allosteric sites on GPCRs has expanded the repertoire of available drug targets and improved receptor subtype selectivity. Here, we conduct a summary of recent progress in the structural determination of cryptic allosteric sites on GPCRs and elucidate the biased signaling mechanisms induced by allosteric modulators. Additionally, we discuss means to identify cryptic allosteric sites and design biased allosteric modulators based on cryptic allosteric sites through structure-based drug design, which is an advanced pharmacotherapeutic approach for treating GPCR-associated diseases.

Ano5Cys360Tyr mutation leads to bone dysfunction of gnathodiaphyseal dysplasia via disturbing Akt signaling.

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease characterized by osteosclerosis of the tubular bones and cemento-osseous lesions of the mandibles. Anoctamin 5 (ANO5) is the pathogenic gene, however, the specific molecular mechanism of GDD remains unclear. Herein, a knockin (Ano5 KI/KI ) mouse model expressing the human mutation p.Cys360Tyr was used to investigate the role of Akt signaling in enhanced osteogenesis and decreased osteoclastogenesis in GDD. Bone marrow-derived macrophages (BMMs) and mouse calvarial osteoblasts (mCOBs) were isolated from homozygous Ano5 KI/KI mice and treated with SC79, a specific Akt activator. The differentiation and F-actin ring formation of osteoclasts were examined by TRAP and phalloidin staining, respectively. Osteoblast differentiation and mineralization were examined by ALP and alizarin red staining. The expression of bone remodeling-related factors was measured by qRT-PCR. Akt activation promoted the generation of TRAP-positive multinucleated osteoclasts and the formation of actin rings in Ano5 KI/KI BMMs cultures, accompanied by increased expression of Nfatc1, Trap, Dc-stamp, Mmp9, Ctsk, and Atp6v0d2. Additionally, Ano5 Cys360Tyr mutation down-regulated the Akt phosphorylation level in osteoblast. ALP activity and matrix mineralization capacity in Ano5 KI/KI osteoblast cultures were inhibited after SC79 stimulation, with reduced expression of Runx2, Opn, Col1a1, and Ocn. Akt activation by SC79 stimulation can obviously rescue abnormal increased osteogenesis and decreased osteoclastogenesis in Ano5 KI/KI mouse model, which demonstrated that disturbed Akt signaling pathway may play a pivotal role in the pathogenesis of GDD, and an Akt activator is probable a therapeutic target for GDD.

Autophagy-targeted Pt(IV) agents: a new horizon in antitumor drug development.

Pt(IV) complexes as prodrugs of Pt(II) drugs exhibit numerous advantages such as enhanced stability, reduced toxicity, increased oral bioavailability, and efficacy in overcoming the drug resistance of Pt(II) compounds, which underscore their significant potential in the advancement of novel Pt anticancer agents. Furthermore, protective autophagy is pivotal in sustaining tumor cell homeostasis and modulating the tumor microenvironment (TME), thereby representing a critical target for the development of antitumor drugs. Specific inhibition or activation of autophagy during chemotherapy would break the internal homeostasis in the TME and increase antitumor activities. Consequently, developing novel Pt(IV) antitumor agents with autophagy-targeting capabilities by incorporating autophagy-regulating moieties into the Pt(IV) framework has emerged as a hot topic in the discovery of novel Pt drugs. Herein, the research progress in novel Pt(IV) antitumor drugs with autophagy-targeted properties is systematically reviewed based on the literature. The future challenges and perspectives of this fascinating class of conjugates are also discussed, aiming to provide new insights and approaches for the future design and investigation of novel Pt antitumor drugs.

Two TAL Effectors of Xanthomonas citri pv. malvacearum Induce Water Soaking by Activating GhSWEET14 Genes in Cotton.

Bacterial blight of cotton (BBC) caused by Xanthomonas citri pv. malvacearum (Xcm) is an important and destructive disease affecting cotton plants. Transcription activator-like effectors (TALEs) released by the pathogen regulate cotton resistance to the susceptibility. In this study, we sequenced the whole genome of Xcm Xss-V2-18 and identified eight tal genes: seven on the plasmids and one on the chromosome. Deletion and complementation experiments of Xss-V2-18 tal genes demonstrated that Tal1b is required for full virulence on cotton. Transcriptome profiling coupled with TALE-binding element prediction revealed that Tal1b targets GhSWEET14A04/D04 and GhSWEET14D02 simultaneously. Expression analysis confirmed the independent inducibility of GhSWEET14A04/D04 and GhSWEET14D02 by Tal1b, whereas GhSWEET14A04/D04 is additionally targeted by Tal1. Moreover, β-glucuronidase and Xa10-mediated hypersensitive response assays indicated that the effector-binding element (EBEs) are required for the direct and specific activation of the candidate targets by Tal1 and Ta1b. These insights enhance our understanding of the underlying mechanisms of bacterial blight in cotton and might lead to improved resistance through EBEs disruption or a TALE-trap strategy.

EFFECT OF TRANSCRIPTION FACTOR MODULATORS ON THE NITRIC OXIDE SYSTEM PARAMETERS IN THE BLOOD OF RATS UNDER LIPOPOLYSACCHARIDE-INDUCED SYSTEMIC INFLAMMATORY RESPONSE

The study aimed to investigate the effect of transcription factor modulators on nitric oxide (NO) system parameters in the blood of rats under lipopolysaccharide (LPS)-induced systemic inflammatory response (SIR). The experiment was conducted on 42 male Wistar rats weighing 180–220 g, divided into 6 groups (7 animals per group): Group 1 included intact rats (Control I); Group 2 involved rats, which underwent LPS-induced systemic inflammatory response (SIR) modeling (Control II). In the remaining groups, transcription factor modulators were administered under SIR modeling: Group 3 received the anticancer drug bortezomib (used to treat multiple myeloma and mantle cell lymphoma), an NF-κB inhibitor (via proteasome suppression); Group 4 received the anticancer agent SR 11302 (investigated as a potential treatment for lung cancer), an inhibitor of the transcription factor AP-1; Group 5 received dimethyl fumarate, a specific activator of the Nrf2–ARE signaling pathway; Group 6 was administered with quercetin, a flavonoid that acts as an NF-κB inhibitor and an Nrf2 pathway activator. The results showed that LPS-induced SIR significantly increased total NOS and iNOS activity while reducing cNOS and arginase activity in blood serum. This indicates the development of nitrosative stress and impaired L-arginine metabolism in rats. The use of NF-κB inhibitors (bortezomib) and AP-1 inhibitors (SR 11302), as well as Nrf2 activators (dimethyl fumarate and quercetin) reduced iNOS activity and partially normalized cNOS activity, demonstrating their anti-inflammatory and metabolic effects. The most effective agents for correcting nitrosative stress in SIR were bortezomib and SR 11302, which reduced iNOS activity to near-intact levels and partially restored the functional activity of cNOS. Most transcription factor modulators (bortezomib, dimethyl fumarate, quercetin) partially restored arginase activity, highlighting their potential role in correcting impaired L-arginine metabolism. However, the AP-1 inhibitor (SR 11302) further decreased arginase activity compared to the LPS-induced group, suggesting possible inhibition of compensatory enzyme mechanisms and an exacerbation of metabolic imbalance. The findings confirm the key roles of the NF-κB, AP-1, and Nrf2 signaling pathways in regulating nitrosative stress, offering promising pharmacological targets for correcting inflammatory and metabolic disturbances.

Change on the Brain? The Neuroscience of Organizational Transformation

True transformations aim to change the core identity of an organization, are often disruptive, and rarely result in their intended outcomes. The objective of this paper is to propose a theoretical approach for more effective transformations via the syntheses of emerging findings in managerial science, organizational psychology, and social cognitive neuroscience. The authored conducted a literature review of traditional methods and the application of neuroscience to organizational transformation, proposing that consideration to leader and employee neuroanatomy can significantly impact transformation success. The emergent five-phase approach - Exploration & Discovery, Surfacing & Co-Creation, Enablement & Prioritization, Implementation, and Empowerment - integrates practices informed by neuroscience to enhance leadership alignment, employee engagement, and change sustainability. By focusing on activities such as vision alignment, co-creation, and leadership development, the approach seeks to optimize brain functions related to trust, motivation, and adaptability. Neuroscientific concepts like neural synchrony, hormone and neurotransmitter release, and specific neural circuit activations are utilized to improve team dynamics, decision-making, and learning. This neuro-informed approach challenges conventional practices by emphasizing co-creative solutioning with employees, piloting programs, and empowering middle managers to lead transformation efforts. Data from case studies demonstrate significant improvements in employee experience and sustainable shifts in organizational behavior. The paper concludes with a call for further research to solidify the emerging intersection of neuroscience and organizational transformation.

The AMPK allosteric activator MK-8722 improves thehistology and spliceopathy in myotonic dystrophy type1(DM1) skeletal muscle.

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSALR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSALR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK.

Thyroid peroxidase antibodies: prevalence and assessment of immunological parameter in the context of search for new predictive markers of hypothyroidism

BACKGROUND:The annual incidence of autoimmune pathologies is increasing. Studying the causes of their development and preventive measures are important. Despite the availability of analysis of antibodies to thyroid peroxidase (TPOAb), statistical data of the prevalence of AIT is incorrect. An identification of key molecular mechanisms is important for developing effective diagnostic and preventive strategies for preventing progression hypothyroidism. AIM:Assessment of the prevalence of TPOAb and the search for correlations of immunological parameters and the degree of thyroid dysfunction in AIT. MATERIALS AND METHODS:We examined 580 people over the age of 18. We measured serum levels of TSH, freeT4, TPOAb, did thyroid ultrasound, collected anamnesis. Part of them we evaluated immunological parameters: Treg; Breg; B10-lymphocytes; IFNγ, IL-17, IL-4 T lymphocytes. RESULTS:An increased level of TPOAb was detected in 143 individuals (24.7%). 73 (51.41%) of them had nodular goiter, 60 (41.96%) had hypothyroidism. We found significant differences between people with high level of TPOAb and healthy individuals in levels of TSH, ultrasound’s signs of autoimmune changes and information about having 3 or more children (p 0,001). We found significant correlation in level of TPOAb and having many children (p=0,037). We found a difference in count of Breg (in vitro incubation with additional activation) in the group of people with high levels of TPOAb and healthy donors, but without low level of IL-10 expression. We didn’t find significant differences in count of Treg, but degree of Treg’s induction was reduced when we added a specific activator. Impaired functional activity can be reason of it. CONCLUSION:Prevalence of high level of TPOAb – 24.6%. Women with 3 or more children had higher prevalence of high level of TPOAb, and significant correlation with level of TPOAb. Having many children can be risk factor of developing AIT. The study showed the expected difference in the amount of Breg in the group of people with high level of TPOAb, however, lower induction of IL-10 wasn’t observed. Further fundamental research is needed with larger target samples of individuals with AIT in the search for new prognostic markers of the development and progression of the disease.

Convergence of type 1 spiral ganglion neuron subtypes onto principal neurons of the anteroventral cochlear nucleus.

The mammalian auditory system encodes sounds with subtypes of spiral ganglion neurons (SGNs) that differ in sound level sensitivity, permitting discrimination across a wide range of levels. Recent work suggests the physiologically-defined SGN subtypes correspond to at least three molecular subtypes. It is not known how information from the different subtypes converges within the cochlear nucleus. We examined this issue using transgenic mice of both sexes that express Cre recombinase in SGNs that are positive for markers of two of these subtypes: CALB2 (calretinin) in type 1a SGNs, and LYPD1 in type 1c SGNs, which correspond to high- and low-sensitivity subtypes, respectively. We crossed these with mice expressing floxxed channelrhodopsin, which allowed specific activation of axons from type 1a or 1c SGNs using optogenetics. We made voltage-clamp recordings from bushy cells in the anteroventral cochlear nucleus (AVCN) and found that the synapses formed by CALB2- and LYPD1-positive SGNs had similar EPSC amplitudes and short-term plasticity. Immunohistochemistry revealed that individual bushy cells receive a mix of 1a, 1b, and 1c synapses with VGluT1-positive puncta of similar sizes. We used optogenetic stimulation during in vivo recordings to classify chopper and primary-like units as receiving vs. not-receiving 1a- or 1c-type inputs. These groups showed no significant difference in threshold or spontaneous rate, suggesting the subtypes do not segregate into distinct processing streams in the AVCN. Our results indicate that principal cells in the AVCN integrate information from all SGN subtypes with extensive convergence, which could optimize sound encoding across a large dynamic range.Significance statement Sound information is carried to the brain by auditory afferents that differ in their sensitivity to sound. Auditory afferents fall into three subtypes differing in their spontaneous and sound-evoked activity. These subtypes can be distinguished by anatomical, physiological, and molecular features. However, it is not well understood how the three subtypes relay information to the brain. We addressed this question using optogenetic stimulation to study the properties of two afferent subtypes in the anteroventral part of the cochlear nucleus. We found that the properties of synapses are indistinguishable between subtypes, and they show extensive convergence, suggesting that combining inputs with different sound level sensitivity is important for processing sound.