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Cureus May 2024The introduction of OpenAI's ChatGPT-4omni (GPT-4o) represents a potential advancement in virtual healthcare and telemedicine. GPT-4o excels in processing audio, visual,...
The introduction of OpenAI's ChatGPT-4omni (GPT-4o) represents a potential advancement in virtual healthcare and telemedicine. GPT-4o excels in processing audio, visual, and textual data in real time, offering possible enhancements in understanding natural language in both English and non-English contexts. Furthermore, the new "Temporary Chat" feature may improve privacy and data confidentiality during interactions, potentially increasing integration with healthcare systems. These innovations promise to enhance communication clarity, facilitate the integration of medical images, and increase data privacy in online consultations. This editorial explores some future implications of these advancements for telemedicine, highlighting the necessity for further research on reliability and the integration of advanced language models with human expertise.
PubMed: 38817799
DOI: 10.7759/cureus.61377 -
International Immunopharmacology Nov 2023Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation...
Metformin, a first-line drug for type-2 diabetes, displays pleiotropic effects on inflammation, aging, and cancer. Obesity triggers a low-grade chronic inflammation leading to insulin resistance, characterized by increased pro-inflammatory cytokines produced by adipocytes and infiltrated immune cells, which contributes to metabolic syndrome. We investigated metformin's differentiation and immunoregulatory properties of human umbilical cord-mesenchymal stem cells (UC-MSC), as cellular basis of its beneficial role in metabolic dysfunctions. Isolation, characterization and multilineage differentiation of UC-MSC were performed using standard protocols and flow-cytometry. Metformin effects on UC-MSC growth was assessed by colony formation and MTT assay, gene and protein expression by qRT-PCR, and western blot analysis. Proliferation of peripheral blood mononuclear cells (PBMCs) co-cultured with metformin-treated UC-MSC-conditioned media was evaluated by dye dilution assay. We show that metformin decreases proliferation and colony formation of UC-MSCs and enhances their adipogenic lineage commitment. Metformin (3 mM) increases PPARγ and downregulates FABP4 mRNA both in basal and in adipogenic culture conditions; however, the modulation of PPARγ expression is unrelated to the antiproliferative effects. Moreover, metformin inhibits UC-MSC inflammatory activity reducing the expression of IL-6, MCP-1, and COX-2. Conditioned media, collected from metformin-treated UC-MSCs, down-regulate CD3 T lymphocyte growth in stimulated PBMCs and, in particular, reduce the CD8 T cell population. These results indicate that metformin may favor new adipocyte formation and potentiate immune suppressive properties of UC-MSCs. Thus, adipose tissue regeneration and anti-inflammatory activity may represent possible mechanisms by which metformin exerts its positive effect on lipid metabolism.
Topics: Humans; Culture Media, Conditioned; Immunosuppressive Agents; Leukocytes, Mononuclear; Metformin; PPAR gamma; Cell Differentiation; Umbilical Cord; Inflammation; Mesenchymal Stem Cells; Cells, Cultured
PubMed: 37844465
DOI: 10.1016/j.intimp.2023.111078 -
Cellular and Molecular Life Sciences :... Sep 2023Allogeneic stem cell transplantation (alloSCT) can be curative for hemato-oncology patients due to effective graft-versus-tumor immunity. However, relapse remains the...
Human CD34-derived complete plasmacytoid and conventional dendritic cell vaccine effectively induces antigen-specific CD8 T cell and NK cell responses in vitro and in vivo.
Allogeneic stem cell transplantation (alloSCT) can be curative for hemato-oncology patients due to effective graft-versus-tumor immunity. However, relapse remains the major cause of treatment failure, emphasizing the need for adjuvant immunotherapies. In this regard, post-transplantation dendritic cell (DC) vaccination is a highly interesting strategy to boost graft-versus-tumor responses. Previously, we developed a clinically applicable protocol for simultaneous large-scale generation of end-stage blood DC subsets from donor-derived CD34 stem cells, including conventional type 1 and 2 DCs (cDC1s and cDC2s), and plasmacytoid DCs (pDCs). In addition, the total cultured end-product (DC-complete vaccine), also contains non-end-stage-DCs (i.e. non-DCs). In this study, we aimed to dissect the phenotypic identity of these non-DCs and their potential immune modulatory functions on the potency of cDCs and pDCs in stimulating tumor-reactive CD8 T and NK cell responses, in order to obtain rationale for clinical translation of our DC-complete vaccine. The non-DC compartment was heterogeneous and comprised of myeloid progenitors and (immature) granulocyte- and monocyte-like cells. Importantly, non-DCs potentiated toll-like receptor-induced DC maturation, as reflected by increased expression of co-stimulatory molecules and enhanced cDC-derived IL-12 and pDC-derived IFN-α production. Additionally, antigen-specific CD8 T cells effectively expanded upon DC-complete vaccination in vitro and in vivo. This effect was strongly augmented by non-DCs in an antigen-independent manner. Moreover, non-DCs did not impair in vitro DC-mediated NK cell activation, degranulation nor cytotoxicity. Notably, in vivo i.p. DC-complete vaccination activated i.v. injected NK cells. Together, these data demonstrate that the non-DC compartment potentiates DC-mediated activation and expansion of antigen-specific CD8 T cells and do not impair NK cell responses in vitro and in vivo. This underscores the rationale for further clinical translation of our CD34-derived DC-complete vaccine in hemato-oncology patients post alloSCT.
Topics: Humans; CD8-Positive T-Lymphocytes; Interleukin-12; Dendritic Cells; Lymphocyte Activation; Antigens, CD34; Cell Adhesion Molecules
PubMed: 37728691
DOI: 10.1007/s00018-023-04923-4 -
Nature Communications Nov 2023The auditory striatum, a sensory portion of the dorsal striatum, plays an essential role in learning and memory. In contrast to its roles and underlying mechanisms in...
The auditory striatum, a sensory portion of the dorsal striatum, plays an essential role in learning and memory. In contrast to its roles and underlying mechanisms in operant conditioning, however, little is known about its contribution to classical auditory fear conditioning. Here, we reveal the function of the auditory striatum in auditory-conditioned fear memory. We find that optogenetically inhibiting auditory striatal neurons impairs fear memory formation, which is mediated through the striatal-amygdala pathway. Using calcium imaging in behaving mice, we find that auditory striatal neuronal responses to conditioned tones potentiate across memory acquisition and expression. Furthermore, nigrostriatal dopaminergic projections plays an important role in modulating conditioning-induced striatal potentiation. Together, these findings demonstrate the existence of a nigro-striatal-amygdala circuit for conditioned fear memory formation and expression.
Topics: Mice; Animals; Dopamine; Acoustic Stimulation; Amygdala; Learning; Fear
PubMed: 37945595
DOI: 10.1038/s41467-023-43066-9 -
BioRxiv : the Preprint Server For... Aug 2023Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and...
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
PubMed: 37645843
DOI: 10.1101/2023.08.10.552854 -
Stem Cell Research & Therapy Jul 2023Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains...
BACKGROUND
Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study.
METHODS
Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency.
RESULTS
FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages.
CONCLUSION
These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.
Topics: Animals; Humans; Mice; Cell Differentiation; Cellular Senescence; Forkhead Transcription Factors; Histone Deacetylases; Mesenchymal Stem Cells; Repressor Proteins
PubMed: 37507770
DOI: 10.1186/s13287-023-03376-7 -
Heliyon Aug 2023The East Hararghe Zone (EHZ) is one of the eastern Ethiopian zones most endowed with diverse landscapes and abundant resources to promote and use for ecotourism...
The East Hararghe Zone (EHZ) is one of the eastern Ethiopian zones most endowed with diverse landscapes and abundant resources to promote and use for ecotourism development. Potential ecotourism sites have, however, hardly ever been explored so far. The objective of this study was to model and identify potential ecotourism sites by combining Geographic Information System (GIS)-based Multi-Criteria Decision-Making (MCDM) and Analytical Hierarchy Process (AHP) methods. Six criteria, including landscape and naturalness, wildlife, topography, accessibility, geology, and climate, were established based on experts' preferences and literature, and the thematic factors for suitability modeling were derived from freely accessible satellite imagery and existing geospatial data and combined using a weighted linear combination (WLC) method. The results reveal that about 26.19% were highly suitable, 35.34% were moderately suitable, 25.28% were marginally suitable, and 13.17% were not suitable. Most areas with high to marginal suitability were found in the southeast, southwest, and uplands in the northern part, while the southernmost extent had the highest proportion of areas unsuitable for ecotourism development. The area under the curve (AUC) assessment has verified the model's performance, resulting in an overall AUC of 74.96%. This suggests that a model-driven map is a reliable spatial support tool for sustainable ecotourism development in areas with diverse landscapes and resources.
PubMed: 37520969
DOI: 10.1016/j.heliyon.2023.e18567 -
Cardiovascular Toxicology May 2024The challenge posed by opioid overdose has become a significant concern for health systems due to the complexities associated with drug prohibition, widespread clinical... (Review)
Review
The challenge posed by opioid overdose has become a significant concern for health systems due to the complexities associated with drug prohibition, widespread clinical use, and potential abuse. In response, healthcare professionals have primarily concentrated on mitigating the hallucinogenic and respiratory depressant consequences of opioid overdose to minimize associated risks. However, it is crucial to acknowledge that most opioids possess the capacity to prolong the QT interval, particularly in cases of overdose, thereby potentially resulting in severe ventricular arrhythmias and even sudden death if timely intervention is not implemented. Consequently, alongside addressing the typical adverse effects of opioids, it is imperative to consider their cardiotoxicity. To enhance comprehension of the correlation between opioids and arrhythmias, identify potential targets for prompt intervention, and mitigate the hazards associated with clinical utilization, an exploration of the interaction between drugs and ion channels, as well as their underlying mechanisms, becomes indispensable. This review primarily concentrates on elucidating the impact of opioid drugs on diverse ion channels, investigating recent advancements in this domain, and attaining a deeper understanding of the mechanisms underlying the prolongation of the QT interval by opioid drugs, along with potential interventions.
Topics: Humans; Long QT Syndrome; Analgesics, Opioid; Animals; Cardiotoxicity; Risk Assessment; Risk Factors; Heart Rate; Action Potentials; Heart Conduction System; Ion Channels; Opiate Overdose
PubMed: 38630336
DOI: 10.1007/s12012-024-09853-6 -
BioRxiv : the Preprint Server For... Sep 2023TrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-β (Aβ)-toxicity. Upregulating TrkB/C signaling could...
A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model.
INTRODUCTION
TrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-β (Aβ)-toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction.
METHODS
PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APP ) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing.
RESULTS
Memory and LTP deficits in APP mice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription.
CONCLUSIONS
BD10-2 prevented APP /Aβ-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.
PubMed: 37781573
DOI: 10.1101/2023.09.18.558138 -
Molecular Pain 2024The anterior cingulate cortex (ACC) is a key cortical area for pain perception, emotional fear and anxiety. Cortical excitation is thought to be the major mechanism for... (Review)
Review
The anterior cingulate cortex (ACC) is a key cortical area for pain perception, emotional fear and anxiety. Cortical excitation is thought to be the major mechanism for chronic pain and its related emotional disorders such as anxiety and depression. GluN2B (or called NR2B) containing NMDA receptors play critical roles for such excitation. Not only does the activation of GluN2B contributes to the induction of the postsynaptic form of LTP (post-LTP), long-term upregulation of GluN2B subunits through tyrosine phosphorylation were also detected after peripheral injury. In addition, it has been reported that presynaptic NMDA receptors may contribute to the modulation of the release of glutamate from presynaptic terminals in the ACC. It is believed that inhibiting subtypes of NMDA receptors and/or downstream signaling proteins may serve as a novel therapeutic mechanism for future treatment of chronic pain, anxiety, and depression.
Topics: Humans; Gyrus Cinguli; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Chronic Pain; Synapses; Long-Term Potentiation
PubMed: 38246915
DOI: 10.1177/17448069241230258