Unique Pathway Research Articles

Proteomics in Acute Heart Transplant Rejection, On Behalf of the GRAfT Investigators.

Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets. Within the prospective, multicenter Genomic Research Alliance for Transplantation study, 181 proteins were evaluated from blood drawn at the time of endomyocardial biopsy; protein fold change, logistic regression, and pathway analyses were conducted, with protein discovery adjusted for a 5% false discovery rate. Among 104 adult heart transplant patients (31% female sex, 53% Black race, median age 52 y), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR). Differential expression was found in 2 proteins during ACR (inflammatory proteins CXCL10 and CD5) and 73 proteins during AMR. The most abundant AMR proteins were the heart failure biomarkers N-terminal pro-B-type natriuretic peptide and suppression of tumorigenicity 2. In univariate logistic regression, odds of identifying ACR on endomyocardial biopsy increased with doubling of CXCL10 (odds ratio [OR] 2.2 [95% confidence interval (CI), 1.3-3.6]) and CD5 (OR 4.7 [95% CI, 1.7-12.9]) concentrations, and odds of AMR increased with doubling of N-terminal pro-B-type natriuretic peptide (OR 13.0 [95% CI, 2.7-62.7) and suppression of tumorigenicity 2 (OR 4.8 [95% CI, 2.1-10.7]) concentrations. After multivariable analysis with clinical covariates, these proteins showed similar odds of ACR or AMR on biopsy. Pathway analysis identified T cell-receptor signaling and cell differentiation as key pathways in ACR and cardiovascular disease and cell turnover in AMR. Proteomic analysis reveals unique biomarkers and biological pathway expression in ACR and AMR. Cardiac injury-associated biomarkers were more pronounced in AMR, whereas inflammatory biomarkers were more pronounced in ACR. Proteomic analysis may provide insights into rejection pathophysiology, detection, and therapy.

Revealing the Overlooked Catalytic Ability of γ-Al2O3: Efficient Activation of Peroxymonosulfate for Enhanced Water Treatment.

Activated alumina (γ-Al2O3) is one of the few nanomaterials manufactured at a ton-scale and successfully implemented in large-scale water treatment. Yet its role in advanced oxidation processes (AOPs) has primarily been limited to functioning as an inert carrier due to its inherently nonredox nature. This study, for the first time, presents the highly efficient capability of γ-Al2O3 to activate peroxymonosulfate (PMS) for selectively eliminating electron-rich organic pollutants in the presence of Cl-. Through experimental and theoretical analysis, we revealed that γ-Al2O3, characterized by uniquely strong Lewis acid sites, enabled robust inner-sphere complexation between PMS and Al(III) sites, triggering the oxidation of Cl- to free chlorine through a distinctive, low-energy-barrier Eley-Rideal pathway. Such a unique pathway resulted in a 42.7-fold increase in free chlorine generation, culminating in a remarkable 145.9-fold enhancement in the degradation of carbamazepine (CBZ) compared with the case without γ-Al2O3. Furthermore, this catalyst exhibited high oxidant utilization efficiency, stable performance in real-world environmental matrices, and sustained long-term activation for over 1206 bed volumes (BV) with a CBZ removal rate exceeding 90% in fixed-bed experiments. These favorable features render γ-Al2O3 an extremely promising nanomaterial for sustainable water treatment initiatives.

Protective effect of UDCA against IL-11- induced cardiac fibrosis is mediated by TGR5 signalling.

Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.

In-situ oxidative polymerization of dopamine triggered by CuO2 in acidic condition and application in "turn-off" sensing.

Dopamine (DA) is a key neurotransmitter whose concentration affects various neurological disorders. Unlike previous methods that synthesize non-fluorescent polydopamine (NFL-PDA) under alkaline conditions, this study introduces a novel "turn-off" sensing method for DA using NFL-PDA synthesized through a unique reaction pathway. In our approach, CuO2 nanodots, created via a simple reduction method, catalyze the formation of hydroxyl radicals (•OH) in acidic conditions, triggering the oxidative polymerization of DA into NFL-PDA. The reaction between DA and CuO2 nanodots in acidic solution was examined to understand the process. UiO-66-NH2 was then used to test NFL-PDA's fluorescence quenching ability and to further investigate the DA determination mechanism. Results showed that fluorescence quenching was due to enhanced non-radiative energy transfer and Förster resonance energy transfer (FRET) between NFL-PDA and UiO-66-NH2. This led to the development of a simple "turn-off" fluorometric DA determination method with a linear range of 0.1-200μmol/L and a limit of detection (LOD) of 0.0575μmol/L. Although this method does not outperform existing NFL-PDA synthesis methods under alkaline conditions, it provides a new synthesis approach and application for sensing DA, contributing to the basic theory of chemical sensing. Additionally, DA determination in human serum samples was successfully achieved, with results consistent with high-performance liquid chromatography (HPLC).

Hydrogen Isotope Labeling of Pharmaceuticals Via Dual Hydrogen Isotope Exchange Pathways Using CdS Quantum Dot Photocatalyst.

Isotopic labeling is a powerful technique extensively used in the pharmaceutical industry. By tracking isotope-labeled molecules, researchers gain unique and invaluable insights into the pharmacokinetics and pharmacodynamics of new drug candidates. Hydrogen isotope labeling is particularly important as hydrogen is ubiquitous in organic molecules in biological systems, and it can be introduced effectively through late-stage hydrogen isotope exchange (HIE). However, hydrogen isotope methods that simultaneously label multiple sites with varying types of C-H bonds in the different types of molecules are still lacking. Herein, we demonstrate a heterogeneous photocatalytic system using a CdS quantum dot catalyst that proceeds via a unique dual HIE pathway mechanism─one occurs in the reaction solution and the other on the catalytic surface─to address it. This unique mechanism unlocked several unique labeling capabilities, including simultaneous labeling of multiple and challenging sites such as secondary α-amino, α-ethereal, allyl, and vinyl sites, providing great versatility in practical uses for pharmaceutical labeling.

Understanding the evolution of domestic dogs

This article discusses the process of domestication, and the outcomes of domestication, and the evolutionary history of dogs. The essay also describes the processes that led to the evolution of domestic dogs and investigates the causes of the enormous variety of dog breeds. This research shows the complex interactions between humans and dogs throughout the history by analyzing genetic, and social aspects. It also provides insights into how this special relationship has formed the diversity of breeds that exist today. Additionally, the article provides a detailed examination of the Chinese Village Dog, an indigenous breed of China, highlighting its unique evolutionary pathway, genetic diversity, and cultural significance. Through the analysis of ancient texts and archaeological findings, this research sheds light on the longstanding relationship between Chinese Village Dogs and human communities, as well as the ongoing challenges and conservation efforts aimed at preserving indigenous Asian dog breeds.

Surface hydroxyls of spinel oxides: A double-edged sword in the peroxymonosulfate activation process

The sulfate-based advanced oxidation process (SR-AOP) mediated by spinel oxides has shown great potential in pollutant degradation. However, the role of surface hydroxyls in the reaction process remains unclear, especially in real environments containing salts. Here, we investigated the role of surface hydroxyls of spinel oxides in activating peroxymonosulfate (PMS). By adjusting the intrinsic composition of the metal elements, we synthesized a CoFeMnO4 spinel with high surface hydroxyls using a simple and scalable co-precipitation method. CoFeMnO4 demonstrated unparalleled activation performance and a unique non-radical activation pathway (dominated by high-valence metal-oxo species and singlet oxygen), achieving 100 % sulfamethoxazole degradation within 4 min with a low concentration of PMS. Surface hydroxyls of CoFeMnO4 played a crucial role in the activation process, serving as adsorption sites for PMS and facilitating its activation. Interestingly, we discovered that several common anions (Cl−, HCO3−, SO42− and NO3−) could undergo ligand exchange with surface hydroxyls of CoFeMnO4, occupying some of sites intended for PMS adsorption, which significantly inhibited the PMS decomposition on the catalyst surface. Further, it was finally discovered that the inhibition of the reaction system by these anions was primarily due to their competition for surface hydroxyls, rather than the commonly believed the consumption of reactive oxygen species by anions. Given the inevitable presence of various anions in real water bodies, this finding highlights the dual nature of surface hydroxyls as active sites in SR-AOPs: While they aid in activation process, the competition from anions for them would diminish the overall system performance.

Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers.

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (SH2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal-alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center. Herein, we report an iron-catalyzed cross-electrophile coupling of tertiary bromides and primary alkyl electrophiles for the formation of all-carbon quaternary centers through a biomimetic SH2 mechanism.

Abstract C047: AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial

Abstract Introduction: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed across solid tumor samples using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates, with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). Preclinical efficacy studies used either AGX101 (in human tumor xenograft models, to study the tumor cell killing MoA) or AGXB01, a rodent surrogate of AGX101, to study vascular and immune MoAs and all three MoAs in syngeneic mouse cancer models. The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: TMFS41 is broadly expressed across solid tumors with increasing scoring intensity in higher grade tumors. In non-human primates, AGX101 exhibited a favorable safety profile, being tolerated at relatively high doses and with dose dependent, monitorable, and reversible effects. In preclinical efficacy studies, AGXB01 and AGX101 as monotherapies demonstrated robust efficacy through each of the three MoAs in multiple syngeneic, xenograft, and orthotopic tumor models in mice and rats as well as non-tumor models of angiogenesis. Measured by exposure, TI was large. Additionally, AGXB01 was shown to potentiate the effects of ICIs in syngeneic mouse models (CT26, Renca, and B16-F10), suggesting a potential synergistic approach in cancer therapy. The first dose level of AGX101 monotherapy in humans has cleared without DLTs. Conclusion: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing. Citation Format: Ildefonso Ismael Rodriguez Rivera, Meredith S. Pelster, Shou-Ching Jaminet, Paul Jaminet, Glen J. Weiss. AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C047.

Biotransformation of Tetrabromobisphenol A and Its Analogs by Selected Gut Bacteria Strains: Implications for Human Health.

Knowledge of the biotransformation of tetrabromobisphenol A (TBBPA) and its related contaminants by human gut microbiota (GM) remains unexplored. Here, TBBPA and its four analogs were incubated with mixed GM strains, and nine rhamnosylated or debrominated transformation products (TPs) were discovered. Remarkably, rhamnosylation was identified as a common and unique microbial transformation pathway for these contaminants, and six of the seven rhamnosylated TPs were reported for the first time. Additionally, a kinetic transformation study also showed a rapid and strong bioaccumulation of TBBPA and TPs by Clostridium manihotivorum. Genomic analysis and phylogenetic studies identified C1.1_02053 as the gene encoding the C. manihotivorum working rhamnosyltransferase (CmRT), showing elevated gene expression with higher TBBPA exposure. Molecular docking identified five critical amino acid residues in CmRT that catalyze TBBPA rhamnosylation, and molecular dynamics simulations further confirmed the stability of the CmRT-TBBPA complex. Dynamic metabolomics analysis showed microbial growth-dependent disturbing effects in C. manihotivorum upon TBBPA exposure, and key metabolic pathways related to rhamnosyltransferase showed changes closely related to the transformation process. These findings provide insights into the unique transformation of environmental contaminants by the GM and highlight the disturbing effects of exogenous chemicals on the GM, as well as the potential impacts on overall human health.

The Extent of Participation and Empowerment of Rural Women in Lac Cultivation in Koderma District of Jharkhand, India

Lac cultivation in Koderma District, Jharkhand, offers a unique pathway for empowering rural women, serving as a significant source of income and socio-economic upliftment. This review examines the depth of women’s participation in various stages of lac production, from inoculation to processing, and how their involvement translates into empowerment. Despite facing challenges like gender discrimination, limited access to resources, and market constraints, women in Koderma have demonstrated resilience and adaptability. Lac cultivation has provided them with financial independence and enhanced social recognition and decision-making power within their households and communities. Initiatives by the government and NGOs have played a critical role in facilitating this shift, offering training, market access, and financial support to enable women to break socio-cultural barriers. However, for sustained empowerment, addressing the existing gaps in technology access, market linkage, and equitable resource distribution is essential. This article aims to explore lac cultivation's role in empowering rural women in Koderma District, Jharkhand, by examining their participation in the production process and its impact on their socio-economic upliftment (Pal G., 2011). It aims to highlight women's challenges, the contributions of government and NGO initiatives, and the need for improved policies, technology, and market access to ensure sustained empowerment and equitable participation in the lac industry.

Characterization and Experimental Use of Multiple Myeloma Bone Marrow Endothelial Cells and Progenitors.

Multiple myeloma (MM) is a plasma cell malignancy that resides within the bone marrow microenvironment, relying heavily on interactions with its cellular components. Among these, endothelial cells (ECs) play a pivotal role in MM progression and the development of therapeutic resistance. In this study, we analyzed publicly available single-cell RNA sequencing data to identify unique pathway activations distinguishing ECs from MM patients and healthy donors. We developed a novel protocol to isolate and culture endothelial progenitor cells (EPCs) and ECs directly from MM patient bone marrow, demonstrating their ability to promote myeloma cell proliferation. Validation studies confirmed that these MM-derived ECs exhibit angiogenic potential as well as the expression of characteristic endothelial lineage markers. These findings underscore the critical role of bone marrow ECs in the MM tumor microenvironment and highlight potential new therapeutic targets to disrupt MM progression.

Uncovering novel polyhydroxyalkanoate biosynthesis genes and unique pathway in yeast hanseniaspora valbyensis for sustainable bioplastic production

This study delves into the exploration of polyhydroxyalkanoate (PHA) biosynthesis genes within wild-type yeast strains, spotlighting the exceptional capabilities of isolate DMG-2. Through meticulous screening, DMG-2 emerged as a standout candidate, showcasing vivid red fluorescence indicative of prolific intracellular PHA granules. Characterization via FTIR spectroscopy unveiled a diverse biopolymer composition within DMG-2, featuring distinct functional groups associated with PHA and polyphosphate. Phylogenetic analysis placed DMG-2 within the Hanseniaspora valbyensis NRRL Y-1626 group, highlighting its distinct taxonomic classification. Subsequent investigation into DMG-2’s PHA biosynthesis genes yielded promising outcomes, with successful cloning and efficient PHA accumulation confirmed in transgenic E. coli cells. Protein analysis of ORF1 revealed its involvement in sugar metabolism, supported by its cellular localization and identification of functional motifs. Genomic analysis revealed regulatory elements within ORF1, shedding light on potential splice junctions and transcriptional networks influencing PHA synthesis pathways. Spectroscopic analysis of the biopolymer extracted from transgenic E. coli DMG2-1 provided insights into its co-polymer nature, comprising segments of PHB, PHV, and polyphosphate. GC-MS analysis further elucidated the intricate molecular architecture of the polymer. In conclusion, this study represents a pioneering endeavor in exploring PHA biosynthesis genes within yeast cells, with isolate DMG-2 demonstrating remarkable potential. The findings offer valuable insights for advancing sustainable bioplastic production and hold significant implications for biotechnological applications.

Tomato roots exhibit distinct, development-specific responses to bacterial-derived peptides.

Plants possess cell-surface recognition receptors that detect molecular patterns from microbial invaders and initiate an immune response. Understanding the conservation of pattern-triggered immunity within different plant organs and across species is crucial to its sustainable and effective use in plant disease management but is currently unclear. We examined the activation and immune response patterns of three pattern recognition receptors (PRRs: Sl FLS2, Sl FLS3, and Sl CORE) in different developmental regions of roots and in leaves of multiple accessions of domesticated and wild tomato ( Solanum lycopersicum and S. pimpinellifolium ) using biochemical and genetic assays. Roots from different tomato accessions differed in the amplitude and dynamics of their immune response, but all exhibited developmental-specific PTI responses in which the root early differentiation zone was the most sensitive to molecular patterns. PRR signaling pathways also showed distinct but occasionally overlapping responses downstream of each immune receptor in tomato roots.These results reveal that each PRR initiates a unique PTI pathway and suggest that the specificity and complexity of tomato root immunity are tightly linked to the developmental stage, emphasizing the importance of spatial and temporal regulation in PTI.

Preparation of high-efficient donor-π-acceptor system with crystalline g-C3N4 as charge transfer module for enhanced photocatalytic hydrogen evolution

Donor-π-acceptor (D-π-A) type photocatalysts with g-C3N4 as π-module have attracted much attention due to their optimized conjugate structure and enhanced electron directed driving. However, the inefficient charges migration of g-C3N4 due to its amorphous or semi-crystalline structure and limitation of available functional groups are present challenges. In this work, the D-π-A type high crystalline carbon nitride (HCCN) has been obtained by in-situ introducing amide and cyanide groups into the high-crystallinity melon framework. The synergistic effect of functional group modification and crystallinity regulation greatly enhances the electron induction driving and charge carrier density. Moreover, the density functional theory calculations demonstrate that the D-π-A structure could induce the local charge distribution of melon units to provide a unique and stable pathway for photoinduced charges migration. The as-prepared HCCN sample shows a superior visible-light photocatalytic performance for hydrogen evolution with an apparent quantum efficiency (AQE) of 12.2 ​% at 420 ​± ​15 ​nm, which is 23.7 times higher than that of original g-C3N4. Finally, the charge separation and transfer processes as well as the possible photocatalytic reaction mechanisms of HCCN sample are also investigated.

Deciphering Rickettsia conorii metabolic pathways: a treasure map to therapeutic targets

Indian tick typhus is an infectious disease caused by intracellular gram-negative bacteria Rickettsia conorii (R. conorii). The bacterium is transmitted to humans through bite of infected ticks and sometimes by lice, fleas or mites. The disease is restricted to some areas with few cases but in last decade it is re-emerging with large number of cases from different areas of India. The insight in to genetic makeup of bacterial pathogens can be derived from their metabolic pathways. In the current study 18 metabolic pathways were found to be unique to the pathogen (R. conorii). A comprehensive analysis revealed 163 proteins implicated in 18 unique metabolic pathways of R. conorii. 140 proteins were reported to be essential for the bacterial survival, 46 were found virulent and 10 were found involved in resistance which can enhance the bacterial pathogenesis. The functional analysis of unique metabolic pathway proteins showed the abundance of plasmid conjugal transfer TrbL/VirB6, aliphatic acid kinase short chain, signal transduction response regulator receiver and components of type IV transporter system domains. The proteins were classified into six broad categories on the basis of predicted domains, i.e., metabolism, transport, gene expression and regulation, antimicrobial resistance, cell signalling and proteolysis. Further, in silico analysis showed that 88 proteins were suitable therapeutic targets which do not showed homology with host proteins. The 43 proteins showed hits with the DrugBank database showing their druggable nature and remaining 45 proteins were classified as novel drug targets that require further validation. The study will help to provide the better understanding of pathogens survival and embark on the development of successful therapies for the management of Indian tick typhus.

Bourdieu and early career researchers (ECRs) in disaster research: A collaborative autoethnography (CAE)

This collaborative autoethnography (CAE) by five emerging disaster researchers explores the transformative role of Bourdieu’s theories in the realm of disaster research. Despite the rapid expansion of disaster scholarship since the late 1970s, the field’s theoretical foundations and frameworks have been relatively underdeveloped. The authors, united by their engagement with Bourdieu’s work in their doctoral research, reflect on how his theories shaped their journeys into Critical Disaster Studies (CDS) scholars and propelled the advancement of disaster theories. The paper navigates the ambiguity and richness of Bourdieu’s concepts, illustrating how they are used beyond their original domains to find relevance in contemporary disaster research. Each author shares their unique pathway for encountering and applying Bourdieu’s theories, revealing a diverse spectrum of applications, from understanding symbolic violence in disaster contexts to analysing social vulnerability and resilience. Through this shared dedication, the authors aim to expand the horizon of social science disaster research and inspire others, especially early career researchers (ECRs), to engage profoundly with Bourdieu’s contribution to the field.

Brain Morphometric Alterations in Focal to Bilateral Tonic-Clonic Seizures in Epilepsy Associated With Excitatory/Inhibitory Imbalance.

Focal to bilateral tonic-clonic seizures (FBTCS) represent the most severe seizure type in temporal lobe epilepsy (TLE), associated with extensive network abnormalities. Nevertheless, the genetic and cellular factors predispose specific TLE patients to FBTCS remain poorly understood. This study aimed to elucidate the relationship between brain morphometric alterations and transcriptional profiles in TLE patients with FBTCS (FBTCS+) compared to those without FBTCS (FBTCS-). We enrolled 126 unilateral TLE patients (89 FBTCS+ and 37 FBTCS-) along with 60 age- and gender-matched healthy controls (HC). We assessed gray matter volume to identify morphometric differences between patients and HC. Partial least squares regression was employed to investigate the association between the morphometric disparities and human brain transcriptomic data obtained from the Allen Human Brain Atlas. Compared with HC, FBTCS+ patients exhibited morphometric alterations in bilateral cortical and subcortical regions. Conversely, FBTCS- patients exhibited more localized alterations. Imaging transcriptomic analysis revealed both FBTCS- and FBTCS+ groups harbored genes that spatially correlated with morphometric alterations. Additionally, pathway enrichment analysis identified common pathways involved in neural development and synaptic function in both groups. The FBTCS- group displayed unique pathway enrichment in catabolic processes. Furthermore, mapping these genes to specific cell types indicated enrichment in excitatory and inhibitory neurons in the FBTCS- group, while FBTCS+ group only enriched in excitatory neurons. The distinct cellular expression differences between FBTCS- and FBTCS+ groups are consistent with the distribution patterns of GABAergic expression. We applied imaging transcriptomic analysis linking the morphometric changes and neurobiology in TLE patients with and without FBTCS, including gene expression, biological pathways, cell types, and neurotransmitter receptors. Our findings revealed abnormalities in inhibitory neurons and altered distribution patterns of GABAergic receptors in FBTCS+, suggesting that an excitatory/inhibitory imbalance may contribute to the increased susceptibility of certain individuals to FBTCS.

PANoptosis in autoimmune diseases interplay between apoptosis, necrosis, and pyroptosis.

PANoptosis is a newly identified inflammatory programmed cell death (PCD) that involves the interplay of apoptosis, necrosis, and pyroptosis. However, its overall biological effects cannot be attributed to any one type of PCD alone. PANoptosis is regulated by a signaling cascade triggered by the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by various sensors. This triggers the assembly of the PANoptosome, which integrates key components from other PCD pathways via adapters and ultimately activates downstream execution molecules, resulting in cell death with necrotic, apoptotic, and pyroptotic features. Autoimmune diseases are characterized by reduced immune tolerance to self-antigens, leading to abnormal immune responses, often accompanied by systemic chronic inflammation. Consequently, PANoptosis, as a unique innate immune-inflammatory PCD pathway, has significant pathophysiological relevance to inflammation and autoimmunity. However, most previous research on PANoptosis has focused on tumors and infectious diseases, leaving its activation and role in autoimmune diseases unclear. This review briefly outlines the characteristics of PANoptosis and summarizes several newly identified PANoptosome complexes, their activation mechanisms, and key components. We also explored the dual role of PANoptosis in diseases and potential therapeutic approaches targeting PANoptosis. Additionally, we review the existing evidence for PANoptosis in several autoimmune diseases and explore the potential regulatory mechanisms involved.

Vitamin D in cardiac fibroblasts: new evidence for a TRP-mediated non-genomic pathway

Abstract Background/Introduction Vitamin D’s (VD) role transcends phosphocalcic metabolism to affect different systems, notably the cardiovascular system in health and diseases. Beyond its genomic effect, VD act through non-genomic calcium (Ca2+) signaling pathways, hinting at a broader spectrum of physiological impacts. Despite the established interactions with cardiomyocytes via the Vitamin D Receptor (VDR), little is known about VD and cardiac fibroblast, a pivotal cell player in cardiac function and disease. Purpose This research aims to reveal Vitamin D's role in modulating cardiac fibroblast function through Transient Receptor Potential (TRP) channels. Methods Utilizing primary cardiac fibroblasts from human and rats, our investigation focused on intracellular calcium signaling. Through Ca2+ imaging techniques combined to synthetic fluorescent VD analogue, we explored Vitamin D's behavior within the cell. The study further employed biochemical assays to elucidate the interaction between VDR on the cell membrane and TRP channels signaling, providing a detailed map of the cellular choreography orchestrated by VD within cardiac fibroblasts. In addition, in vitro and ex vivo heart perfusion experiments were incorporated to assess cardiac cGMP production in response to VD. Results Our findings reveal a unique pathway wherein VD induces Ca2+ oscillations in human and rat cardiac fibroblasts specifically through the TRPC3 channel, sidelining other calcium sources. This process is regulated by the interaction between TRPC3 and the membrane-bound VDR, harmonizing with phospholipase C signaling to a crescendo of cGMP production in cardiac fibroblasts, and across the entire heart. This was associated with less pro-fibrotic potential of cardiac fibroblasts. Conclusion This study provides the first evidence of a TRP-mediated, VD non-genomic pathway within human and rat cardiac fibroblasts. Our findings herald a promising horizon for investigating vitamin D’s antifibrotic potential in heart disease.