Pro-resolving lipid mediator reduces amyloid-ß42-induced gene expression in human monocyte-derived microglia.

JOURNAL/nrgr/04.03/01300535-202503000-00031/figure1/v/2024-06-17T092413Z/r/image-tiff Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-ß. With this objective, we analyzed the relevance of human monocyte-derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-ß42-induced Alzheimer's disease-like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease-like neuroinflammation in human brain microglia after incubation with amyloid-ß42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-ß42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-ß42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-ß42-induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

Principles of miRNA/miRNA* function in plant MIRNA processing.

MicroRNAs (miRNAs) are essential regulators of gene expression, defined by their unique biogenesis, which requires the precise excision of the small RNA from an imperfect fold-back precursor. Unlike their animal counterparts, plant miRNA precursors exhibit variations in sizes and shapes. Plant MIRNAs can undergo processing in a base-to-loop or loop-to-base direction, with DICER-LIKE1 (DCL1) releasing the miRNA after two cuts (two-step MIRNAs) or more (sequential MIRNAs). In this study, we demonstrate the critical role of the miRNA/miRNA* duplex region in the processing of miRNA precursors. We observed that endogenous MIRNAs frequently experience suboptimal processing in vivo due to mismatches in the miRNA/miRNA* duplex, a key region that fine-tunes miRNA levels. Enhancing the interaction energy of the miRNA/miRNA* duplex in two-step MIRNAs results in a substantial increase in miRNA levels. Conversely, sequential MIRNAs display distinct and specific requirements for the miRNA/miRNA* duplexes along their foldback structure. Our work establishes a connection between the miRNA/miRNA* structure and precursor processing mechanisms. Furthermore, we reveal a link between the biological function of miRNAs and the processing mechanism of their precursors with the evolution of plant miRNA/miRNA* duplex structures.

Orbital-selective time-domain signature of nematicity dynamics in the charge-density-wave phase of La1.65Eu0.2Sr0.15CuO4.

Understanding the interplay between charge, nematic, and structural ordering tendencies in cuprate superconductors is critical to unraveling their complex phase diagram. Using pump-probe time-resolved resonant X-ray scattering on the (0 0 1) Bragg peak at the Cu [Formula: see text] and O [Formula: see text] resonances, we investigate nonequilibrium dynamics of [Formula: see text] nematic order and its association with both charge density wave (CDW) order and lattice dynamics in La[Formula: see text]Eu[Formula: see text]Sr[Formula: see text]CuO[Formula: see text]. The orbital selectivity of the resonant X-ray scattering cross-section allows nematicity dynamics associated with the planar O 2[Formula: see text] and Cu 3[Formula: see text] states to be distinguished from the response of anisotropic lattice distortions. A direct time-domain comparison of CDW translational-symmetry breaking and nematic rotational-symmetry breaking reveals that these broken symmetries remain closely linked in the photoexcited state, consistent with the stability of CDW topological defects in the investigated pump fluence regime.

Salmonella Typhimurium expansion in the inflamed murine gut is dependent on aspartate derived from ROS-mediated microbiota lysis.

Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.

A long journey to the colon: The role of the small intestine microbiota in intestinal disease.

The small intestine represents a complex and understudied gut niche with significant implications for human health. Indeed, many infectious and non-infectious diseases center within the small intestine and present similar clinical manifestations to large intestinal disease, complicating non-invasive diagnosis and treatment. One major neglected aspect of small intestinal diseases is the feedback relationship with the resident collection of commensal organisms, the gut microbiota. Studies focused on microbiota-host interactions in the small intestine in the context of infectious and non-infectious diseases are required to identify potential therapeutic targets dissimilar from those used for large bowel diseases. While sparsely populated, the small intestine represents a stringent commensal bacterial microenvironment the host relies upon for nutrient acquisition and protection against invading pathogens (colonization resistance). Indeed, recent evidence suggests that disruptions to host-microbiota interactions in the small intestine impact enteric bacterial pathogenesis and susceptibility to non-infectious enteric diseases. In this review, we focus on the microbiota's impact on small intestine function and the pathogenesis of infectious and non-infectious diseases of the gastrointestinal (GI) tract. We also discuss gaps in knowledge on the role of commensal microorganisms in proximal GI tract function during health and disease.

Neurochemical and Neurophysiological Effects of Intravenous Administration of N,N-dimethyltryptamine in Rats.

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well-characterized, similar studies in animal models as well as data on the neurochemical effects of DMT are generally lacking, which are critical for mechanistic understanding. In the current study, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of three different doses of DMT (0.75 mg/kg, 3.75 mg/kg, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites along with a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and increase in power in delta (1-4 Hz), medium gamma (65-115), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. In addition, we provide the first measurements of endogenous DMT in these cortical sites at levels comparable to serotonin and dopamine, which together with a previous study in occipital cortex, suggests a physiological role for endogenous DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with DMT.

Arabidopsis AGO1 N-terminal extension acts as an essential hub for PRMT5 interaction and post-translational modifications.

Plant ARGONAUTE (AGO) proteins play pivotal roles regulating gene expression through small RNA (sRNA) -guided mechanisms. Among the 10 AGO proteins in Arabidopsis thaliana, AGO1 stands out as the main effector of post-transcriptional gene silencing. Intriguingly, a specific region of AGO1, its N-terminal extension (NTE), has garnered attention in recent studies due to its involvement in diverse regulatory functions, including subcellular localization, sRNA loading and interactions with regulatory factors. In the field of post-translational modifications (PTMs), little is known about arginine methylation in Arabidopsis AGOs. In this study, we show that NTE of AGO1 (NTEAGO1) undergoes symmetric arginine dimethylation at specific residues. Moreover, NTEAGO1 interacts with the methyltransferase PRMT5, which catalyzes its methylation. Notably, we observed that the lack of symmetric dimethylarginine has no discernible impact on AGO1's subcellular localization or miRNA loading capabilities. However, the absence of PRMT5 significantly alters the loading of a subgroup of sRNAs into AGO1 and reshapes the NTEAGO1 interactome. Importantly, our research shows that symmetric arginine dimethylation of NTEs is a common process among Arabidopsis AGOs, with AGO1, AGO2, AGO3 and AGO5 undergoing this PTM. Overall, this work deepens our understanding of PTMs in the intricate landscape of RNA-associated gene regulation.

Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region.

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Exploiting the Hessian for a Better Convergence of the SCF-RDMFT Procedure.

One-body reduced density matrix functional theory provides an alternative to density functional theory, which is able to treat static correlation while keeping a relatively low computation scaling. Its disadvantageous cost comes mainly from a slow convergence of the self-consistent energy optimization. To improve on that problem, we propose in this work the use of the Hessian of the energy, including the coupling term. We show that using the exact Hessian is very effective at reducing the number of iterations. However, since the exact Hessian is too expensive to use in practice, we propose an approximation based on an inexpensive exact part and BFGS updates.

A maternal dorsoventral prepattern revealed by an asymmetric distribution of ventralizing molecules before fertilization in Xenopus laevis.

The establishment of the embryonic dorsoventral axis in Xenopus occurs when the radial symmetry around the egg's animal-vegetal axis is broken to give rise to the typical symmetry of Bilaterians. We have previously shown that the Notch1 protein is ventrally enriched during early embryogenesis in Xenopus laevis and zebrafish and exerts ventralizing activity through ß-Catenin destabilization and the positive regulation of ventral center genes in X. laevis. These findings led us to further investigate when these asymmetries arise. In this work, we show that the asymmetrical distribution of Notch1 protein and mRNA precedes cortical rotation and even fertilization in X. laevis. Moreover, we found that in unfertilized eggs transcripts encoded by the ventralizing gene bmp4 are also asymmetrically distributed in the animal hemisphere and notch1 transcripts accumulate consistently on the same side of the eccentric maturation point. Strikingly, a Notch1 asymmetry orthogonal to the animal-vegetal axis appears during X. laevis oogenesis. Thus, we show for the first time a maternal bias in the distribution of molecules that are later involved in ventral patterning during embryonic axialization, strongly supporting the hypothesis of a dorsoventral prepattern or intrinsic bilaterality of Xenopus eggs before fertilization.

Novel lipid mediator 7S,14R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss.

Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ ß-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 ß-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.

The Optimization of a Natural Language Processing Approach for the Automatic Detection of Alzheimer's Disease Using GPT Embeddings.

The development of noninvasive and cost-effective methods of detecting Alzheimer's disease (AD) is essential for its early prevention and mitigation. We optimize the detection of AD using natural language processing (NLP) of spontaneous speech through the use of audio enhancement techniques and novel transcription methodologies. Specifically, we utilized Boll Spectral Subtraction to improve audio fidelity and created transcriptions using state-of-the-art AI services-locally-based Wav2Vec and Whisper, alongside cloud-based IBM Cloud and Rev AI-evaluating their performance against traditional manual transcription methods. Support Vector Machine (SVM) classifiers were then trained and tested using GPT-based embeddings of transcriptions. Our findings revealed that AI-based transcriptions largely outperformed traditional manual ones, with Wav2Vec (enhanced audio) achieving the best accuracy and F-1 score (0.99 for both metrics) for locally-based systems and Rev AI (standard audio) performing the best for cloud-based systems (0.96 for both metrics). Furthermore, this study revealed the detrimental effects of interviewer speech on model performance in addition to the minimal effect of audio enhancement. Based on our findings, current AI transcription and NLP technologies are highly effective at accurately detecting AD with available data but struggle to classify probable AD and mild cognitive impairment (MCI), a prodromal stage of AD, due to a lack of training data, laying the groundwork for the future implementation of an automatic AD detection system.

Lessons from genetic studies in Alzheimer disease.

Research on Alzheimer disease (AD) genetics has provided critical advances to the knowledge of AD pathophysiological mechanisms. The etiology of AD can be divided into monogenic (autosomal dominant inheritance) and complex (multifactorial determinism). In monogenic AD, recent advances mainly concern mutation-associated mechanisms, presymptomatic clinical studies, and the search for modifiers of ages of onset that are still ongoing. In complex AD, genetic factors can be further categorized into three classes: (i) the APOE-ɛ4 and ɛ2 common alleles that represent a category by themselves as they are both common and with a strong impact on AD risk; (ii) common variants with a modest effect, identified in genome-wide association studies (GWAS); and (iii) rare variants with a moderate-to-strong effect, identified in case-control sequencing studies. Regarding APOE, odds ratios, available in multiple ethnicities, can now be converted into penetrance curves, although such curves remain to be performed in diverse ethnicities. In addition, advances in the understanding of mechanisms have been recently reported and rare APOE variants add to the complexity. In the GWAS category, novel loci have been discovered thanks to larger studies, doubling the number of hits as compared to the previous reference meta-analysis. However, such modest risk factors cannot be used in the clinic, neither individually, nor in genetic risk scores. In the category of rare variants, two novel genes, ABCA1 and ATP8B4 now add to the three main ones, TREM2, SORL1, and ABCA7. The study of such rare variants suggests oligogenic inheritance in some families, as also suggested by digenic penetrance curves for SORL1 loss-of-function variants with APOE-ɛ4. Cumulate frequencies of definite (so-called) rare risk factors are 2.3% to 3.6% (depending on thresholds on odds ratios) in control databases and many more remain to be classified and identified, showing how important these risk factors may be as part of the complex determinism of AD. A better understanding of these rare risk factors and their combined effects on each other, with common variants, and with environmental factors, should allow for a prediction of AD risk and, eventually, preventive medicine. Taken together, most genetic determinants of AD, in monogenic and in complex forms, point toward the aggregation of Aß as a pivotal triggering factor, such that targeting it may be efficient as prevention in at-risk individuals. The role of neuroinflammation, microglia, and Tau pathology modulation are important sources of research for disease modification.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

Temporal Considerations in Brain Metastases Radiation Therapy: The Intersection of Chronobiology and Patient Profiles.

The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing's impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017-2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan-Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment (n = 158) showed a trend toward improved overall survival vs. afternoon (n = 79); the median survival was 158 vs. 79 days (p = 0.20, HR = 0.84, CI95% 0.84-0.91). Subgroup benefits for morning treatment in females (p = 0.04) and trends in controlled primary disease (p = 0.11) and breast cancer metastases (p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors' relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci.

Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

The Optimization of a Natural Language Processing Approach for the Automatic Detection of Alzheimer's Disease Using GPT Embeddings.

As the impact of Alzheimer's disease (AD) is projected to grow in the coming decades as the world's population ages, the development of noninvasive and cost-effective methods of detecting AD is essential for the early prevention and mitigation of the progressive disease, alleviating its expected global impact. This study analyzes audio processing techniques and transcription methodologies to optimize the detection of AD through the natural language processing (NLP) of spontaneous speech. We enhanced audio fidelity using Boll Spectral Subtraction and evaluated the transcription accuracy of state-of-the-art AI services-locally-based Wav2Vec and Whisper, alongside cloud-based IBM Cloud and Rev AI-against traditional manual transcription methods. The choice between local and cloud-based solutions hinges on a trade-off between privacy, ongoing costs, and computational requirements. Leveraging OpenAI's GPT for word embeddings, we enhanced the training of Support Vector Machine (SVM) classifiers, which were crucial in analyzing transcripts and refining detection accuracy. Our findings reveal that AI-driven transcriptions significantly outperform manual counterparts when classifying AD and Control samples, with Wav2Vec using enhanced audio exhibiting the highest accuracy and F-1 scores (0.99 for both metrics) for locally based systems and Rev AI using unenhanced audio leading cloud-based methods with comparable precision (0.96 for both metrics). The study also uncovers the detrimental effect of including interviewer speech in recordings on model performance, advocating for the exclusion of such interactions to improve data quality for AD classification algorithms. Our comprehensive evaluation demonstrates that AI transcription (both Cloud and Local) and NLP technologies in their current forms can classify AD, as well as probable AD and mild cognitive impairment (MCI), a prodromal stage of AD, accurately but suffer from a lack of available training data. The insights garnered from this research lay the groundwork for future advancements in the noninvasive monitoring and early detection of cognitive impairments through linguistic analysis.

A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

Sperm induction of somatic cell-cell fusion as a novel functional test.

The fusion of mammalian gametes requires the interaction between IZUMO1 on the sperm and JUNO on the oocyte. We have recently shown that ectopic expression of mouse IZUMO1 induces cell-cell fusion and that sperm can fuse to fibroblasts expressing JUNO. Here, we found that the incubation of mouse sperm with hamster fibroblasts or human epithelial cells in culture induces the fusion between these somatic cells and the formation of syncytia, a pattern previously observed with some animal viruses. This sperm-induced cell-cell fusion requires a species-matching JUNO on both fusing cells, can be blocked by an antibody against IZUMO1, and does not rely on the synthesis of new proteins. The fusion is dependent on the sperm's fusogenic capacity, making this a reliable, fast, and simple method for predicting sperm function during the diagnosis of male infertility.

Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases.

The thioredoxin (TXN) system is an NADPH + H+/FAD redox-triggered effector that sustains homeostasis, bioenergetics, detoxifying drug networks, and cell survival in oxidative stress-related diseases. Elovanoid (ELV)-N34 is an endogenously formed lipid mediator in neural cells from omega-3 fatty acid precursors that modulate neuroinflammation and senescence gene programming when reduction-oxidation (redox) homeostasis is disrupted, enhancing cell survival. Limited proteolysis (LiP) screening of human retinal pigment epithelial (RPE) cells identified TXNRD1 isoforms 2, 3, or 5, the reductase of the TXN system, as an intracellular target of ELV-N34. TXNRD1 silencing confirmed that the ELV-N34 target was isoform 2 or 3. This lipid mediator induces TXNRD1 structure changes that modify the FAD interface domain, leading to its activity modulation. The addition of ELV-N34 decreased membrane and cytosolic TXNRD1 activity, suggesting localizations for the targeted reductase. These results show for the first time that the lipid mediator ELV-N34 directly modulates TXNRD1 activity, underling its protection in several pathologies when uncompensated oxidative stress (UOS) evolves.