Sci Adv. 2024 Aug 23;10(34):eadi6286. doi: 10.1126/sciadv.adi6286. Epub 2024 Aug 21.

ABSTRACT

Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained by resident cells. Despite its broad importance to biology and medicine, tissue mechanical homeostasis remains poorly understood. To explore cell-mediated control of tissue stiffness, we developed mutations in the mechanosensitive protein talin 1 to alter cellular sensing of ECM. Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 increased cell spreading and tension exertion on compliant substrates. These mutations promote binding of the ARP2/3 complex subunit ARPC5L, which mediates the change in substrate stiffness sensing. Ascending aortas from mice bearing these mutations showed less fibrillar collagen, reduced axial stiffness, and lower rupture pressure. Together, these results demonstrate that cellular stiffness sensing contributes to ECM mechanics, directly supporting the mechanical homeostasis hypothesis and identifying a mechanosensitive interaction within talin that contributes to this mechanism.

PMID:39167642 | DOI:10.1126/sciadv.adi6286

Plant J. 2024 Aug 21. doi: 10.1111/tpj.16996. Online ahead of print.

ABSTRACT

As a dynamic and reversible post-transcriptional marker, N6-methyladenosine (m6A) plays an important role in the regulation of biological functions, which are mediated by m6A pathway components including writers (MT-A70, FIP37, VIR and HAKAI family), erasers (ALKBH family) and readers (YTH family). There is an urgent need for a comprehensive analysis of m6A pathway components across species at evolutionary levels. In this study, we identified 4062 m6A pathway components from 154 plant species including green algae, utilizing large-scale phylogenetic to explore their origin and evolution. We discovered that the copy number of writers was conserved among different plant lineages, with notable expansions in the ALKBH and YTH families. Synteny network analysis revealed conserved genomic contexts and lineage-specific transpositions. Furthermore, we used Direct RNA Sequencing (DRS) to reveal the Poly(A) length (PAL) and m6A ratio profiles in six angiosperms species, with a particular focus on the m6A pathway components. The ECT1/2-Poeaece4 sub-branches (YTH family) with unique genomic contexts exhibited significantly higher expression level than genes of other ECT1/2 poeaece sub-branches (ECT1/2-Poeaece1-3), accompanied by lower m6A modification and PAL. Besides, conserved m6A sites distributed in CDS and 3'UTR were detected in the ECT1/2-Poaceae4, and the dual-luciferase assay further demonstrated that these conserved m6A sites in the 3'UTR negatively regulated the expression of Firefly luciferase (LUC) gene. Finally, we developed transcription factor regulatory networks for m6A pathway components, using yeast one-hybrid assay demonstrated that PheBPC1 could interact with the PheECT1/2-5 promoter. Overall, this study presents a comprehensive evolutionary and functional analysis of m6A pathway components and their modifications in plants, providing a valuable resource for future functional analysis in this field.

PMID:39167634 | DOI:10.1111/tpj.16996

Circulation. 2024 Aug 21. doi: 10.1161/CIRCULATIONAHA.124.069864. Online ahead of print.

ABSTRACT

BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.

METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics.

RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-β/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH.

CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

PMID:39167456 | DOI:10.1161/CIRCULATIONAHA.124.069864

Theory Biosci. 2024 Aug 21. doi: 10.1007/s12064-024-00424-5. Online ahead of print.

ABSTRACT

Understanding the ecological and evolutionary dynamics of populations is critical for both basic and applied purposes in a variety of biological contexts. Although several modeling frameworks have been developed to simulate eco-evolutionary dynamics, many fewer address how to model structured populations. In a prior paper, we put forth the first modeling approach to simulate eco-evolutionary dynamics in structured populations under the G function modeling framework. However, this approach does not allow for accurate simulation under fluctuating environmental conditions. To address this limitation, we draw on the study of periodic differential equations to propose a modified approach that uses a different definition of fitness more suitable for fluctuating environments. We illustrate this method with a simple toy model of life history trade-offs. The generality of this approach allows it to be used in a variety of biological contexts.

PMID:39167330 | DOI:10.1007/s12064-024-00424-5

Alzheimers Dement. 2024 Aug 21. doi: 10.1002/alz.14152. Online ahead of print.

ABSTRACT

INTRODUCTION: CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials.

METHODS: Unbiased analysis of tandem-mass tag mass spectrometry (TMT-MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC cohort (NCT03493282). Comparative analyses and a meta-analysis with the interim SHINE cohort (NCT03507790; SHINE-A) followed by network analysis (weighted gene co-expression network analysis [WGCNA]) were used to understand the biological impact of CT1812.

RESULTS: CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta-analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment-associated networks driven by S2R. DISCUSSION: Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development.

HIGHLIGHTS: This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282) Comparative analyses identified biomarkers replicating across trials/cohorts Two independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE-A]) were used in a meta-analysis Amyloid beta (Aβ) & synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment-related correlates emerge Network analyses revealed sigma-2 receptor (S2R)-interacting proteins that may be "drivers" of changes.

PMID:39166791 | DOI:10.1002/alz.14152

Clin Transl Gastroenterol. 2024 Aug 21. doi: 10.14309/ctg.0000000000000762. Online ahead of print.

ABSTRACT

INTRODUCTION: Reflux bile acids are thought to promote EAC, but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression.

METHODS: Subjects with and without BE were enrolled in this multi-center cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression.

RESULTS: 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia (p=0.004). Increasing cholic acid was associated with high grade dysplasia/EAC compared to non-BE, even after adjusting for EAC risk factors (aOR 2.03, 95% CI 1.11-3.71) as was the combination of unconjugated primary bile acids (aOR 1.81, 95% CI 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes.

DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, pro-neoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

PMID:39166758 | DOI:10.14309/ctg.0000000000000762

Plant Cell Environ. 2024 Aug 21. doi: 10.1111/pce.15059. Online ahead of print.

ABSTRACT

Mesophyll conductance ( g m ${g}_{{\rm{m}}}$ ) describes the efficiency with which CO 2 ${\mathrm{CO}}_{2}$ moves from substomatal cavities to chloroplasts. Despite the stipulated importance of leaf architecture in affecting g m ${g}_{{\rm{m}}}$ , there remains a considerable ambiguity about how and whether leaf anatomy influences g m ${g}_{{\rm{m}}}$ . Here, we employed nonlinear machine-learning models to assess the relationship between 10 leaf architecture traits and g m ${g}_{{\rm{m}}}$ . These models used leaf architecture traits as predictors and achieved excellent predictability of g m ${g}_{{\rm{m}}}$ . Dissection of the importance of leaf architecture traits in the models indicated that cell wall thickness and chloroplast area exposed to internal airspace have a large impact on interspecific variation in g m ${g}_{{\rm{m}}}$ . Additionally, other leaf architecture traits, such as leaf thickness, leaf density and chloroplast thickness, emerged as important predictors of g m ${g}_{{\rm{m}}}$ . We also found significant differences in the predictability between models trained on different plant functional types. Therefore, by moving beyond simple linear and exponential models, our analyses demonstrated that a larger suite of leaf architecture traits drive differences in g m ${g}_{{\rm{m}}}$ than has been previously acknowledged. These findings pave the way for modulating g m ${g}_{{\rm{m}}}$ by strategies that modify its leaf architecture determinants.

PMID:39166340 | DOI:10.1111/pce.15059

Plant Direct. 2024 Aug 19;8(8):e626. doi: 10.1002/pld3.626. eCollection 2024 Sep.

ABSTRACT

Shoot branches grow from axillary buds and play a crucial role in shaping shoot architecture and determining crop yield. Shade signals inactivate phytochrome B (phyB) and induce bud dormancy, thereby inhibiting shoot branching. Prior transcriptome profiling of axillary bud dormancy in a phyB-deficient mutant (58M, phyB-1) and bud outgrowth in wild-type (100M, PHYB) sorghum genotypes identified differential expression of genes associated with flowering, plant hormones, and sugars, including SbCN2, SbNCED3, SbCKX1, SbACO1, SbGA2ox1, and SbCwINVs. This study examined the expression of these genes during bud dormancy induced by shade and defoliation in 100M sorghum. The aim was to elucidate the molecular mechanisms activated by shade in axillary buds by comparing them with those activated by defoliation. The expression of marker genes for sugar levels suggests shade and defoliation reduce the sugar supply to the buds and induce bud dormancy. Intriguingly, both shade signals and defoliation downregulated SbNCED3, suggesting that ABA might not play a role in promoting axillary bud dormancy in sorghum. Whereas the cytokinin (CK) degrading gene SbCKX1 was upregulated solely by shade signals in the buds, the CK inducible genes SbCGA1 and SbCwINVs were downregulated during both shade- and defoliation-induced bud dormancy. This indicates a decrease in CK levels in the dormant buds. Shade signals dramatically upregulated SbCN2, an ortholog of the Arabidopsis TFL1 known for inhibiting flowering, whereas defoliation did not increase SbCN2 expression in the buds. Removing shade temporarily downregulated SbCN2 in dormant buds, further indicating its expression is not always correlated with bud dormancy. Because shade signals also trigger a systemic early flowering signal, SbCN2 might be activated to protect the buds from transitioning to flowering before growing into branches. In conclusion, this study demonstrates that shade signals activate two distinct molecular mechanisms in sorghum buds: one induces dormancy by reducing CK and sugars, whereas the other inhibits flowering by activating SbCN2. Given the agricultural significance of TFL1-like genes, the rapid regulation of SbCN2 by light signals in axillary buds revealed in this study warrants further investigation to explore its potential in crop improvement strategies.

PMID:39166257 | PMC:PMC11333302 | DOI:10.1002/pld3.626

Front Plant Sci. 2024 Aug 6;15:1416216. doi: 10.3389/fpls.2024.1416216. eCollection 2024.

ABSTRACT

High-quality seeds provide valuable nutrients to human society and ensure successful seedling establishment. During maturation, seeds accumulate storage compounds that are required to sustain seedling growth during germination. This review focuses on the epigenetic repression of the embryonic and seed maturation programs in seedlings. We begin with an extensive overview of mutants affecting these processes, illustrating the roles of core proteins and accessory components in the epigenetic machinery by comparing mutants at both phenotypic and molecular levels. We highlight how omics assays help uncover target-specific functional specialization and coordination among various epigenetic mechanisms. Furthermore, we provide an in-depth discussion on the Seed dormancy 4 (Sdr4) transcriptional corepressor family, comparing and contrasting their regulation of seed germination in the dicotyledonous species Arabidopsis and two monocotyledonous crops, rice and wheat. Finally, we compare the similarities in the activation and repression of the embryonic and seed maturation programs through a shared set of cis-regulatory elements and discuss the challenges in applying knowledge largely gained in model species to crops.

PMID:39166233 | PMC:PMC11333834 | DOI:10.3389/fpls.2024.1416216

Heliyon. 2024 Jul 26;10(15):e35290. doi: 10.1016/j.heliyon.2024.e35290. eCollection 2024 Aug 15.

ABSTRACT

In the context of global climate change, drought occurrence in streams of alpine origin is a recent phenomenon, whose impact is still poorly investigated. In this study, we adopted a three-disciplinary approach to investigate the response of an Alpine river (NW Italy) to severe drought conditions occurred in the year 2022. We hypothesised that the considerable loss in the water flow could exacerbate wastewater treatment plant (WWTP) discharge effects, lowering dilution capacity of the stream system and then increasing chemical/microbial pollution and altering benthic community characteristics. To assess river response to drought conditions of the considered year, the concentration of the main chemical variables, faecal indicator bacteria, pathogen presence and structural/functional organisation of benthic macroinvertebrates and diatom communities were measured monthly in the reaches located upstream and downstream of a WWTP (January-December 2022). Main environmental variables, such as flow velocity, water depth, and flow regime, were also considered. A multivariate analysis approach was then applied to emphasise correlations between selected variables and flow regime. Comparing upstream and downstream sections over the considered year, a common behaviour of chemical/microbiological parameters was observed, with generally higher concentrations of nutrients and bacterial indicators downstream of the local WWTP. Moreover, a positive correlation between water scarcity and nutrients/bacterial concentrations was revealed. The macroinvertebrate communities responded accordingly, both in terms of density and biological metric shift. Interestingly, differences between the two sections were strictly associated with hydrological conditions, with higher dissimilarities found in low-flow conditions. As the magnitude and duration of drought events are projected to increase in the years to come in different parts of Europe, this work can serve as a first building block and as a hint for future studies aimed at improving our knowledge about the consequences of these events that is pivotal for planning effective management strategies.

PMID:39165936 | PMC:PMC11334679 | DOI:10.1016/j.heliyon.2024.e35290

Biotechnol Adv. 2024 Aug 18:108432. doi: 10.1016/j.biotechadv.2024.108432. Online ahead of print.

ABSTRACT

Enabling the transition towards a future circular bioeconomy based on industrial biomanufacturing necessitates the development of efficient and versatile microbial platforms for sustainable chemical and fuel production. Recently, there has been growing interest in engineering non-model microbes as superior biomanufacturing platforms due to their broad substrate range and high resistance to stress conditions. Among these non-conventional microbes, red yeasts belonging to the genus Rhodotorula have emerged as promising industrial chassis for the production of specialty chemicals such as oleochemicals, organic acids, fatty acid derivatives, terpenoids, and other valuable compounds. Advancements in genetic and metabolic engineering techniques, coupled with systems biology analysis, have significantly enhanced the production capacity of red yeasts. These developments have also expanded the range of substrates and products that can be utilized or synthesized by these yeast species. This review comprehensively examines the current efforts and recent progress made in red yeast research. It encompasses the exploration of available substrates, systems analysis using multi-omics data, establishment of genome-scale models, development of efficient molecular tools, identification of genetic elements, and engineering approaches for the production of various industrially relevant bioproducts. Furthermore, strategies to improve substrate conversion and product formation both with systematic and synthetic biology approaches are discussed, along with future directions and perspectives in improving red yeasts as more versatile biotechnological chassis in contributing to a circular bioeconomy. The review aims to provide insights and directions for further research in this rapidly evolving field. Ultimately, harnessing the capabilities of red yeasts will play a crucial role in paving the way towards next-generation sustainable bioeconomy.

PMID:39163921 | DOI:10.1016/j.biotechadv.2024.108432

Curr Biol. 2024 Aug 19;34(16):R788-R790. doi: 10.1016/j.cub.2024.07.008.

ABSTRACT

Regenerative organisms such as plants must have specific signals that respond to damage and instruct remnant tissue to undergo repair. A recent paper identifies a long-sought candidate for the signal that links injury to regenerative programs.

PMID:39163843 | DOI:10.1016/j.cub.2024.07.008

Curr Biol. 2024 Aug 19;34(16):R764-R767. doi: 10.1016/j.cub.2024.06.024.

ABSTRACT

Rubisco (D-ribulose 1,5-bisphosphate carboxylase/oxygenase) is the most abundant enzyme in the world, constituting up to half of the soluble protein content in plant leaves. Such is its ubiquity that its chemical fingerprint can be detected in the geological record spanning billions of years. Rubisco catalyses the conversion of inorganic CO2 into organic sugars, which underpin almost all of the biosphere, including our entire food chain. Due to its central role in the global carbon cycle, rubisco has been the subject of intense research for over 50 years. Rubisco is often considered inefficient due to its slow rate of carboxylation compared with other central metabolism enzymes, and its promiscuous oxygenase activity, which competes with the productive carboxylation reaction. It is hoped that engineering improved CO2 fixation will have significant advantages in agriculture and climate change mitigation. However, rubisco has proven difficult to engineer, with decades of efforts yielding limited results. Recent research has focused on reconstructing the evolutionary trajectory of rubisco to help elucidate its cryptic origins. Such evolutionary studies have led to a better understanding of both the origins of more complex rubisco forms and the broader relationship between rubisco's structure and function.

PMID:39163833 | DOI:10.1016/j.cub.2024.06.024

Malar J. 2024 Aug 20;23(1):251. doi: 10.1186/s12936-024-05079-7.

ABSTRACT

BACKGROUND: Plasmodium falciparum oocysts undergo growth and maturation in a unique setting within the mosquito midgut, firmly situated between the epithelium and the basal lamina. This location exposes them to specific nutrient exchange and metabolic processes while in direct contact with the mosquito haemolymph. The limited availability of in vitro culture systems for growth of the various P. falciparum mosquito stages hampers study of their biology and impedes progress in combatting malaria.

METHODS: An artificial in vitro environment was established to mimic this distinctive setting, transitioning from a 2D culture system to a 3D model capable of generating fully mature oocysts that give rise to in vitro sporozoites.

RESULTS: A two-dimensional (2D) chamber slide was employed along with an extracellular matrix composed of type IV collagen, entactin, and gamma laminin. This matrix facilitated development of the optimal medium composition for cultivating mature P. falciparum oocysts in vitro. However, the limitations of this 2D culture system in replicating the in vivo oocyst environment prompted a refinement of the approach by optimizing a three-dimensional (3D) alginate matrix culture system. This new system offered improved attachment, structural support, and nutrient exchange for the developing oocysts, leading to their maturation and the generation of sporozoites.

CONCLUSIONS: This technique enables the in vitro growth of P. falciparum oocysts and sporozoites.

PMID:39164764 | DOI:10.1186/s12936-024-05079-7

Genome Biol. 2024 Aug 20;25(1):227. doi: 10.1186/s13059-024-03369-6.

ABSTRACT

BACKGROUND: The design of nucleotide sequences with defined properties is a long-standing problem in bioengineering. An important application is protein expression, be it in the context of research or the production of mRNA vaccines. The rate of protein synthesis depends on the 5' untranslated region (5'UTR) of the mRNAs, and recently, deep learning models were proposed to predict the translation output of mRNAs from the 5'UTR sequence. At the same time, large data sets of endogenous and reporter mRNA translation have become available.

RESULTS: In this study, we use complementary data obtained in two different cell types to assess the accuracy and generality of currently available models for predicting translational output. We find that while performing well on the data sets on which they were trained, deep learning models do not generalize well to other data sets, in particular of endogenous mRNAs, which differ in many properties from reporter constructs.

CONCLUSIONS: These differences limit the ability of deep learning models to uncover mechanisms of translation control and to predict the impact of genetic variation. We suggest directions that combine high-throughput measurements and machine learning to unravel mechanisms of translation control and improve construct design.

PMID:39164757 | DOI:10.1186/s13059-024-03369-6

Microb Cell Fact. 2024 Aug 20;23(1):231. doi: 10.1186/s12934-024-02504-z.

ABSTRACT

BACKGROUND: Global warming causes an increase in the levels of sugars in grapes and hence in ethanol after wine fermentation. Therefore, alcohol reduction is a major target in modern oenology. Deletion of the MKS1 gene, a negative regulator of the Retrograde Response pathway, in Saccharomyces cerevisiae was reported to increase glycerol and reduce ethanol and acetic acid in wine. This study aimed to obtain mutants with a phenotype similar to that of the MKS1 deletion strain by subjecting commercial S. cerevisiae wine strains to an adaptive laboratory evolution (ALE) experiment with the lysine toxic analogue S-(2-aminoethyl)-L-cysteine (AEC).

RESULTS: In laboratory-scale wine fermentation, isolated AEC-resistant mutants overproduced glycerol and reduced acetic acid. In some cases, ethanol was also reduced. Whole-genome sequencing revealed point mutations in the Retrograde Response activator Rtg2 and in the homocitrate synthases Lys20 and Lys21. However, only mutations in Rtg2 were responsible for the overactivation of the Retrograde Response pathway and ethanol reduction during vinification. Finally, wine fermentation was scaled up in an experimental cellar for one evolved mutant to confirm laboratory-scale results, and any potential negative sensory impact was ruled out.

CONCLUSIONS: Overall, we have shown that hyperactivation of the Retrograde Response pathway by ALE with AEC is a valid approach for generating ready-to-use mutants with a desirable phenotype in winemaking.

PMID:39164751 | DOI:10.1186/s12934-024-02504-z

J Neuroinflammation. 2024 Aug 20;21(1):207. doi: 10.1186/s12974-024-03188-3.

ABSTRACT

Despite advances in antimicrobial and anti-inflammatory treatment, inflammation and its consequences remain a major challenge in the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic inflammation has the potential to worsen the condition of body tissues and ultimately lead to significant impairment of their functionality. Although the central nervous system has long been considered immune privileged to peripheral immune responses, recent research has shown that strong immune responses in the periphery also affect the brain, leading to reactive microglia, which belong to the innate immune system and reside in the brain, and neuroinflammation. The inflammatory response is primarily a protective mechanism to defend against pathogens and tissue damage. However, excessive and chronic inflammation can have negative effects on neuronal structure and function. Neuroinflammation underlies the pathogenesis of many neurological and neurodegenerative diseases and can accelerate their progression. Consequently, targeting inflammatory signaling pathways offers potential therapeutic strategies for various neuropathological conditions, particularly Parkinson's and Alzheimer's disease, by curbing inflammation. Here the blood-brain barrier is a major hurdle for potential therapeutic strategies, therefore it would be highly advantageous to foster and utilize brain innate anti-inflammatory mechanisms. The tricarboxylic acid cycle-derived metabolite itaconate is highly upregulated in activated macrophages and has been shown to act as an immunomodulator with anti-inflammatory and antimicrobial functions. Mesaconate, an isomer of itaconate, similarly reduces the inflammatory response in macrophages. Nevertheless, most studies have focused on its esterified forms and its peripheral effects, while its influence on the CNS remained largely unexplored. Therefore, this study investigated the immunomodulatory and therapeutic potential of endogenously synthesized itaconate and its isomer mesaconate in lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show that both itaconate and mesaconate reduce LPS-induced neuroinflammation, as evidenced by lower levels of inflammatory mediators, reduced microglial reactivity and a rescue of synaptic plasticity, the cellular correlate of learning and memory processes in the brain. Overall, this study emphasizes that both itaconate and mesaconate have therapeutic potential for neuroinflammatory processes in the brain and are of remarkable importance due to their endogenous origin and production, which usually leads to high tolerance.

PMID:39164713 | DOI:10.1186/s12974-024-03188-3

Commun Biol. 2024 Aug 20;7(1):1020. doi: 10.1038/s42003-024-06694-5.

ABSTRACT

Expression profiling in spatially defined regions is crucial for systematically understanding tissue complexity. Here, we report a method of photo-irradiation for in-situ barcoding hybridization and ligation sequencing, named PBHL-seq, which allows targeted expression profiling from the photo-irradiated region of interest in intact fresh frozen and formalin fixation and paraffin embedding (FFPE) tissue samples. PBHL-seq uses photo-caged oligodeoxynucleotides for in situ reverse transcription followed by spatially targeted barcoding of cDNAs to create spatially indexed transcriptomes of photo-illuminated regions. We recover thousands of differentially enriched transcripts from different regions by applying PBHL-seq to OCT-embedded tissue (E14.5 mouse embryo and mouse brain) and FFPE mouse embryo (E15.5). We also apply PBHL-seq to the subcellular microstructures (cytoplasm and nucleus, respectively) and detect thousands of differential expression genes. Thus, PBHL-seq provides an accessible workflow for expression profiles from the region of interest in frozen and FFPE tissue at subcellular resolution with areas expandable to centimeter scale, while preserving the sample intact for downstream analysis to promote the development of transcriptomics.

PMID:39164496 | DOI:10.1038/s42003-024-06694-5

Sci Rep. 2024 Aug 20;14(1):19341. doi: 10.1038/s41598-024-70294-w.

ABSTRACT

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.

PMID:39164364 | DOI:10.1038/s41598-024-70294-w

Hum Mol Genet. 2024 Aug 21:ddae120. doi: 10.1093/hmg/ddae120. Online ahead of print.

ABSTRACT

Variants of talin-1 (TLN1) have recently been linked with spontaneous coronary artery dissection (SCAD) a condition where a tear can form in the wall of a heart artery necessitating immediate medical care. One talin-1 variant, A2013T, has an extensive familial pedigree of SCAD, which led to the screening for, and identification of, further talin-1 variants in SCAD patients. Here we evaluated these variants with commonly used pathogenicity prediction tools and found it challenging to reliably classify SCAD-associated variants, even A2013T where the evidence of a causal role is strong. Using biochemical and cell biological methods, we show that SCAD-associated variants in talin-1, which would typically be classified as non-pathogenic, still cause a measurable impact on protein structure and cell behaviour, including cell movement and wound healing capacity. Together, this indicates that even subtle variants in central mechanosensitive adapter proteins, can give rise to significant health impacts at the individual level, suggesting the need for a possible re-evaluation of the scoring criteria for pathogenicity prediction for talin variants.

PMID:39163585 | DOI:10.1093/hmg/ddae120