Diabetes Care. 2023 Jul 18:dc230314. doi: 10.2337/dc23-0314. Online ahead of print.

ABSTRACT

OBJECTIVE: Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific lipidomic signatures with habitual diets and modified diabetes risk by using a trial and a cohort.

RESEARCH DESIGN AND METHODS: We included 231 Chinese with overweight and prediabetes in a randomized feeding trial with Mediterranean, traditional, or transitional diets (control diet) from February to September 2019. Plasma lipidomic profiles were measured at baseline, third month, and sixth month by high-throughput targeted liquid chromatography-mass spectrometry. Associations of the identified lipids with habitual dietary intakes were examined in another lipidomic database of a Chinese cohort (n = 1,117). The relationships between diet-induced changes of lipidomic species and diabetes risk factors were further investigated through both individual lipids and relevant modules in the trial.

RESULTS: Out of 364 lipidomic species, 26 altered across groups, including 12 triglyceride (TAG) fractions, nine plasmalogens, four phosphatidylcholines (PCs), and one phosphatidylethanolamine. TAG fractions and PCs were associated with habitual fish intake while plasmalogens were associated with red meat intake in the cohort. Of the diet-related lipidomic metabolites, 10 TAG fractions and PC(16:0/22:6) were associated with improved Matsuda index (β = 0.12 to 0.42; PFDR < 0.030). Two plasmalogens were associated with deteriorated fasting glucose (β = 0.29 to 0.31; PFDR < 0.014). Similar results were observed for TAG and plasmalogen related modules.

CONCLUSIONS: These fish- and red meat-related lipidomic signatures sensitively reflected different diets and modified type 2 diabetes risk factors, critical for optimizing dietary patterns.

PMID:37463495 | DOI:10.2337/dc23-0314

Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2306420120. doi: 10.1073/pnas.2306420120. Epub 2023 Jul 18.

ABSTRACT

To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen Plasmodium falciparum employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.

PMID:37463201 | DOI:10.1073/pnas.2306420120

Cell Rep. 2023 Jul 17;42(7):112801. doi: 10.1016/j.celrep.2023.112801. Online ahead of print.

ABSTRACT

How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.

PMID:37463107 | DOI:10.1016/j.celrep.2023.112801

J Clin Invest. 2023 Jul 18:e163325. doi: 10.1172/JCI163325. Online ahead of print.

ABSTRACT

RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematological ma-lignancies. We previously reported that co-expression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harbor-ing chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromo-somal instability (CIN) remains unclear. Here, we demonstrate that SF3B1 mutation promotes centro-meric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromo-some segregation, altered spindle architecture and aneuploidy, which can be alleviated by removal of cen-R-loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlies augmentation of cen-R-loop as overexpression of the normal isoform, but not the altered form, mitigates mitotic stress in SF3B1 mutant cells. Our study underscores the critical role of novel splice variants in linking RNA splicing dysregulation and CIN, and highlights cen-R-loop augmen-tation as a key mechanism for leukemogenesis.

PMID:37463047 | DOI:10.1172/JCI163325

J Exp Med. 2023 Sep 4;220(9):e20230054. doi: 10.1084/jem.20230054. Epub 2023 Jul 18.

ABSTRACT

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

PMID:37462944 | DOI:10.1084/jem.20230054

DNA Cell Biol. 2023 Jul 18. doi: 10.1089/dna.2023.0226. Online ahead of print.

ABSTRACT

Fibroblast growth factor (FGF) signaling is conserved from cnidaria to mammals (Ornitz and Itoh, 2022) and it regulates several critical processes such as differentiation, proliferation, apoptosis, cell migration, and embryonic development. One pivotal process FGF signaling controls is the division of vertebrate paraxial mesoderm into repeated segmented units called somites (i.e., somitogenesis). Somite segmentation occurs periodically and sequentially in a head-to-tail manner, and lays down the plan for compartmentalized development of the vertebrate body axis (Gomez et al., 2008). These somites later give rise to vertebrae, tendons, and skeletal muscle. Somite segments form sequentially from the anterior end of the presomitic mesoderm (PSM). The periodicity of somite segmentation is conferred by the segmentation clock, comprising oscillatory expression of Hairy and enhancer-of-split (Her/Hes) genes in the PSM. The positional information for somite boundaries is instructed by the double phosphorylated extracellular signal-regulated kinase (ppERK) gradient, which is the relevant readout of FGF signaling during somitogenesis (Sawada et al., 2001; Delfini et al., 2005; Simsek and Ozbudak, 2018; Simsek et al., 2023). In this review, we summarize the crosstalk between the segmentation clock and FGF/ppERK gradient and discuss how that leads to periodic somite boundary formation. We also draw attention to outstanding questions regarding the interconnected roles of the segmentation clock and ppERK gradient, and close with suggested future directions of study.

PMID:37462914 | DOI:10.1089/dna.2023.0226

mBio. 2023 Jul 18:e0121623. doi: 10.1128/mbio.01216-23. Online ahead of print.

ABSTRACT

We have discovered a new cluster of genes that is found exclusively in the Actinobacteria phylum. This locus includes genes for the 2-aminophenol meta-cleavage pathway and the shell proteins of a bacterial microcompartment (BMC) and has been named aromatics (ARO) for its putative role in the breakdown of aromatic compounds. In this study, we provide details about the distribution and composition of the ARO BMC locus and conduct phylogenetic, structural, and functional analyses of the first two enzymes in the catabolic pathway: a unique 2-aminophenol dioxygenase, which is exclusively found alongside BMC shell genes in Actinobacteria, and a semialdehyde dehydrogenase, which works downstream of the dioxygenase. Genomic analysis reveals variations in the complexity of the ARO loci across different orders. Some loci are simple, containing shell proteins and enzymes for the initial steps of the catabolic pathway, while others are extensive, encompassing all the necessary genes for the complete breakdown of 2-aminophenol into pyruvate and acetyl-CoA. Furthermore, our analysis uncovers two subtypes of ARO BMC that likely degrade either 2-aminophenol or catechol, depending on the presence of a pathway-specific gene within the ARO locus. The precise precursor of 2-aminophenol, which serves as the initial substrate and/or inducer for the ARO pathway, remains unknown, as our model organism Micromonospora rosaria cannot utilize 2-aminophenol as its sole energy source. However, using enzymatic assays, we demonstrate the dioxygenase's ability to cleave both 2-aminophenol and catechol in vitro, in collaboration with the aldehyde dehydrogenase, to facilitate the rapid conversion of these unstable and toxic intermediates. IMPORTANCE Bacterial microcompartments (BMCs) are proteinaceous organelles that are widespread among bacteria and provide a competitive advantage in specific environmental niches. Studies have shown that the genetic information necessary to form functional BMCs is encoded in loci that contain genes encoding shell proteins and the enzymatic core. This allows the bioinformatic discovery of BMCs with novel functions and expands our understanding of the metabolic diversity of BMCs. ARO loci, found only in Actinobacteria, contain genes encoding for phylogenetically remote shell proteins and homologs of the meta-cleavage degradation pathway enzymes that were shown to convert central aromatic intermediates into pyruvate and acetyl-CoA in gamma Proteobacteria. By analyzing the gene composition of ARO BMC loci and characterizing two core enzymes phylogenetically, structurally, and functionally, we provide an initial functional characterization of the ARO BMC, the most unusual BMC identified to date, distinctive among the repertoire of studied BMCs.

PMID:37462359 | DOI:10.1128/mbio.01216-23

bioRxiv. 2023 Jul 16:2023.07.07.545904. doi: 10.1101/2023.07.07.545904. Preprint.

ABSTRACT

Insect humoral immune responses are regulated in part by protease cascades, whose components circulate as zymogens in the hemolymph. In mosquitoes, these cascades consist of clip domain serine proteases (cSPs) and/or their non-catalytic homologs (cSPHs), which form a complex network, whose molecular make-up is not fully understood. Using a systems biology approach, based on a co-expression network of gene family members that function in melanization and co-immunoprecipitation using the serine protease inhibitor (SRPN)2, a key negative regulator of the melanization response in mosquitoes, we identify the cSP CLIPB4 from the African malaria mosquito Anopheles gambiae as a central node in this protease network. CLIPB4 is tightly co-expressed with SRPN2 and forms protein complexes with SRPN2 in the hemolymph of immune-challenged female mosquitoes. Genetic and biochemical approaches validate our network analysis and show that CLIPB4 is required for melanization and antibacterial immunity, acting as a prophenoloxidase (proPO)-activating protease, which is inhibited by SRPN2. In addition, we provide novel insight into the structural organization of the cSP network in An. gambiae, by demonstrating that CLIPB4 is able to activate proCLIPB8, a cSP upstream of the proPO-activating protease CLIPB9. These data provide the first evidence that, in mosquitoes, cSPs provide branching points in immune protease networks and deliver positive reinforcement in proPO activation cascades.

PMID:37461554 | PMC:PMC10350057 | DOI:10.1101/2023.07.07.545904

Elife. 2023 Jul 18;12:e83870. doi: 10.7554/eLife.83870.

ABSTRACT

Mannose has anticancer activity that inhibits cell proliferation and enhances the efficacy of chemotherapy. How mannose exerts its anticancer activity, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphates (dNTPs). This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, pharmacological inhibition of de novo dNTP biosynthesis was sufficient to retard cell cycle progression, sensitize cells to cisplatin, and inhibit dormant origin firing, suggesting dNTP loss-induced genomic instability as a central mechanism for the anticancer activity of mannose.

PMID:37461317 | DOI:10.7554/eLife.83870

Am J Primatol. 2023 Jul 17:e23537. doi: 10.1002/ajp.23537. Online ahead of print.

ABSTRACT

In primates, as well as in other mammals, play fighting (PF) is a complex form of playful activity that is structurally similar to real fighting (RF) and may also be used in a competitive way. Here, we verify the structural key differences that can distinguish PF from RF in adult chimpanzees (Pan troglodytes). We collected 962 h of video recording on 30 adult individuals belonging to four chimpanzee groups (Mona Chimpanzee Sanctuary, Spain; La Vallée des Singes and ZooParc de Beauval, France). We applied different indices-two of which were borrowed from the ecological measures of biodiversity-to test for structural differences between PF (345 sessions) and RF (461 sessions) in the levels of behavior repetition (Repeatability of Same Behavior Index, RSBI), distribution uniformity (Pielou Index, J), variability (Shannon Index, H') and, symmetry (i.e., reciprocal exchange of offensive/defensive behaviors; Asymmetry Index, AI). Moreover, we compared the session duration between PF and RF. We found that duration and RSBI were higher in PF than RF while AI was higher in RF than PF. No difference was found between J and H'. Interestingly, both females and males maintained similar ranking positions (determined via Normalized David's scores) in RF and PF. Our study indicates that session duration, behavior repetition, and symmetry can be distinctive structural key features of PF whereas dominance role-reversal, behavior variability, and distribution uniformity were not. PF in adult chimpanzees may have elements of serious contexts (e.g., absence of role-reversal as in RF) which is in line with the view that play is a blended, multifunctional behavior deriving from the re-combination of different behavioral systems. Our findings highlight the need to investigate play structure and manifestation in a nuanced way to better understand the actual motivation that underlies what appears to be play.

PMID:37461284 | DOI:10.1002/ajp.23537

Environ Toxicol Pharmacol. 2023 Jul 15:104232. doi: 10.1016/j.etap.2023.104232. Online ahead of print.

ABSTRACT

Endocrine disruptors (EDCs) are emerging contaminants that are harmful to health. Human exposure occurs mainly through ingestion or dermal contact, but inhalation could be an additional exposure route; therefore, this study was conducted to evaluate the oestrogenic activity of airborne particulate matter (PM). Outdoor PM was collected for a year in five Italian sites and extracted with organic solvents (four seasonal extracts/site). The oestrogenic activity was assessed using a gene reporter assay (MELN), and the risk to human health through inhalation was quantified using the results. Moreover, extracts were analysed to assess cytotoxicity (WST-1 and LDH assays) on human bronchial cells (BEAS-2B). The extracts induced a significant cytotoxicity and oestrogenic activity. Oestrogenic activity showed a seasonal trend and was correlated with concentrations of benzo(a)pyrene and toxic equivalency factor. Although a low inhalation cancer risk was found, this study confirmed that oestrogenic activity in air could contribute to overall health risks due to EDC exposure.

PMID:37459960 | DOI:10.1016/j.etap.2023.104232

Nat Immunol. 2023 Jul 17. doi: 10.1038/s41590-023-01557-3. Online ahead of print.

ABSTRACT

Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The mechanisms by which infants and young children mount effective immune responses to respiratory pathogens are unknown. Through investigation of lungs and lung-associated lymph nodes from infant and pediatric organ donors aged 0-13 years, we show that bronchus-associated lymphoid tissue (BALT), containing B cell follicles, CD4+ T cells and functionally active germinal centers, develop during infancy. BALT structures are prevalent around lung airways during the first 3 years of life, and their numbers decline through childhood coincident with the accumulation of memory T cells. Single-cell profiling and repertoire analysis reveals that early life lung B cells undergo differentiation, somatic hypermutation and immunoglobulin class switching and exhibit a more activated profile than lymph node B cells. Moreover, B cells in the lung and lung-associated lymph nodes generate biased antibody responses to multiple respiratory pathogens compared to circulating antibodies, which are mostly specific for vaccine antigens in the early years of life. Together, our findings provide evidence for BALT as an early life adaptation for mobilizing localized immune protection to the diverse respiratory challenges during this formative life stage.

PMID:37460638 | DOI:10.1038/s41590-023-01557-3

PLoS One. 2023 Jul 17;18(7):e0282551. doi: 10.1371/journal.pone.0282551. eCollection 2023.

ABSTRACT

Short tandem repeats (STRs) are short repeated sequences commonly found in the human genome and valuable in forensic science, used for human identity and relatedness markers. Next-generation sequencing (NGS) technologies, e.g., ForenSeq Signature Prep, can sequence STRs, inferring length-based alleles and single nucleotide polymorphisms (SNPs) and providing valuable insights into population and sub-population structures. Despite the potential benefits of NGS for STRs, no open-source software platform integrates the collection, management, and analysis of STR data from NGS into one place. Users must use multiple programs to process their STR data and then collect the results into a separate database or a file system folder. Moreover, analyzing repeat structures (STR repeat motifs) may require learning multiple software tools, making the process inefficient and cumbersome. To address this gap, we introduce the STRategy, a standalone web-based application supporting essential STR data management and analysis capabilities. The STRategy allows users to collect their data into its database, automatically calculates forensic parameters, and visualizes the analyzed data in various forms. Users can search the database using different options, such as by profile, loci, and genotypes, with and without a specific test kit. Moreover, users can also find the nucleotide variants of a locus among the samples. We designed the STRategy for internal use in a laboratory or an organization. Hence, our system includes role-based access control that allows users to search for or access specific data based on their responsibilities. The administrator role can customize the system, for example, configure maps according to the samples' geographic data, and manage reference STR repeat motifs. A laboratory or an organization can download and install a copy of STRategy on their local system using Docker, as described in https://github.com/cucpbioinfo/STRategy. In summary, the STRategy is an end-to-end system that provides users with a database to collect the analyzed STR data from NGS, the dynamic analyses of forensic parameters, and the variants of STR patterns according to the newly added samples, which are then explorable via various search options and visualizations. The system is helpful for both forensic investigations and forensic genetics.

PMID:37459339 | DOI:10.1371/journal.pone.0282551

PLoS Biol. 2023 Jul 17;21(7):e3002190. doi: 10.1371/journal.pbio.3002190. eCollection 2023 Jul.

ABSTRACT

Our basic understanding of carbon cycling in the biosphere remains qualitative and incomplete, precluding our ability to effectively engineer novel solutions to climate change. How can we attempt to engineer the unknown? This challenge has been faced before in plant biology, providing a roadmap to guide future efforts. We use examples from over a century of photosynthesis research to illustrate the key principles that will set future plant engineering on a solid footing, namely, an effort to identify the key control variables, quantify the effects of systematically tuning these variables, and use theory to account for these observations. The main contributions of plant synthetic biology will stem not from delivering desired genotypes but from enabling the kind of predictive understanding necessary to rationally design these genotypes in the first place. Only then will synthetic plant biology be able to live up to its promise.

PMID:37459291 | DOI:10.1371/journal.pbio.3002190

J Biomol Struct Dyn. 2023 Jul 17:1-12. doi: 10.1080/07391102.2023.2236714. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID‑19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (Mpro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 Mpro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 Mpro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 Mpro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 Mpro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-Mpro complex with MM-GBSA binding free energy (ΔGbind) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma.

PMID:37458994 | DOI:10.1080/07391102.2023.2236714

Anim Cogn. 2023 Jul 17. doi: 10.1007/s10071-023-01809-7. Online ahead of print.

ABSTRACT

Nonlinear phenomena (NLP) in animal vocalizations arise from irregularities in the oscillation of the vocal folds. Various non-mutually exclusive hypotheses have been put forward to explain the occurrence of NLP, from adaptive to physiological ones. Non-human primates often display NLP in their vocalizations, yet the communicative role of these features, if any, is still unclear. We here investigate the occurrence of NLP in the song of a singing primate, the indri (Indri indri), testing for the effect of sex, age, season, and duration of the vocal display on their emission. Our results show that NLP occurrence in indri depends on phonation, i.e., the cumulative duration of all the units emitted by an individual, and that NLP have higher probability to be emitted in the later stages of the song, probably due to the fatigue indris may experience while singing. Furthermore, NLP happen earlier in the vocal display of adult females than in that of the adult males, and this is probably due to the fact that fatigue occurs earlier in the former because of a greater contribution within the song. Our findings suggest, therefore, that indris may be subjected to physiological constraints during the singing process which may impair the production of harmonic sounds. However, indris may still benefit from emitting NLP by strengthening the loudness of their signals for better advertising their presence to the neighboring conspecific groups.

PMID:37458893 | DOI:10.1007/s10071-023-01809-7

EMBO Rep. 2023 Jul 17:e54709. doi: 10.15252/embr.202254709. Online ahead of print.

ABSTRACT

Endocytosis regulates the turnover of cell surface localized receptors, which are crucial for plants to rapidly respond to stimuli. The evolutionary ancient TPLATE complex (TPC) plays an essential role in endocytosis in Arabidopsis plants. Knockout or knockdown of single TPC subunits causes male sterility and seedling lethality phenotypes, complicating analysis of the roles of TPC during plant development. Partially functional alleles of TPC subunits however only cause mild developmental deviations. Here, we took advantage of the partially functional TPLATE allele, WDXM2, to investigate a role for TPC-dependent endocytosis in receptor-mediated signaling. We discovered that reduced TPC-dependent endocytosis confers a hypersensitivity to very low doses of CLAVATA3 peptide signaling. This hypersensitivity correlated with the abundance of the CLAVATA3 receptor protein kinase CLAVATA1 at the plasma membrane. Genetic and biochemical analysis as well as live-cell imaging revealed that TPC-dependent regulation of CLAVATA3-dependent internalization of CLAVATA1 from the plasma membrane is required for shoot stem cell homeostasis. Our findings provide evidence that TPC-mediated endocytosis and degradation of CLAVATA1 is a mechanism to dampen CLAVATA3-mediated signaling during plant development.

PMID:37458257 | DOI:10.15252/embr.202254709

Quant Plant Biol. 2023 Jul 10;4:e6. doi: 10.1017/qpb.2023.6. eCollection 2023.

ABSTRACT

Plants are complex systems made up of many interacting components, ranging from architectural elements such as branches and roots, to entities comprising cellular processes such as metabolic pathways and gene regulatory networks. The collective behaviour of these components, along with the plant's response to the environment, give rise to the plant as a whole. Properties that result from these interactions and cannot be attributed to individual parts alone are called emergent properties, occurring at different time and spatial scales. Deepening our understanding of plant growth and development requires computational tools capable of handling a large number of interactions and a multiscale approach connecting properties across scales. There currently exist few methods able to integrate models across scales, or models capable of predicting new emergent plant properties. This perspective explores current approaches to modelling emergent behaviour in plants, with a focus on how current and future tools can handle multiscale plant systems.

PMID:37457895 | PMC:PMC10345286 | DOI:10.1017/qpb.2023.6

Front Cell Neurosci. 2023 Jun 29;17:1205261. doi: 10.3389/fncel.2023.1205261. eCollection 2023.

ABSTRACT

INTRODUCTION: Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking.

METHODS: In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology.

RESULTS: We show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent.

CONCLUSION: This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.

PMID:37457817 | PMC:PMC10346859 | DOI:10.3389/fncel.2023.1205261

MedComm (2020). 2023 Jul 14;4(4):e327. doi: 10.1002/mco2.327. eCollection 2023 Aug.

ABSTRACT

Nanoparticles (NPs) have become one of the most popular objects of scientific study during the past decades. However, despite wealth of study reports, still there is a gap, particularly in health toxicology studies, underlying mechanisms, and related evaluation models to deeply understanding the NPs risk effects. In this review, we first present a comprehensive landscape of the applications of NPs on health, especially addressing the role of NPs in medical diagnosis, therapy. Then, the toxicity of NPs on health systems is introduced. We describe in detail the effects of NPs on various systems, including respiratory, nervous, endocrine, immune, and reproductive systems, and the carcinogenicity of NPs. Furthermore, we unravels the underlying mechanisms of NPs including ROS accumulation, mitochondrial damage, inflammatory reaction, apoptosis, DNA damage, cell cycle, and epigenetic regulation. In addition, the classical study models such as cell lines and mice and the emerging models such as 3D organoids used for evaluating the toxicity or scientific study are both introduced. Overall, this review presents a critical summary and evaluation of the state of understanding of NPs, giving readers more better understanding of the NPs toxicology to remedy key gaps in knowledge and techniques.

PMID:37457660 | PMC:PMC10349198 | DOI:10.1002/mco2.327