Nat Commun. 2023 Dec 6;14(1):8070. doi: 10.1038/s41467-023-43760-8.

ABSTRACT

Dung removal by macrofauna such as dung beetles is an important process for nutrient cycling in pasturelands. Intensification of farming practices generally reduces species and functional diversity of terrestrial invertebrates, which may negatively affect ecosystem services. Here, we investigate the effects of cattle-grazing intensification on dung removal by dung beetles in field experiments replicated in 38 pastures around the world. Within each study site, we measured dung removal in pastures managed with low- and high-intensity regimes to assess between-regime differences in dung beetle diversity and dung removal, whilst also considering climate and regional variations. The impacts of intensification were heterogeneous, either diminishing or increasing dung beetle species richness, functional diversity, and dung removal rates. The effects of beetle diversity on dung removal were more variable across sites than within sites. Dung removal increased with species richness across sites, while functional diversity consistently enhanced dung removal within sites, independently of cattle grazing intensity or climate. Our findings indicate that, despite intensified cattle stocking rates, ecosystem services related to decomposition and nutrient cycling can be maintained when a functionally diverse dung beetle community inhabits the human-modified landscape.

PMID:38057312 | DOI:10.1038/s41467-023-43760-8

Nat Commun. 2023 Dec 6;14(1):8080. doi: 10.1038/s41467-023-43143-z.

ABSTRACT

The ability of marine bacteria to direct their movement in response to chemical gradients influences inter-species interactions, nutrient turnover, and ecosystem productivity. While many bacteria are chemotactic towards small metabolites, marine organic matter is predominantly composed of large molecules and polymers. Yet, the signalling role of these large molecules is largely unknown. Using in situ and laboratory-based chemotaxis assays, we show that marine bacteria are strongly attracted to the abundant algal polysaccharides laminarin and alginate. Unexpectedly, these polysaccharides elicited stronger chemoattraction than their oligo- and monosaccharide constituents. Furthermore, chemotaxis towards laminarin was strongly enhanced by dimethylsulfoniopropionate (DMSP), another ubiquitous algal-derived metabolite. Our results indicate that DMSP acts as a methyl donor for marine bacteria, increasing their gradient detection capacity and facilitating their access to polysaccharide patches. We demonstrate that marine bacteria are capable of strong chemotaxis towards large soluble polysaccharides and uncover a new ecological role for DMSP in enhancing this attraction. These navigation behaviours may contribute to the rapid turnover of polymers in the ocean, with important consequences for marine carbon cycling.

PMID:38057294 | DOI:10.1038/s41467-023-43143-z

Dev Cell. 2023 Nov 30:S1534-5807(23)00583-X. doi: 10.1016/j.devcel.2023.11.008. Online ahead of print.

ABSTRACT

Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.

PMID:38056453 | DOI:10.1016/j.devcel.2023.11.008

Anal Chem. 2023 Dec 6. doi: 10.1021/acs.analchem.3c02924. Online ahead of print.

ABSTRACT

Untargeted metabolomics is an analytical approach with numerous applications serving as an effective metabolic phenotyping platform to characterize small molecules within a biological system. Data quality can be challenging to evaluate and demonstrate in metabolomics experiments. This has driven the use of pooled quality control (QC) samples for monitoring and, if necessary, correcting for analytical variance introduced during sample preparation and data acquisition stages. Described herein is a scoping literature review detailing the use of pooled QC samples in published untargeted liquid chromatography-mass spectrometry (LC-MS) based metabolomics studies. A literature query was performed, the list of papers was filtered, and suitable articles were randomly sampled. In total, 109 papers were each reviewed by at least five reviewers, answering predefined questions surrounding the use of pooled quality control samples. The results of the review indicate that use of pooled QC samples has been relatively widely adopted by the metabolomics community and that it is used at a similar frequency across biological taxa and sample types in both small- and large-scale studies. However, while many studies generated and analyzed pooled QC samples, relatively few reported the use of pooled QC samples to improve data quality. This demonstrates a clear opportunity for the field to more frequently utilize pooled QC samples for quality reporting, feature filtering, analytical drift correction, and metabolite annotation. Additionally, our survey approach enabled us to assess the ambiguity in the reporting of the methods used to describe the generation and use of pooled QC samples. This analysis indicates that many details of the QC framework are missing or unclear, limiting the reader's ability to determine which QC steps have been taken. Collectively, these results capture the current state of pooled QC sample usage and highlight existing strengths and deficiencies as they are applied in untargeted LC-MS metabolomics.

PMID:38055671 | DOI:10.1021/acs.analchem.3c02924

Elife. 2023 Dec 6;12:RP88874. doi: 10.7554/eLife.88874.

ABSTRACT

Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.

PMID:38055613 | DOI:10.7554/eLife.88874

J Chem Inf Model. 2023 Dec 6. doi: 10.1021/acs.jcim.3c01602. Online ahead of print.

ABSTRACT

Inflammation is a biological response to harmful stimuli, aiding in the maintenance of tissue homeostasis. However, excessive or persistent inflammation can precipitate a myriad of pathological conditions. Although current treatments such as NSAIDs, corticosteroids, and immunosuppressants are effective, they can have side effects and resistance issues. In this backdrop, anti-inflammatory peptides (AIPs) have emerged as a promising therapeutic approach against inflammation. Leveraging machine learning methods, we have the opportunity to accelerate the discovery and investigation of these AIPs more effectively. In this study, we proposed an advanced framework by ensemble machine learning and deep learning for AIP prediction. Initially, we constructed three individual models with extremely randomized trees (ET), gated recurrent unit (GRU), and convolutional neural networks (CNNs) with attention mechanism and then used stacking architecture to build the final predictor. By utilizing various sequence encodings and combining the strengths of different algorithms, our predictor demonstrated exemplary performance. On our independent test set, our model achieved an accuracy, MCC, and F1-score of 0.757, 0.500, and 0.707, respectively, clearly outperforming other contemporary AIP prediction methods. Additionally, our model offers profound insights into the feature interpretation of AIPs, establishing a valuable knowledge foundation for the design and development of future anti-inflammatory strategies.

PMID:38054927 | DOI:10.1021/acs.jcim.3c01602

Adv Sci (Weinh). 2023 Dec 6:e2308030. doi: 10.1002/advs.202308030. Online ahead of print.

ABSTRACT

Cells are small, closed spaces filled with various types of macromolecules. Although it is shown that the characteristics of biochemical reactions in vitro are quite different from those in living cells, the role of the co-existence of various macromolecules in cell-size space remains still elusive. Here, using a constructive approach, it is demonstrated that the co-existence of various macromolecules themselves has the ability to tune protein localization for spatiotemporal regulation and a biochemical reaction system in a cell-size space. Both experimental and theoretical analyses reveal that enhancement of interfacial effects by a large surface-area-to-volume ratio facilitates membrane localization of molecules in the cell-size space, and the interfacial effects are alleviated by competitive binding to lipid membranes among multiple proteins even if their membrane affinities are weak. These results indicate that competition for membrane binding among various macromolecules in the cell-size space plays a role in regulating the spatiotemporal molecular organization and biochemical reaction networks. These findings shed light on the importance of surrounding molecules for biochemical reactions using purified elements in small spaces.

PMID:38054641 | DOI:10.1002/advs.202308030

J Extracell Vesicles. 2023 Dec;12(12):e12387. doi: 10.1002/jev2.12387.

ABSTRACT

Natural killer cell-derived extracellular vesicles (NK-EVs) have shown promising potential as biotherapeutics for cancer due to their unique attributes as cytotoxic nanovesicles against cancer cells and immune-modulatory activity towards immune cells. However, a biomanufacturing workflow is needed to produce clinical-grade NK-EVs for pre-clinical and clinical applications. This study established a novel biomanufacturing workflow using a closed-loop hollow-fibre bioreactor to continuously produce NK-EVs from the clinically relevant NK92-MI cell line under serum-free, Xeno-free and feeder-free conditions following GMP-compliant conditions. The NK92 cells grown in the bioreactor for three continuous production lots resulted in large quantities of both NK cell and NK-EV biotherapeutics at the end of each production lot (over 109 viable cells and 1013 EVs), while retaining their cytotoxic payload (granzyme B and perforin), pro-inflammatory cytokine (interferon-gamma) content and cytotoxicity against the human leukemic cell line K562 with limited off-target toxicity against healthy human fibroblast cells. This scalable biomanufacturing workflow has the potential to facilitate the clinical translation of adoptive NK cell-based and NK-EV-based immunotherapies for cancer with GMP considerations.

PMID:38054534 | DOI:10.1002/jev2.12387

J Exp Biol. 2023 Dec 6:jeb.246848. doi: 10.1242/jeb.246848. Online ahead of print.

ABSTRACT

Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at the individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided by adaptations in oxidative physiology at the macroevolutionary scale. However, this hypothesis remains unexplored. Here, we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species (681 individuals with blood glucose and 1021 individuals with oxidative state data). We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no clear evidence for blood glucose concentration being correlated with either antioxidant or lipid damage levels at the macroevolutionary scale, as opposed to the hypothesis postulating that high blood glucose levels entail oxidative costs. The only exception was the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings support the hypothesis that birds evolved adaptations preventing the (glyc)oxidative costs of high blood glucose observed at the within-species level. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds and possibly the paradoxical combination of long lifespan and high blood glucose levels relative to mammals.

PMID:38054362 | DOI:10.1242/jeb.246848

Plant Genome. 2023 Dec 6:e20411. doi: 10.1002/tpg2.20411. Online ahead of print.

ABSTRACT

On account of its competence to accept and donate electrons, iron (Fe) is an essential element across all forms of life, including plants. Maintaining Fe homeostasis requires precise orchestration of its uptake, trafficking, and translocation in order to meet the demand for Fe sinks such as plastids. Plants harboring defects in the systemic Fe transporter OPT3 (OLIGOPEPTIDE TRANSPORTER 3) display constitutive Fe deficiency responses and accumulate toxic levels of Fe in their leaves. Similarly, ectopic expression of IRONMAN (IMA) genes, encoding a family of phloem-localized signaling peptides, triggers the uptake and accumulation of Fe by inhibiting the putative Fe sensor BRUTUS. This study aims at elucidating the mechanisms operating between OPT3-mediated systemic Fe transport, activation of IMA genes in the phloem, and activation of Fe uptake in the root epidermis. Transcriptional profiling of opt3-2 mutant and IMA1/IMA3 overexpressing (IMA Ox) lines uncovered a small subset of genes that were consistently differentially expressed across all three genotypes and Fe-deficient control plants, constituting potential novel regulators of cellular Fe homeostasis. In particular, expression of the the F-box protein At1g73120 was robustly induced in all genotypes, suggesting a putative function in the posttranslational regulation of cellular Fe homeostasis. As further constituents of this module, two plastid-encoded loci that putatively produce transfer ribonucleic acid (tRNA)-derived small ribonucleic acids are possibly involved in retrograde control of root Fe uptake.

PMID:38054209 | DOI:10.1002/tpg2.20411

iScience. 2023 Oct 27;26(12):108340. doi: 10.1016/j.isci.2023.108340. eCollection 2023 Dec 15.

ABSTRACT

Sorafenib induces ferroptosis, making it a useful treatment against advanced liver hepatocellular carcinoma (LIHC). However, sorafenib resistance is extremely common among LIHC patients. Here, we used a comprehensive approach to investigate the effects of ABHD12, which regulates tumorigenesis and sorafenib resistance in LIHC. We validated ABHD12 expression was upregulated in LIHC tissue, which correlated with worse overall survival and related to tumor size or stage. ABHD12 facilitated a pro-tumorigenic phenotype involving increased cell proliferation, migration, and clonogenicity as well as sorafenib resistance. Knockout of ABHD12 sensitized liver cancer cells to sorafenib-induced ferroptosis. Co-delivery of sorafenib and ABHD12 inhibitor into a nude mouse model enhanced therapeutic efficacy for LIHC. Our study demonstrates that ABHD12 contributes to tumor growth and sorafenib resistance in liver cancer, which indicate the promising potential of ABHD12 in diagnosis and prognosis as well as highlight the potential therapeutic applications for co-delivery of sorafenib and ABHD12 inhibitor.

PMID:38053637 | PMC:PMC10694648 | DOI:10.1016/j.isci.2023.108340

Nat Struct Mol Biol. 2023 Dec 5. doi: 10.1038/s41594-023-01130-4. Online ahead of print.

ABSTRACT

Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates. We observe extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, which strongly associate with transcriptional changes, although distinct groups of genes are irresponsive to topological changes. In each lineage, a high degree of connectivity, or 'hubness', positively correlates with levels of gene expression and enriches for cell-type specific and essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation across lineages compared to genes in linear proximity or within the same contact domains. By incorporating 3D chromatin features, we build a predictive model for transcriptional regulation (3D-HiChAT) that outperforms models using only 1D promoter or proximal variables to predict levels and cell-type specificity of gene expression. Using 3D-HiChAT, we identify, in silico, candidate functional enhancers and hubs in each cell lineage, and with CRISPRi experiments, we validate several enhancers that control gene expression in their respective lineages. Our study identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to comprehensively understand lineage-specific transcriptional behaviors.

PMID:38053013 | DOI:10.1038/s41594-023-01130-4

Nat Commun. 2023 Dec 5;14(1):8033. doi: 10.1038/s41467-023-43899-4.

ABSTRACT

Endonucleases have recently widely used in molecular diagnostics. Here, we report a strategy to exploit the properties of Argonaute (Ago) proteins for molecular diagnostics by introducing an artificial nucleic acid circuit with Ago protein (ANCA) method. The ANCA is designed to perform a continuous autocatalytic reaction through cross-catalytic cleavage of the Ago protein, enabling one-step, amplification-free, and isothermal DNA detection. Using the ANCA method, carbapenemase-producing Klebsiella pneumoniae (CPKP) are successfully detected without DNA extraction and amplification steps. In addition, we demonstrate the detection of carbapenem-resistant bacteria in human urine and blood samples using the method. We also demonstrate the direct identification of CPKP swabbed from surfaces using the ANCA method in conjunction with a three-dimensional nanopillar structure. Finally, the ANCA method is applied to detect CPKP in rectal swab specimens from infected patients, achieving sensitivity and specificity of 100% and 100%, respectively. The developed method can contribute to simple, rapid and accurate diagnosis of CPKP, which can help prevent nosocomial infections.

PMID:38052830 | DOI:10.1038/s41467-023-43899-4

Nat Commun. 2023 Dec 5;14(1):8044. doi: 10.1038/s41467-023-43839-2.

NO ABSTRACT

PMID:38052805 | DOI:10.1038/s41467-023-43839-2

Life Sci Alliance. 2023 Dec 4;7(2):e202302146. doi: 10.26508/lsa.202302146. Print 2024 Feb.

ABSTRACT

Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in the Gleason grade group (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or overtreatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign sample runs from 278 patients. Three proteins (F5, TMEM126B, and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomize prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management.

PMID:38052461 | DOI:10.26508/lsa.202302146

Cell Rep Med. 2023 Nov 28:101306. doi: 10.1016/j.xcrm.2023.101306. Online ahead of print.

ABSTRACT

Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic approaches. We identified two promoters of "BMP resistance" in cancer cachexia, specifically the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling, rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutic potential for targeting the ERFE-FKBP12 axis.

PMID:38052214 | DOI:10.1016/j.xcrm.2023.101306

Hum Reprod. 2023 Dec 5:dead247. doi: 10.1093/humrep/dead247. Online ahead of print.

ABSTRACT

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins?

SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3.

WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures.

STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation.

MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle.

LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/).

LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility.

WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility.

STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests.

TRIAL REGISTRATION NUMBER: N/A.

PMID:38052102 | DOI:10.1093/humrep/dead247

PLoS Pathog. 2023 Dec 5;19(12):e1011807. doi: 10.1371/journal.ppat.1011807. Online ahead of print.

ABSTRACT

Malaria is caused by the rapid proliferation of Plasmodium parasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics in Plasmodium falciparum and knowlesi using super-resolution time-lapse microscopy. This confirmed that the number of daughter cells was consistent with a model in which a counter mechanism regulates multiplication yet incompatible with a timer mechanism. P. falciparum cell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce fewer merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection.

PMID:38051755 | DOI:10.1371/journal.ppat.1011807

Cancer Res Commun. 2023 Dec 5. doi: 10.1158/2767-9764.CRC-22-0464. Online ahead of print.

ABSTRACT

Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer (CRC) is an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite cause other than possible sociodemographic, socioeconomic, education, nutrition, delivery of healthcare, screening, and cultural factors. A primary limitation in this field is the lack of and small sample size of Black/AA studies. Thus, this study aimed to investigate whether differences in gene expression contribute to this ongoing unanswered racial disparity issue. In this study, we examined transcriptomic data of Black/AA and White patient cohorts using a bioinformatic and systems biology approach. We performed a Kaplan Meier overall survival analysis between both patient cohorts across critical CRC signal transduction networks (STNs), to determine the differences in significant genes across each cohort. Other bioinformatic analyses performed included PROGENy (pathway responsive genes for activity inference), RNA Sequencing differential expression using DESeq2, multivariable-adjusted regression, and other associated Kaplan Meier analyses. These analyses identified novel prognostic genes independent from each cohort, 176 differentially expressed genes (DEG), and specific patient cohort STN survival associations. Despite the overarching limitation, the results revealed several novel differences in gene expression between the CRC Black/AA and White patient cohorts, which allows one to dive deeper into and understand the behaviour on a systems level of what could be driving this racial difference across CRC. Concretely, this information can guide precision medicine approaches tailored specifically for CRC racial disparities.

PMID:38051091 | DOI:10.1158/2767-9764.CRC-22-0464

mSystems. 2023 Dec 5:e0069723. doi: 10.1128/msystems.00697-23. Online ahead of print.

ABSTRACT

Staphylococcus saprophyticus is the second most common bacteria associated with urinary tract infections (UTIs) in women. The antimicrobial treatment regimen for uncomplicated UTI is normally nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or a fluoroquinolone without routine susceptibility testing of S. saprophyticus recovered from urine specimens. However, TMP-SMX-resistant S. saprophyticus has been detected recently in UTI patients, as well as in our cohort. Herein, we investigated the understudied resistance patterns of this pathogenic species by linking genomic antibiotic resistance gene (ARG) content to susceptibility phenotypes. We describe ARG associations with known and novel SCCmec configurations as well as phage elements in S. saprophyticus, which may serve as intervention or diagnostic targets to limit resistance transmission. Our analyses yielded a comprehensive database of phenotypic data associated with the ARG sequence in clinical S. saprophyticus isolates, which will be crucial for resistance surveillance and prediction to enable precise diagnosis and effective treatment of S. saprophyticus UTIs.

PMID:38051037 | DOI:10.1128/msystems.00697-23