Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2414333121. doi: 10.1073/pnas.2414333121. Epub 2024 Nov 25.

ABSTRACT

Hinge sites of proteins play a key role in mediating conformational mechanics. Among them, those involved in the most collective modes of motion, also called global hinges, are of particular interest, as they support cooperative rearrangements that are often functional. Yet, the utility of targeting global hinges for modulating function remains to be established. We present here a systematic study of a series of proteins resolved in drug-bound forms to examine the probabilistic occurrence of spatial overlaps between hinge sites and drug-binding pockets. Our analysis reveals a high propensity of drug binding to hinge sites compared to random. Notably, one-third of currently approved drugs are colocalized with hinge sites. These mechanosensitive sites are predictable by simple models such as the Gaussian Network Model. Their targeting thus emerges as a viable strategy for developing a new class of drugs that would exploit and modulate the target proteins' intrinsic dynamics, and potentially alleviate drug-resistance when used in combination with orthosteric or allosteric drugs.

PMID:39585988 | DOI:10.1073/pnas.2414333121

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2418345121. doi: 10.1073/pnas.2418345121. Epub 2024 Nov 25.

ABSTRACT

Cyanobacteria are highly abundant in the marine photic zone and primary drivers of the conversion of inorganic carbon into biomass. To date, all studied cyanobacterial lineages encode carbon fixation machinery relying upon form I Rubiscos within a CO2-concentrating carboxysome. Here, we report that the uncultivated anoxic marine zone (AMZ) IB lineage of Prochlorococcus from pelagic oxygen-deficient zones (ODZs) harbors both form I and form II Rubiscos, the latter of which are typically noncarboxysomal and possess biochemical properties tuned toward low-oxygen environments. We demonstrate that these cyanobacterial form II enzymes are functional in vitro and were likely acquired from proteobacteria. Metagenomic analysis reveals that AMZ IB are essentially restricted to ODZs in the Eastern Pacific, suggesting that form II acquisition may confer an advantage under low-O2 conditions. AMZ IB populations express both forms of Rubisco in situ, with the highest form II expression at depths where oxygen and light are low, possibly as a mechanism to increase the efficiency of photoautotrophy under energy limitation. Our findings expand the diversity of carbon fixation configurations in the microbial world and may have implications for carbon sequestration in natural and engineered systems.

PMID:39585972 | DOI:10.1073/pnas.2418345121

Am J Physiol Regul Integr Comp Physiol. 2024 Nov 25. doi: 10.1152/ajpregu.00201.2024. Online ahead of print.

ABSTRACT

Hypobaric hypoxia (HH) occurring at high altitude activates the sympathetic nervous system (SNS) and increases circulating erythropoietin (Epo) levels. Epo stimulates red blood cell production (erythropoiesis), enhancing oxygen transport in arterial blood to counteract hypoxemia. Present study tested the hypothesis that SNS contributes to Epo activation by HH through epinephrine (Epi) release from the adrenal medullae. Adult male C57B6 mice were exposed to 18 hours of HH (0.4 atm), and renal Epo mRNA and plasma Epo levels were measured. HH increased Epo mRNA and plasma Epo levels, and SNS activation, as indicated by elevated plasma NE and Epi levels. In adrenalmedullectomized mice, HH-induced Epo response was reduced, correlating with decreased circulating NE and absence of Epi elevation. Epi, but not NE infusion, mimicked the effects of HH in room air breathing mice. Epo responses to HH were reduced with β-adrenergic receptor (AR) blockade using dl-propranolol and in β2 adrenergic receptor knockout mice. Mice with heterozygous Hif-2α deficiency (Hif-2α+/-), but not Hif-1α+/-, showed attenuated the Epo gene activation and elevated plasma Epo levels in response to HH and Epi infusion. These results demonstrate that adrenal Epi facilitates the Epo gene activation by HH through interaction of β2 AR with HIF-2α.

PMID:39585744 | DOI:10.1152/ajpregu.00201.2024

Cell Tissue Res. 2024 Nov 25. doi: 10.1007/s00441-024-03930-6. Online ahead of print.

ABSTRACT

The present study explores the advantages of enriching the freezing medium with membrane lipids and antioxidants in improving the outcome of prepubertal testicular tissue cryopreservation. For the study, testicular tissue from Swiss albino mice of prepubertal age group (2 weeks) was cryopreserved by slow freezing method either in control freezing medium (CFM; containing DMSO and FBS in DMEM/F12) or test freezing medium (TFM; containing soy lecithin, phosphatidylserine, phosphatidylethanolamine, cholesterol, vitamin C, sodium selenite, DMSO and FBS in DMEM/F12 medium) and stored in liquid nitrogen for at least one week. The tissues were thawed and enzymatically digested to assess viability, DNA damage, and oxidative stress in the testicular cells. The results indicate that TFM significantly mitigated freeze-thaw-induced cell death, DNA damage, and lipid peroxidation compared to tissue cryopreserved in CFM. Further, a decrease in Cyt C, Caspase-3, and an increase in Gpx4 mRNA transcripts were observed in tissues frozen with TFM. Spermatogonial germ cells (SGCs) collected from tissues frozen with TFM exhibited higher cell survival and superior DNA integrity compared to those frozen in CFM. Proteomic analysis revealed that SGCs experienced a lower degree of freeze-thaw-induced damage when cryopreserved in TFM, as evident from an increase in the level of proteins involved in mitigating the heat stress response, transcriptional and translational machinery. These results emphasize the beneficial role of membrane lipids and antioxidants in enhancing the cryosurvival of prepubertal testicular tissue offering a significant stride towards improving the clinical outcome of prepubertal testicular tissue cryopreservation.

PMID:39585364 | DOI:10.1007/s00441-024-03930-6

iScience. 2024 Oct 23;27(11):111233. doi: 10.1016/j.isci.2024.111233. eCollection 2024 Nov 15.

ABSTRACT

Natural killer (NK) cells play a pivotal role against cancer, both by direct killing of malignant cells and by promoting adaptive immune response though cytokine and chemokine secretion. In the lung tumor microenvironment (TME), NK cells are scarce and dysfunctional. By conducting single-cell transcriptomic analysis of lung tumors, and exploring pseudotime, we uncovered that the intratumoral maturation trajectory of NK cells is disrupted in a tumor stage-dependent manner, ultimately resulting in the selective exclusion of the cytotoxic subset. Using functional assays, we observed intratumoral NK cell death and a reduction in cytotoxic capacities depending on the tumor stage. Finally, our analyses of human public dataset on lung cancer corroborate these findings, revealing a parallel dysfunctional maturation process of NK cells during tumor progression. These results highlight additional mechanisms by which tumor cells escape from NK cell cytotoxicity, therefore paving the way for tailored therapeutic strategies.

PMID:39583926 | PMC:PMC11585790 | DOI:10.1016/j.isci.2024.111233

Ecol Evol. 2024 Nov 24;14(11):e70614. doi: 10.1002/ece3.70614. eCollection 2024 Nov.

ABSTRACT

Bats exhibit a greater capacity to tolerate diverse viruses than other terrestrial mammals. To address these questions, we utilized evolutionary and bibliometric analyses to explore the immunological characteristics of bats and identify contemporary research hotspots in bat immunity. To investigate the historical interactions between bats and viral infections, we used tBLASTn software to identify the integrated endogenous retroviruses within the genomes of nine bat species and seven other mammals. To elucidate the immune characteristics of bats, we used the OrthoFinder, CAFE, and Gene Ontology analyses to identify the phylogenetic trees and homologous genes, expanded/contracted gene families, and associated signaling pathways of 28 mammalian genomes. We also used a bibliometric analysis of the "immune system of bats" to identify research hotspots and deepen our understanding of the immune mechanisms in bats. Significant integrations of Gammaretroviruses, Spumaretroviruses, and Deltaretroviruses were observed within bat genomes. Notable expansions in gene families included Type III interferon, heat-shock protein 90 (HSP90), and members of the tumor necrosis factor receptor superfamily (TNFRSF). These expanded gene families are involved in signaling pathways related to "transcription and replication of influenza virus RNA," "COVID-19-related pathways," and "positive regulation of protein phosphorylation." Notable contractions were observed in the "type I interferon" and "antibody-related gene families." Bibliometric analysis further underscored the several significance of critical immune genes, such as HSP90, Type I interferon, Type III interferon, and TNF. The exploration of research hotspots revealed two predominant themes: "efficient and varied antiviral responses" and "dampened inflammation to prevent excessive inflammatory reactions," thereby elucidating the mechanisms underlying the immune adaptations of bats. Through the evolutionary and bibliometric analyses, we identified several critical immune genes and signaling pathways related to bat immunity. Currently, research on the immune system of bats primarily focuses on the themes of "efficient antiviral responses" and "inflammation suppression."

PMID:39583041 | PMC:PMC11586106 | DOI:10.1002/ece3.70614

J Allergy Clin Immunol Glob. 2024 Oct 18;4(1):100353. doi: 10.1016/j.jacig.2024.100353. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare inherited disorder that predisposes an individual to develop vasogenic edema. Bradykinin release, which increases vascular permeability, results in angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes involved in bradykinin generation and mutations in genes that encode the C1 inhibitor of complement factor 1, which prevent its synthesis (type I HAE), form a dysfunctional protein (type II HAE), or have normal functioning C1-INH (type III HAE, aka HAE-III).

OBJECTIVES: The goals of this study were to use a systems biology analysis to identify novel biomarkers to aid in the diagnosis of HAE-III and to elucidate its underlying pathogenic mechanisms.

METHODS: Blood samples were obtained from HAE-III subjects and age- and sex-matched healthy controls. DNA, RNA, and protein purified from the samples were subjected to multiomics analysis using a 1-shot liquid chromatography-mass spectrometry-based multiomics platform (Omni-MS, Dalton Bioanalytics) to profile proteins, lipids, electrolytes, and metabolites enabling concurrent analysis of diverse analyte classes.

RESULTS: A total of 1647 novel identifications that included genes, proteins, and metabolites were made when comparing HAE-III samples to control samples. Our identification library included MSFragger for protein identification, LipiDex for lipid identification, and Compound Discoverer for metabolite identification, enabling differential expression analysis. Key findings included a significant increase in the expression levels of galectin-3, lysosomal α-glucosidase, platelet factor 4, and platelet-derived growth factor subunit A in HAE-III subjects compared to controls, all of which generate an immunomodulatory response.

CONCLUSION: Galectin-3 plays a critical role in eosinophil recruitment and airway allergic inflammation. It may contribute to chronic inflammation and fibrosis resulting in leaky vasculature, and it could be a potential therapeutic target in HAE-III.

PMID:39583036 | PMC:PMC11583700 | DOI:10.1016/j.jacig.2024.100353

Comput Struct Biotechnol J. 2024 Nov 4;23:3999-4010. doi: 10.1016/j.csbj.2024.10.045. eCollection 2024 Dec.

ABSTRACT

In systems biology, the study of biological pathways plays a central role in understanding the complexity of biological systems. The massification of pathway data made available by numerous online databases in recent years has given rise to an important need for standardization of this data. The BioPAX format (Biological Pathway Exchange) emerged in 2010 as a solution for standardizing and exchanging pathway data across databases. BioPAX is a Semantic Web format associated to an ontology. It is highly expressive, allowing to finely describe biological pathways at the molecular and cellular levels, but the associated intrinsic complexity may be an obstacle to its widespread adoption. Here, we report on the use of the BioPAX format in 2024. We compare how the different pathway databases use BioPAX to standardize their data and point out possible avenues for improvement to make full use of its potential. We also report on the various tools and software that have been developed to work with BioPAX data. Finally, we present a new concept of abstraction on BioPAX graphs that would allow to specifically target areas in a BioPAX graph needed for a specific analysis, thus differentiating the format suited for representation and the abstraction suited for contextual analysis.

PMID:39582893 | PMC:PMC11585474 | DOI:10.1016/j.csbj.2024.10.045

Comput Struct Biotechnol J. 2024 Oct 24;23:3967-3988. doi: 10.1016/j.csbj.2024.10.028. eCollection 2024 Dec.

ABSTRACT

The recently described canal-1 tomato mutant, which has a variegated leaf phenotype, has been shown to affect canalization of yield. The corresponding protein is orthologous to AtSCO2 -SNOWY COTYLEDON 2, which has suggested roles in thylakoid biogenesis. Here we characterize the canal-1 mutant through a multi-omics approach, by comparing mutant to wild-type tissues. While white canal-1 leaves are devoid of chlorophyll, green leaves of the mutant appear wild-type-like, despite an impaired protein function. Transcriptomic data suggest that green mutant leaves compensate for this impaired protein function by upregulation of transcription of photosystem assembly and photosystem component genes, thereby allowing adequate photosystem establishment, which is reflected in their wild-type-like proteome. White canal-1 leaves, however, likely fail to reach a certain threshold enabling this overcompensation, and plastids get trapped in an undeveloped state, while additionally suffering from high light stress, indicated by the overexpression of ELIP homolog genes. The metabolic profile of white and to a lesser degree also green tissues revealed upregulation of amino acid levels, that was at least partially mediated by transcriptional and proteomic upregulation. These combined changes are indicative of a stress response and suggest that white tissues behave as carbon sinks. In summary, our work demonstrates the relevance of the SCO2 protein in both photosystem assembly and as a consequence in the canalization of yield.

PMID:39582891 | PMC:PMC11584773 | DOI:10.1016/j.csbj.2024.10.028

Front Immunol. 2024 Nov 8;15:1481243. doi: 10.3389/fimmu.2024.1481243. eCollection 2024.

ABSTRACT

The development of T follicular helper (Tfh) cells is an ongoing process resulting in the formation of various Tfh subsets. Despite advancements, the precise impact of T cell receptor (TCR) stimulation on this process remains incompletely understood. This study explores how TCR-CD3 signaling strength influences naive CD4+ T cell differentiation into Tfh-like cells and the concurrent expression of interleukin-21 (IL-21), interleukin-4 (IL-4), and interferon-gamma (IFN-γ). Strong TCR-CD3 stimulation induces proliferation and increased IL-21 expression in Tfh-like cells, which exhibit a characteristic phenotype expressing CXCR5 and PD1. The coexpression of IL-4 and IFN-γ in IL-21-producing Tfh-like cells is controlled by the strength TCR-CD3 stimulation; low stimulation favors IL-4, while strong stimulation enhances IFN-γ secretion. Exogenous addition of the effector cytokines IL-21 and IL-4 further modulate cytokine coexpression. These findings highlight the intricate regulatory mechanisms governing cytokine production and plasticity in Tfh-like cells, providing insights into B cell response modulation. In vivo, antigen availability may regulate Tfh cell plasticity, impacting subsequent B cell differentiation, emphasizing the need for further exploration through animal models or antigen-specific Tfh cell analyses in human lymph node biopsies.

PMID:39582865 | PMC:PMC11581847 | DOI:10.3389/fimmu.2024.1481243

Front Plant Sci. 2024 Nov 8;15:1457587. doi: 10.3389/fpls.2024.1457587. eCollection 2024.

ABSTRACT

INTRODUCTION: Heavy ions of the galactic cosmic radiation dominate the radiation risks and biological effects for plants under spaceflight conditions. However, the biological effects and sensitive genes caused by heavy ions with different linear energy transfer (LET) values have not been thoroughly studied.

METHODS: To comprehensively analyze the biological effects of heavy ions with different LET values on rice under spaceflight conditions, we utilized the Shijian-10 recoverable satellite (SJ-10) to transport the dehydrated rice seeds on a 12.5-day mission in a 252 km low Earth orbit (LEO), and obtained rice plants hit by individual heavy ions with LET values ranging from 18 keV/μm to 213 keV/μm. The transcriptome and methylation sequencing were conducted on above plants, and a bioinformatics pipeline based on single-sample networks (SSNs) and genetic algorithms (GA) was developed to analyze the multi-omics expression profiles in this work. Note that SSNs can depict the gene interaction patterns within a single sample. The LET regression models were constructed from both gene expression and interaction pattern perspectives respectively, and the radiation response genes that played significant roles in the models were identified. We designed a gene selection algorithm based on GA to enhance the performance of LET regression models.

RESULTS: The experimental results demonstrate that all our models exhibit excellent regression performance (R2 values close to 1), which indicates that both gene expressions and interaction patterns can reflect the molecular changes caused by heavy ions with different LET values. LET-related genes (genes exhibiting strong correlation with LET values) and radiation-responsive genes were identified, primarily involved in DNA damage and repair, oxidative stress, photosynthesis, nucleic acid metabolism, energy metabolism, amino acid/protein metabolism, and lipid metabolism, etc. DNA methylation plays a crucial role in responding to heavy ions stressors and regulates the aforementioned processes.

DISCUSSION: To the best of our knowledge, this is the first study to report the multi-omics changes in plants after exposure to heavy ions with different LET values under spaceflight conditions.

PMID:39582626 | PMC:PMC11581881 | DOI:10.3389/fpls.2024.1457587

Biosystems. 2024 Nov 22:105376. doi: 10.1016/j.biosystems.2024.105376. Online ahead of print.

ABSTRACT

Biophysical, developmental and systems-biology considerations enable deeper understanding why cancer is life-threatening despite intensive research. Here we use two metaphors. Both conceive the cell-genome and the encoded molecular system as an interacting gene-regulatory-network(GRN). According to Waddington's epigenetic(quasi-potential)-landscape, an instrumental tool in ontogenetics, individual interaction-patterns(=expression-profiles) within this GRN represent possible cell-states with different stabilities. Network-interactions with low stability are represented on peaks. Unstable interactions strive towards regions with higher stability located at lower altitude in valleys termed attractors that correspond to stable cell phenotypes. Cancer cells are seen as GRNs adopting aberrant semi-stable attractor states(cancer-attractor). In the second metaphor, Wright's phylogenetic fitness(adaptive)-landscape, each genome(=GRN) is assigned a specific position in the landscape according to its structure and reproductive fitness in the specific environment. High elevation signifies high fitness and low altitude low fitness. Selection ensures that mutant GRNs evolve and move from valleys to peaks. The genetic flexibility is highlighted in the fitness-landscape, while non-genetic flexibility is captured in the quasi-potential landscape. These models resolve several inconsistencies that have puzzled cancer researchers, such as the fact that phenotypes generated by non-genetic mechanisms coexist in a single tumor with phenotypes caused by mutations and they mitigate conflicts between cancer theories that claim cancer is caused by mutation(somatic-mutation-theory) or by disruption of tissue architecture(tissue-organization-field-theory). Nevertheless, spontaneous mutations play key-roles in cancer. Remarkable, fundamental natural laws such as the second-law-of-thermodynamics and quantum-mechanics state that mutations are inevitable events. The good side of this is that without mutational variability in DNA, evolutionary development would not have occurred, but its bad side is that the occurrence of cancer is essentially inevitable. In summary, both landscapes together fully describe the behavior of cancer under normal and stressful conditions such as chemotherapy. Thus, the landscapes-attractor-model fully describes cancer cell behavior and offers new perspectives for future treatment.

PMID:39581534 | DOI:10.1016/j.biosystems.2024.105376

Clin Exp Allergy. 2024 Nov 24. doi: 10.1111/cea.14602. Online ahead of print.

NO ABSTRACT

PMID:39581189 | DOI:10.1111/cea.14602

Breast. 2024 Nov 22;79:103851. doi: 10.1016/j.breast.2024.103851. Online ahead of print.

ABSTRACT

This study evaluates the global inequalities of breast cancer incidence and mortality from 2022 to 2050 with the latest GLOBOCAN estimates. It focuses on disparities across continents, age groups and Human Development Index (HDI) levels. In 2022, Africa shows the highest positive slope values of age-standardized rates (world) of mortality vs. incidence, both for those under 40 (0.346) and those 40 and older (0.335). These values contrast with those for Asia (0.085, 0.208), Europe (0.002, -0.014), Latin America and the Caribbean (0.17, 0.303), Northern America (-0.078, -0.188), and Oceania (0.166, -0.001). In both age groups, lower HDI levels are correlated with higher slope values and vice versa. Projections to 2050 indicate significant increases in the burden of breast cancer, with persistent yet varied disparities and differences. This highlights the need for differentiated strategies in breast cancer prevention, early-stage diagnosis, and treatment.

PMID:39580931 | DOI:10.1016/j.breast.2024.103851

Bioorg Med Chem. 2024 Nov 20;117:118016. doi: 10.1016/j.bmc.2024.118016. Online ahead of print.

ABSTRACT

The 2-((2-chloroethyl)amino)ethane-1-thiol (CAET)-based chemical trapping strategy is a practical tool for mechanistic studies of E3-catalysed ubiquitination. However, the construction of ubiquitination intermediate mimics (E2-Ub-substrate conjugates) via CAET has been limited to peptides, while its application to folded protein substrates remains unexplored. Here, we report that disulfide bond formation between E2-Ub (RAD6A-Ub) and the folded protein substrate PCNA (proliferating cell nuclear antigen) occurs upon the addition of the PCNA-associated E3 ligase RAD18. Leveraging this finding, we employed intein splicing technology to generate a stable, covalently linked RAD18-RAD6A-Ub-PCNA complex, enabling chemical crosslinking mass spectrometry (CX-MS) analysis to study the structure of this complex. This work showcases use of a substrate-associated E3 ligase to promote disulfide bond formation between an E2-Ub conjugate and a folded substrate for CAET-based trapping, thereby expanding the scope of this technique.

PMID:39580855 | DOI:10.1016/j.bmc.2024.118016

Proteomics. 2024 Nov 24:e202400207. doi: 10.1002/pmic.202400207. Online ahead of print.

ABSTRACT

Blacks are more prone to salt-sensitive hypertension than Whites. This cross-sectional analysis of a multi-ethnic cohort aimed to search for proteins potentially involved in the susceptibility to salt sensitivity, hypertension, and hypertension-related complications. The study included individuals enrolled in African Prospective Study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), Flemish Study of the Environment, Genes and Health Outcomes (FLEMENGHO), Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID)-Austria, and Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform Trial (UPRIGHT-HTM). Sequenced urinary peptides detectable in 70% of participants allowed the identification of parental proteins and were compared between Blacks and Whites. Of 513 urinary peptides, 300 had significantly different levels among healthy Black (n = 476) and White (n = 483) South Africans sharing the same environment. Analyses contrasting 582 Blacks versus 1731 Whites, and Sub-Saharan Blacks versus European Whites replicated the findings. COL4A1, COL4A2, FGA, PROC, MGP, MYOCD, FYXD2, and UMOD were identified as the most likely candidates underlying the racially different susceptibility to salt sensitivity, hypertension, and related complications. Enriched pathways included hemostasis, platelet activity, collagens, biology of the extracellular matrix, and protein digestion and absorption. Our study suggests that MGP and MYOCD being involved in cardiovascular function, FGA and PROC in coagulation, FYXD2 and UMOD in salt homeostasis, and COL4A1 and COL4A2 as major components of the glomerular basement membrane are among the many proteins potentially incriminated in the higher susceptibility of Blacks compared to Whites to salt sensitivity, hypertension, and its complication. Nevertheless, these eight proteins and their associated pathways deserve further exploration in molecular and human studies as potential targets for intervention to reduce the excess risk of hypertension and cardiovascular complications in Blacks versus Whites.

PMID:39580674 | DOI:10.1002/pmic.202400207

Commun Biol. 2024 Nov 24;7(1):1562. doi: 10.1038/s42003-024-07287-y.

ABSTRACT

Many prokaryotes form Bacterial Microcompartments (BMCs) that encapsulate segments of specialized metabolic pathways to enhance catalysis. The various functions of metabolosomes, catabolic BMCs, are dictated by the signature enzyme that processes initial substrates of the confined pathway. The components and native functions of several metabolosomes have been experimentally characterized; however one of the most prevalent across all bacteria has yet to be studied. Sugar Phosphate Utilizing (SPU) BMC loci encode enzymes predicted to be involved in sugar phosphate metabolism. The SPU genetic loci are found in organisms occupying habitats ranging from soils to hot springs, highlighting the ubiquity of the SPU BMC. We bioinformatically characterized seven SPU subtypes, all which contain an enzyme unique to SPU BMCs, a deoxyribose 5-phosphate aldolase (DERA). Here, we define the fundamental characteristics of SPU BMCs and have expressed, purified, and characterized a set of SPU core enzymes. These include a protein-protein complex formed between a SPU BMC DERA and a predicted ribose 5-phosphate isomerase. Further, we show that the SPU BMC DERA is catalytically active and propose that it acts as the universal signature enzyme for the SPU BMC, with implications for fundamental understanding and biotechnological applications of SPU BMCs.

PMID:39580597 | DOI:10.1038/s42003-024-07287-y

Nat Commun. 2024 Nov 23;15(1):10183. doi: 10.1038/s41467-024-54547-w.

ABSTRACT

Chromothripsis is a frequent form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or multiple chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumour, as well as changes in response to treatment. Here we analyse single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma and neural stem cells (n = 9). We reconstruct the order of somatic events, identify early alterations likely linked to chromothripsis and depict the contribution of chromothripsis to malignancy. We characterise subclonal variation of chromothripsis and its effects on extrachromosomal circular DNA, cancer drivers and putatively druggable targets. Furthermore, we highlight the causative role and the fitness consequences of specific rearrangements in neural progenitors.

PMID:39580568 | DOI:10.1038/s41467-024-54547-w

NPJ Syst Biol Appl. 2024 Nov 23;10(1):137. doi: 10.1038/s41540-024-00457-y.

ABSTRACT

Based on high-throughput metabolomics data, the recently introduced inverse differential Jacobian algorithm can infer regulatory factors and molecular causality within metabolic networks close to steady-state. However, these studies assumed perturbations acting independently on each metabolite, corresponding to metabolic system fluctuations. In contrast, emerging evidence puts forward internal network fluctuations, particularly from gene expression fluctuations, leading to correlated perturbations on metabolites. Here, we propose a novel approach that exploits these correlations to quantify relevant metabolic interactions. By integrating enzyme-related fluctuations in the construction of an appropriate fluctuation matrix, we are able to exploit the underlying reaction network structure for the inverse Jacobian algorithm. We applied this approach to a model-based artificial dataset for validation, and to an experimental breast cancer dataset with two different cell lines. By highlighting metabolic interactions with significantly changed interaction strengths, the inverse Jacobian approach identified critical dynamic regulation points which are confirming previous breast cancer studies.

PMID:39580513 | DOI:10.1038/s41540-024-00457-y

Anal Chim Acta. 2024 Dec 15;1332:343363. doi: 10.1016/j.aca.2024.343363. Epub 2024 Oct 25.

ABSTRACT

BACKGROUND: Simple, fast and low-cost paper-based analytical devices (PADs) have a good application prospect for point-of-care detection of GSH. However, effective immobilization of functional nanomaterials onto cellulose, as a critical factor in the construction of PADs, presents numerous difficulties and challenges.

RESULTS: In this study, we have developed an exceptionally straightforward and environmentally friendly synthetic approach by using ovalbumin (OVA) as a bio-mineralization template for the preparation of MnO2 nanosheets. The MnO2 nanosheets produced in the solution phase exhibited excellent intrinsic nano-enzyme activity and biodegradability. The OVA-MnO2 nanosheets can effectively oxidize Amplex red in the absence of H2O2, enabling sensitive detection of GSH with a linear range of 5 nM-10 μM and a detection limit as low as 2.8 nM. Furthermore, we utilized this method to facilitate in situ synthesis of OVA-MnO2 nanosheets directly on paper substrates. This approach eliminates the need for conventional stirring and centrifugation steps, greatly simplifying the fabrication process while reducing material usage and time expenditure. Characterization of the chemical composition and morphology confirmed the intimate growth of the 2D nano-enzymes on the cellulose fibers. Utilizing smartphone capabilities, the OVA-MnO2 nanosheet-modified PAD enabled instrument-free detection of GSH, demonstrating high sensitivity (0.74 μM) and a wide linear response range (1-1000 μM).

SIGNIFICANCE: The synthesis of MnO2 nanosheets directly on cellulose substrates substantially streamlines the modification workflow of PADs and reduces detection costs, offering new avenues for clinical diagnostics of relevant diseases.

PMID:39580175 | DOI:10.1016/j.aca.2024.343363