Cardiovasc Diabetol. 2024 Jul 16;23(1):254. doi: 10.1186/s12933-024-02315-x.

ABSTRACT

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms. A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS. We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes - thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S - were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant. The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus.

PMID:39014464 | DOI:10.1186/s12933-024-02315-x

Nat Rev Microbiol. 2024 Jul 16. doi: 10.1038/s41579-024-01073-7. Online ahead of print.

ABSTRACT

The association between plants and arbuscular mycorrhizal fungi (AMF) affects plant performance and ecosystem functioning. Recent studies have identified AMF-associated bacteria as cooperative partners that participate in AMF-plant symbiosis: specific endobacteria live inside AMF, and hyphospheric bacteria colonize the soil that surrounds the extraradical hyphae. In this Review, we describe the concept of a plant-AMF-bacterium continuum, summarize current advances and provide perspectives on soil microbiology. First, we review the top-down carbon flow and the bottom-up mineral flow (especially phosphorus and nitrogen) in this continuum, as well as how AMF-bacteria interactions influence the biogeochemical cycling of nutrients (for example, carbon, phosphorus and nitrogen). Second, we discuss how AMF interact with hyphospheric bacteria or endobacteria to regulate nutrient exchange between plants and AMF, and the possible molecular mechanisms that underpin this continuum. Finally, we explore future prospects for studies on the hyphosphere to facilitate the utilization of AMF and hyphospheric bacteria in sustainable agriculture.

PMID:39014094 | DOI:10.1038/s41579-024-01073-7

Sci Rep. 2024 Jul 16;14(1):16446. doi: 10.1038/s41598-024-65936-y.

ABSTRACT

Selective drugs with a relatively narrow spectrum can reduce the side effects of treatments compared to broad-spectrum antibiotics by specifically targeting the pathogens responsible for infection. Furthermore, combating an infectious pathogen, especially a drug-resistant microorganism, is more efficient by attacking multiple targets. Here, we combined synthetic lethality with selective drug targeting to identify multi-target and organism-specific potential drug candidates by systematically analyzing the genome-scale metabolic models of six different microorganisms. By considering microorganisms as targeted or conserved in groups ranging from one to six members, we designed 665 individual case studies. For each case, we identified single essential reactions as well as double, triple, and quadruple synthetic lethal reaction sets that are lethal for targeted microorganisms and neutral for conserved ones. As expected, the number of obtained solutions for each case depends on the genomic similarity between the studied microorganisms. Mapping the identified potential drug targets to their corresponding pathways highlighted the importance of key subsystems such as cell envelope biosynthesis, glycerophospholipid metabolism, membrane lipid metabolism, and the nucleotide salvage pathway. To assist in the validation and further investigation of our proposed potential drug targets, we introduced two sets of targets that can theoretically address a substantial portion of the 665 cases. We expect that the obtained solutions provide valuable insights into designing narrow-spectrum drugs that selectively cause system-wide damage only to the target microorganisms.

PMID:39014020 | DOI:10.1038/s41598-024-65936-y

Nat Commun. 2024 Jul 16;15(1):5969. doi: 10.1038/s41467-024-50342-9.

ABSTRACT

The proficiency of phyllosphere microbiomes in efficiently utilizing plant-provided nutrients is pivotal for their successful colonization of plants. The methylotrophic capabilities of Methylobacterium/Methylorubrum play a crucial role in this process. However, the precise mechanisms facilitating efficient colonization remain elusive. In the present study, we investigate the significance of methanol assimilation in shaping the success of mutualistic relationships between methylotrophs and plants. A set of strains originating from Methylorubrum extorquens AM1 are subjected to evolutionary pressures to thrive under low methanol conditions. A mutation in the phosphoribosylpyrophosphate synthetase gene is identified, which converts it into a metabolic valve. This valve redirects limited C1-carbon resources towards the synthesis of biomass by up-regulating a non-essential phosphoketolase pathway. These newly acquired bacterial traits demonstrate superior colonization capabilities, even at low abundance, leading to increased growth of inoculated plants. This function is prevalent in Methylobacterium/Methylorubrum strains. In summary, our findings offer insights that could guide the selection of Methylobacterium/Methylorubrum strains for advantageous agricultural applications.

PMID:39013920 | DOI:10.1038/s41467-024-50342-9

Sci Rep. 2024 Jul 16;14(1):16385. doi: 10.1038/s41598-024-65572-6.

ABSTRACT

Previous fMRI research found increased brain responses in men with pedophilic interest to non-sexual pictures of child and animal faces. This raised the question of whether an aberrant nurturing system could be linked to pedophilia. To further explore this hypothesis, 20 pedohebephilic and 23 teleiophilic men performed a target detection task with adult versus infant human and animal faces, which measured selective attention towards the baby schema by comparing reaction times to infant versus adult targets that were presented amongst distractors of the other category. Since the response to baby schema can be influenced by steroid hormones, saliva samples were additionally collected to determine endogenous testosterone, progesterone, estradiol and cortisol. Contrary to expectations, all men did not react faster to infant than adult faces. Yet, pedohebephilic men were more distracted by infant's faces than teleiophilic men. Pedohebephilic men with higher testosterone were faster in orienting attention to infant targets in the context of adult distractors. This association was not observed in teleiophilic men. Our results support the idea of an overactive nurturing system in pedophilia, which may be influenced by the endogenous testosterone level.

PMID:39013917 | DOI:10.1038/s41598-024-65572-6

NPJ Syst Biol Appl. 2024 Jul 16;10(1):75. doi: 10.1038/s41540-024-00400-1.

ABSTRACT

Mathematical models of biochemical reaction networks are an important and emerging tool for the study of cell signaling networks involved in disease processes. One promising potential application of such mathematical models is the study of how disease-causing mutations promote the signaling phenotype that contributes to the disease. It is commonly assumed that one must have a thorough characterization of the network readily available for mathematical modeling to be useful, but we hypothesized that mathematical modeling could be useful when there is incomplete knowledge and that it could be a tool for discovery that opens new areas for further exploration. In the present study, we first develop a mechanistic mathematical model of a G-protein coupled receptor signaling network that is mutated in almost all cases of uveal melanoma and use model-driven explorations to uncover and explore multiple new areas for investigating this disease. Modeling the two major, mutually-exclusive, oncogenic mutations (Gαq/11 and CysLT2R) revealed the potential for previously unknown qualitative differences between seemingly interchangeable disease-promoting mutations, and our experiments confirmed oncogenic CysLT2R was impaired at activating the FAK/YAP/TAZ pathway relative to Gαq/11. This led us to hypothesize that CYSLTR2 mutations in UM must co-occur with other mutations to activate FAK/YAP/TAZ signaling, and our bioinformatic analysis uncovers a role for co-occurring mutations involving the plexin/semaphorin pathway, which has been shown capable of activating this pathway. Overall, this work highlights the power of mechanism-based computational systems biology as a discovery tool that can leverage available information to open new research areas.

PMID:39013872 | DOI:10.1038/s41540-024-00400-1

Sci Signal. 2024 Jul 16;17(845):eadd8913. doi: 10.1126/scisignal.add8913. Epub 2024 Jul 16.

ABSTRACT

Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions.

PMID:39012939 | DOI:10.1126/scisignal.add8913

PLoS Biol. 2024 Jul 16;22(7):e3002709. doi: 10.1371/journal.pbio.3002709. eCollection 2024 Jul.

ABSTRACT

RNA viruses have notoriously high mutation rates due to error-prone replication by their RNA polymerase. However, natural selection concentrates variability in a few key viral proteins. To test whether this stems from different mutation tolerance profiles among viral proteins, we measured the effect of >40,000 non-synonymous mutations across the full proteome of coxsackievirus B3 as well as >97% of all possible codon deletions in the nonstructural proteins. We find significant variation in mutational tolerance within and between individual viral proteins, which correlated with both general and protein-specific structural and functional attributes. Furthermore, mutational fitness effects remained stable across cell lines, suggesting selection pressures are mostly conserved across environments. In addition to providing a rich dataset for understanding virus biology and evolution, our results illustrate that incorporation of mutational tolerance data into druggable pocket discovery can aid in selecting targets with high barriers to drug resistance.

PMID:39012844 | DOI:10.1371/journal.pbio.3002709

Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2403739121. doi: 10.1073/pnas.2403739121. Epub 2024 Jul 16.

ABSTRACT

Natural kinesin motors are tethered to their cargoes via short C-terminal or N-terminal linkers, whose docking against the core motor domain generates directional force. It remains unclear whether linker docking is the only process contributing directional force or whether linker docking is coupled to and amplifies an underlying, more fundamental force-generating mechanical cycle of the kinesin motor domain. Here, we show that kinesin motor domains tethered via double-stranded DNAs (dsDNAs) attached to surface loops drive robust microtubule (MT) gliding. Tethering using dsDNA attached to surface loops disconnects the C-terminal neck-linker and the N-terminal cover strand so that their dock-undock cycle cannot exert force. The most effective attachment positions for the dsDNA tether are loop 2 or loop 10, which lie closest to the MT plus and minus ends, respectively. In three cases, we observed minus-end-directed motility. Our findings demonstrate an underlying, potentially ancient, force-generating core mechanical action of the kinesin motor domain, which drives, and is amplified by, linker docking.

PMID:39012822 | DOI:10.1073/pnas.2403739121

mSystems. 2024 Jul 16:e0062724. doi: 10.1128/msystems.00627-24. Online ahead of print.

ABSTRACT

Clostridia are abundant in the human gut and comprise families associated with host health such as Oscillospiraceae, which has been correlated with leanness. However, culturing bacteria within this family is challenging, leading to their detection primarily through 16S rRNA amplicon sequencing, which has a limited ability to unravel diversity at low taxonomic levels, or by shotgun metagenomics, which is hindered by its high costs and complexity. In this cross-sectional study involving 114 Colombian adults, we used an amplicon-based sequencing strategy with alternative markers-gyrase subunit B (gyrB) and DNA K chaperone heat protein 70 (dnaK)-that evolve faster than the 16S rRNA gene. Comparing the diversity and abundance observed with the three markers in our cohort, we found a reduction in the diversity of Clostridia, particularly within Lachnospiraceae and Oscillospiraceae among obese individuals [as measured by the body mass index (BMI)]. Within Lachnospiraceae, the diversity of Ruminococcus_A negatively correlated with BMI. Within Oscillospiraceae, the genera CAG-170 and Vescimonas also exhibited this negative correlation. In addition, the abundance of Vescimonas was negatively correlated with BMI. Leveraging shotgun metagenomic data, we conducted a phylogenetic and genomic characterization of 120 metagenome-assembled genomes from Vescimonas obtained from a larger sample of the same cohort. We identified 17 of the 72 reported species. The functional annotation of these genomes showed the presence of multiple carbohydrate-active enzymes, particularly glycosyl transferases and glycoside hydrolases, suggesting potential beneficial roles in fiber degradation, carbohydrate metabolism, and butyrate production.

IMPORTANCE: The gut microbiota is diverse across various taxonomic levels. At the intra-species level, it comprises multiple strains, some of which may be host-specific. However, our understanding of fine-grained diversity has been hindered by the use of the conserved 16S rRNA gene. While shotgun metagenomics offers higher resolution, it remains costly, may fail to identify specific microbes in complex samples, and requires extensive computational resources and expertise. To address this, we employed a simple and cost-effective analysis of alternative genetic markers to explore diversity within Clostridia, a crucial group within the human gut microbiota whose diversity may be underestimated. We found high intra-species diversity for certain groups and associations with obesity. Notably, we identified Vescimonas, an understudied group. Making use of metagenomic data, we inferred functionality, uncovering potential beneficial roles in dietary fiber and carbohydrate degradation, as well as in short-chain fatty acid production.

PMID:39012154 | DOI:10.1128/msystems.00627-24

Biol Methods Protoc. 2024 Jul 2;9(1):bpae048. doi: 10.1093/biomethods/bpae048. eCollection 2024.

ABSTRACT

Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here, we introduce MetaboLiteLearner, a lightweight machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry to predict changes in the metabolite composition of metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Despite its simplicity, the model learned captured shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting cellular adaptations associated with metastasis to specific organs. Integrating machine learning and metabolomics paves the way for new insights into complex cellular adaptations.

PMID:39011352 | PMC:PMC11249387 | DOI:10.1093/biomethods/bpae048

J Agric Food Chem. 2024 Jul 15. doi: 10.1021/acs.jafc.4c01000. Online ahead of print.

ABSTRACT

A sensitive high-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS/MSMRM) method, leveraging both technique and internal calibration, was developed for the simultaneous and comprehensive quantitative analysis of 46 antioxidants and antioxidant precursors in different beer types without any cleanup procedure. Combined with their in vitro antioxidant activity, a dose-activity estimation exposed a group of 10 key antioxidants, namely, tryptophan, tyrosine, hordatine A, hordatine B, procyanidin B3, prodelphinidin B3, tachioside (3-methoxy-4-hydroxyphenyl-β-d-glucopyranoside), (+)-catechin, tyrosol, and ferulic acid. To study the effect of antioxidants in spiking and aging studies, another liquid chromatography-MS (LC-MS)-based method was developed, monitoring markers for oxidation in beer. A positive effect of the antioxidants on the flavor stability at naturally relevant concentrations was shown by a slowing of oxygen-dependent aging reactions highlighted in beer storage trials under oxygen atmosphere. Thereby, a doubling of the natural concentration of all investigated antioxidants in beer revealed a limit inhibition of 67% on the degradation of cis-isocohumulone to hydroxy-cis-alloisocohumulone.

PMID:39010731 | DOI:10.1021/acs.jafc.4c01000

BMC Musculoskelet Disord. 2024 Jul 16;25(1):547. doi: 10.1186/s12891-024-07669-7.

ABSTRACT

OBJECTIVE: This study aimed to evaluate a new deep-learning model for diagnosing avascular necrosis of the femoral head (AVNFH) by analyzing pelvic anteroposterior digital radiography.

METHODS: The study sample included 1167 hips. The radiographs were independently classified into 6 stages by a radiologist using their simultaneous MRIs. After that, the radiographs were given to train and test the deep learning models of the project including SVM and ANFIS layer using the Python programming language and TensorFlow library. In the last step, the test set of hip radiographs was provided to two independent radiologists with different work experiences to compare their diagnosis performance to the deep learning models' performance using the F1 score and Mcnemar test analysis.

RESULTS: The performance of SVM for AVNFH detection (AUC = 82.88%) was slightly higher than less experienced radiologists (79.68%) and slightly lower than experienced radiologists (88.4%) without reaching significance (p-value > 0.05). Evaluation of the performance of SVM for pre-collapse AVNFH detection with an AUC of 73.58% showed significantly higher performance than less experienced radiologists (AUC = 60.70%, p-value < 0.001). On the other hand, no significant difference is noted between experienced radiologists and SVM for pre-collapse detection. ANFIS algorithm for AVNFH detection with an AUC of 86.60% showed significantly higher performance than less experienced radiologists (AUC = 79.68%, p-value = 0.04). Although reaching less performance compared to experienced radiologists statistically not significant (AUC = 88.40%, p-value = 0.20).

CONCLUSIONS: Our study has shed light on the remarkable capabilities of SVM and ANFIS as diagnostic tools for AVNFH detection in radiography. Their ability to achieve high accuracy with remarkable efficiency makes them promising candidates for early detection and intervention, ultimately contributing to improved patient outcomes.

PMID:39010001 | DOI:10.1186/s12891-024-07669-7

Genet Sel Evol. 2024 Jul 15;56(1):54. doi: 10.1186/s12711-024-00920-8.

ABSTRACT

BACKGROUND: Mastitis is a disease that incurs significant costs in the dairy industry. A promising approach to mitigate its negative effects is to genetically improve the resistance of dairy cattle to mastitis. A meta-analysis of genome-wide association studies (GWAS) across multiple breeds for clinical mastitis (CM) and its indicator trait, somatic cell score (SCS), is a powerful method to identify functional genetic variants that impact mastitis resistance.

RESULTS: We conducted meta-analyses of eight and fourteen GWAS on CM and SCS, respectively, using 30,689 and 119,438 animals from six dairy cattle breeds. Methods for the meta-analyses were selected to properly account for the multi-breed structure of the GWAS data. Our study revealed 58 lead markers that were associated with mastitis incidence, including 16 loci that did not overlap with previously identified quantitative trait loci (QTL), as curated at the Animal QTLdb. Post-GWAS analysis techniques such as gene-based analysis and genomic feature enrichment analysis enabled prioritization of 31 candidate genes and 14 credible candidate causal variants that affect mastitis.

CONCLUSIONS: Our list of candidate genes can help to elucidate the genetic architecture underlying mastitis resistance and provide better tools for the prevention or treatment of mastitis, ultimately contributing to more sustainable animal production.

PMID:39009986 | DOI:10.1186/s12711-024-00920-8

Nat Struct Mol Biol. 2024 Jul 15. doi: 10.1038/s41594-024-01358-8. Online ahead of print.

NO ABSTRACT

PMID:39009854 | DOI:10.1038/s41594-024-01358-8

Nat Immunol. 2024 Jul 15. doi: 10.1038/s41590-024-01901-1. Online ahead of print.

ABSTRACT

Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.

PMID:39009838 | DOI:10.1038/s41590-024-01901-1

Nat Commun. 2024 Jul 15;15(1):5935. doi: 10.1038/s41467-024-49692-1.

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

PMID:39009593 | DOI:10.1038/s41467-024-49692-1

Life Sci Alliance. 2024 Jul 15;7(10):e202402924. doi: 10.26508/lsa.202402924. Print 2024 Oct.

ABSTRACT

In humans, a neomorphic isocitrate dehydrogenase mutation (idh-1neo) causes increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of an idh-1neo mutation are not well understood. We created a Caenorhabditis elegans model to study the effects of the idh-1neo mutation in a whole animal. Comparing the phenotypes exhibited by the idh-1neo to ∆dhgd-1 (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in idh-1neo mutant animals that leads to increased embryonic lethality. Through a genetic screen, we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. In addition, supplementation with alternate sources of one-carbon donors suppresses the lethal phenotype. Our results indicate that the idh-1neo mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding of how this oncogenic mutation rewires cellular metabolism.

PMID:39009411 | DOI:10.26508/lsa.202402924

Elife. 2024 Jul 15;12:RP89656. doi: 10.7554/eLife.89656.

ABSTRACT

Previously, Tuller et al. found that the first 30-50 codons of the genes of yeast and other eukaryotes are slightly enriched for rare codons. They argued that this slowed translation, and was adaptive because it queued ribosomes to prevent collisions. Today, the translational speeds of different codons are known, and indeed rare codons are translated slowly. We re-examined this 5' slow translation 'ramp.' We confirm that 5' regions are slightly enriched for rare codons; in addition, they are depleted for downstream Start codons (which are fast), with both effects contributing to slow 5' translation. However, we also find that the 5' (and 3') ends of yeast genes are poorly conserved in evolution, suggesting that they are unstable and turnover relatively rapidly. When a new 5' end forms de novo, it is likely to include codons that would otherwise be rare. Because evolution has had a relatively short time to select against these codons, 5' ends are typically slightly enriched for rare, slow codons. Opposite to the expectation of Tuller et al., we show by direct experiment that genes with slowly translated codons at the 5' end are expressed relatively poorly, and that substituting faster synonymous codons improves expression. Direct experiment shows that slow codons do not prevent downstream ribosome collisions. Further informatic studies suggest that for natural genes, slow 5' ends are correlated with poor gene expression, opposite to the expectation of Tuller et al. Thus, we conclude that slow 5' translation is a 'spandrel'--a non-adaptive consequence of something else, in this case, the turnover of 5' ends in evolution, and it does not improve translation.

PMID:39008347 | DOI:10.7554/eLife.89656

Plant Cell Environ. 2024 Jul 15. doi: 10.1111/pce.15032. Online ahead of print.

ABSTRACT

Aluminum-dependent stoppage of root growth requires the DNA damage response (DDR) pathway including the p53-like transcription factor SUPPRESSOR OF GAMMA RADIATION 1 (SOG1), which promotes terminal differentiation of the root tip in response to Al dependent cell death. Transcriptomic analyses identified Al-induced SOG1-regulated targets as candidate mediators of this growth arrest. Analysis of these factors either as loss-of-function mutants or by overexpression in the als3-1 background shows ERF115, which is a key transcription factor that in other scenarios is rate-limiting for damaged stem cell replenishment, instead participates in transition from an actively growing root to one that has terminally differentiated in response to Al toxicity. This is supported by a loss-of-function erf115 mutant raising the threshold of Al required to promote terminal differentiation of Al hypersensitive als3-1. Consistent with its key role in stoppage of root growth, a putative ERF115 barley ortholog is also upregulated following Al exposure, suggesting a conserved role for this ATR-dependent pathway in Al response. In contrast to other DNA damage agents, these results show that ERF115 and likely related family members are important determinants of terminal differentiation of the root tip following Al exposure and central outputs of the SOG1-mediated pathway in Al response.

PMID:39007549 | DOI:10.1111/pce.15032