Diabetol Metab Syndr. 2025 Feb 19;17(1):63. doi: 10.1186/s13098-025-01630-x.

ABSTRACT

Posttraumatic stress disorder (PTSD) patients have a high comorbidity with type 2 diabetes (T2D). Whether PTSD influences the risk of diabetes is still not known. We used GWAS data from European ancestry of PTSD (23,121 cases and 151,447 controls) and T2D (80,154 cases and 853,816 controls) to investigate the bidirectional associations between PTSD and T2D by the Mendelian randomization (MR) analysis. We showed that PTSD was causally associated with higher odds of T2D (OR = 1.04, 95% CI: 1.01-1.06, P = 0.0086), but not vice versa. Our study suggests that PTSD may increase the risk of T2D. PTSD sufferers should be screened for T2D and its precursor known as metabolic syndrome.

PMID:39972391 | DOI:10.1186/s13098-025-01630-x

Nature. 2025 Feb;638(8051):E23-E29. doi: 10.1038/s41586-024-08497-4.

NO ABSTRACT

PMID:39972229 | DOI:10.1038/s41586-024-08497-4

Nature. 2025 Feb 19. doi: 10.1038/s41586-025-08586-y. Online ahead of print.

ABSTRACT

Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.

PMID:39972134 | DOI:10.1038/s41586-025-08586-y

Nature. 2025 Feb 19. doi: 10.1038/s41586-025-08588-w. Online ahead of print.

ABSTRACT

The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.

PMID:39972131 | DOI:10.1038/s41586-025-08588-w

Nature. 2025 Feb 19. doi: 10.1038/s41586-024-08508-4. Online ahead of print.

ABSTRACT

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P = 0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.

PMID:39972124 | DOI:10.1038/s41586-024-08508-4

Nat Commun. 2025 Feb 19;16(1):1763. doi: 10.1038/s41467-025-57031-1.

ABSTRACT

Regulatory sequences encode crucial gene expression signals, yet the sequence characteristics that determine their functionality across species remain obscure. Deep generative models have demonstrated considerable potential in various inverse design applications, especially in engineering genetic elements. Here, we introduce DeepCROSS, a generative artificial intelligence framework for the inverse design of cross-species and species-preferred 5' regulatory sequences in bacteria. DeepCROSS constructs a meta-representation using 1.8 million regulatory sequences from thousands of bacterial genomes to depict the general constraints of regulatory sequences, employs artificial intelligence-guided massively parallel reporter assay experiments in E. coli and P. aeruginosa to explore the potential sequence space, and performs multi-task optimization to obtain de novo regulatory sequences. The optimized regulatory sequences achieve similar or better performance to functional natural regulatory sequences, with high success rates and low sequence similarities with the natural genome. Collectively, DeepCROSS efficiently navigates the sequence-function landscape and enables the inverse design of cross-species and species-preferred 5' regulatory sequences.

PMID:39971994 | DOI:10.1038/s41467-025-57031-1

Cell Death Dis. 2025 Feb 19;16(1):111. doi: 10.1038/s41419-025-07389-3.

ABSTRACT

Cardiac hypertrophy is a cellular process characterized by the increased size of cardiomyocytes in response to a high workload or stress. 17-beta estradiol (E2) has cardioprotective and anti-hypertrophic effects by maintaining mitochondrial network and function. MUL1 is a mitochondrial ubiquitin ligase directly involved in the control of mitochondrial fission and mitophagy. Studies from our group and others have previously shown that cardiomyocyte hypertrophy is associated with mitochondrial fission and dysfunction. These findings led us to study in vitro whether E2 regulates MUL1 to prevent cardiac hypertrophy, mitochondrial fission, and dysfunction induced by the catecholamine norepinephrine (NE). Our results showed that NE induces hypertrophy in cultured rat cardiomyocytes. Pre-treatment with E2 (10-100 nM) prevented the NE-dependent increases in cell perimeter and the hypertrophic stress markers ANP and BNP at both the protein and mRNA levels. NE induced the fragmentation of the mitochondrial network and reduced ATP levels, effects that were both prevented by E2. In silico analysis suggested a putative binding site for estrogen receptors on the MUL1 gene promoter. In accordance with this finding, E2 prevented increases in MUL1 mRNA and protein levels induced by NE. Our data also showed that a siRNA MUL1 knockdown counteracted NE-induced cardiomyocyte hypertrophy and mitochondrial dysfunction, mirroring the protective effect triggered by E2. In contrast, a MUL1 adenovirus did not prevent the E2 protection from cardiomyocyte hypertrophy. Further, in vivo analysis in a transgenic mouse model overexpressing MUL1 revealed that only young male mice overexpressed the protein. Consequently, they exhibited increased levels of the hypertrophic marker ANP, an elevated heart weight, and larger cardiomyocyte size. Therefore, our data demonstrate that 17-beta estradiol prevents cardiac myocyte hypertrophy by regulating MUL1.

PMID:39971924 | DOI:10.1038/s41419-025-07389-3

Cell Death Dis. 2025 Feb 19;16(1):108. doi: 10.1038/s41419-025-07420-7.

ABSTRACT

Stargardt disease is an inherited retinopathy affecting approximately 1:8000 individuals. It is characterised by biallelic variants in ABCA4 which encodes a vital protein for the recycling of retinaldehydes in the retina. Despite its prevalence and impact, there are currently no treatments available for this condition. Furthermore, 35% of STGD1 cases remain genetically unsolved. To investigate the cellular and molecular characteristics associated with STGD1, we generated iPSCs from two monoallelic unresolved (PT1 & PT2), late-onset STGD1 cases with the heterozygous complex allele - c.[5461-10 T > C;5603 A > T]. Both patient iPSCs and those from a biallelic affected control (AC) carrying -c.4892 T > C and c.4539+2001G > A, were differentiated to retinal organoids, which developed all key retinal neurons and photoreceptors with outer segments positive for ABCA4 expression. We observed patient-specific disruption to lamination with OPN1MW/LW+ cone photoreceptor retention in the retinal organoid centre during differentiation. Photoreceptor retention was more severe in the AC case affecting both cones and rods, suggesting a genotype/phenotype correlation. scRNA-Seq suggests retention may be due to the induction of stress-related pathways in photoreceptors. Whole genome sequencing successfully identified the missing alleles in both cases; PT1 reported c.-5603A > T in homozygous state and PT2 uncovered a rare hypomorph - c.-4685T > C. Furthermore, retinal organoids were able to recapitulate the retina-specific splicing defect in PT1 as shown by long-read RNA-seq data. Collectively, these results highlight the suitability of retinal organoids in STGD1 modelling. Their ability to display genotype-phenotype correlations enhances their utility as a platform for therapeutic development.

PMID:39971915 | DOI:10.1038/s41419-025-07420-7

Annu Rev Biomed Eng. 2025 Feb 19. doi: 10.1146/annurev-bioeng-102723-065309. Online ahead of print.

ABSTRACT

Understanding interaction mechanisms within cells, tissues, and organisms is crucial for driving developments across biology and medicine. Mathematical modeling is an essential tool for simulating such biological systems. Building on experiments, mechanistic models are widely used to describe small-scale intracellular networks. The development of sequencing techniques and computational tools has recently enabled multiscale models. Combining such larger scale network modeling with mechanistic modeling provides us with an opportunity to reveal previously unknown disease mechanisms and pharmacological interventions. Here, we review systems biology models from mechanistic models to multiscale models that integrate multiple layers of cellular networks and discuss how they can be used to shed light on disease states and even wellness-related states. Additionally, we introduce several methods that increase the certainty and accuracy of model predictions. Thus, combining mechanistic models with emerging mathematical and computational techniques can provide us with increasingly powerful tools to understand disease states and inspire drug discoveries.

PMID:39971380 | DOI:10.1146/annurev-bioeng-102723-065309

Cancer Lett. 2025 Feb 17:217565. doi: 10.1016/j.canlet.2025.217565. Online ahead of print.

ABSTRACT

Over 50% of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

PMID:39971122 | DOI:10.1016/j.canlet.2025.217565

J Appl Biomech. 2025 Feb 18:1-10. doi: 10.1123/jab.2024-0104. Online ahead of print.

ABSTRACT

The calf raise test (CRT) is commonly used to assess triceps surae muscle-tendon unit function. Often, a metronome set to 60 beats/min (30 repetitions/min) is used to set the cadence of calf raise repetitions, but studies report using cadences ranging from 30 to 120 beats/min. We investigated the effect of cadence on CRT outcomes, accounting for the potential confounders of sex, age, body mass index, and physical activity. Thirty-six healthy individuals (50% female) performed single-leg calf raise repetitions to volitional exhaustion in 3 randomized cadence conditions, 7 days apart: 30, 60, and 120 beats/min. Repetitions, total vertical displacement, total work, peak height, and peak power were recorded using the validated Calf Raise application. Cadence significantly affected all CRT outcomes (P ≤ .008), except repetitions (P = .200). Post hoc analysis revealed 60 beats/min resulted in significantly greater total vertical displacement and work than 30 and 120 beats/min. Peak height was greater at 60 and 120 than 30 beats/min, and peak power was greater at 120 beats/min. Males generated greater work and peak power (P ≤ .001), whereas individuals with greater body mass index completed less repetitions (P = .008), achieved lower total vertical displacements (P = .003), and generated greater peak power (P = .005). CRT cadence is important to consider when interpreting CRT outcomes and comparing data between studies.

PMID:39970923 | DOI:10.1123/jab.2024-0104

Am J Hum Genet. 2025 Feb 13:S0002-9297(25)00020-5. doi: 10.1016/j.ajhg.2025.01.020. Online ahead of print.

ABSTRACT

Africa's environmental, cultural, and genetic diversity can profoundly shape population responses to infectious diseases, including malaria caused by Plasmodium falciparum. Differences in malaria susceptibility among populations are documented, but the underlying mechanisms remain poorly understood. Notably, the Fulani ethnic group in Africa is less susceptible to malaria compared to other sympatric groups, such as the Mossi. They exhibit lower disease rates and parasite load as well as enhanced serological protection. However, elucidating the molecular and cellular basis of this protection has been challenging in part due to limited immunological characterization at the cellular level. To address this question, we performed single-cell transcriptomic profiling of peripheral blood mononuclear cells from 126 infected and non-infected Fulani and Mossi children in rural Burkina Faso. This analysis generated over 70,000 single-cell transcriptomes and identified 30 distinct cell subtypes. We report a profound effect of ethnicity on the transcriptional landscape, particularly within monocyte populations. Differential expression analysis across cell subtypes revealed ethnic-specific immune signatures under both infected and non-infected states. Specifically, monocytes and T cell subtypes of the Fulani exhibited reduced pro-inflammatory responses, while their B cell subtypes displayed stronger activation and inflammatory profiles. Furthermore, single-cell expression quantitative trait locus (eQTL) analysis in monocytes of infected children revealed several significant regulatory variants with ethnicity-specific effects on immune-related genes, including CD36 and MT2A. Overall, we identify ethnic, cell-type-specific, and genetic regulatory effects on host immune responses to malaria and provide valuable single-cell eQTL and transcriptomic datasets from under-represented populations.

PMID:39970911 | DOI:10.1016/j.ajhg.2025.01.020

Hamostaseologie. 2025 Feb;45(1):49-62. doi: 10.1055/a-2486-6758. Epub 2025 Feb 19.

ABSTRACT

Binding of platelet activators to their receptors initiates a signal transduction network, where intracellular signal is filtered, amplified, and transformed. Computational systems biology methods could be a powerful tool to address and analyze dynamics and regulation of the crucial steps in this cascade. Here we review these approaches and show the logic of their use for a relatively simple case of SFLLRN-induced procoagulant activity. Use of a typical model is employed to track signaling events along the main axis, from the binding of the peptide to PAR1 receptor down to the mPTP opening. Temporal dynamics, concentration dependence, formation of calcium oscillations and their deciphering, and role of stochasticity are quantified for all essential signaling molecules and their complexes. The initial step-wise activation stimulus is transformed to a peak at the early stages, then to oscillation calcium spikes, and then back to a peak shape. The model can show how both amplitude and width of the peak encode the information about the activation level, and show the principle of decoding calcium oscillations via integration of the calcium signal by the mitochondria. Use of stochastic algorithms can reveal that the complexes of Gq, in particular the complex of phospholipase C with Gq, which are the limiting steps in the cascade with their numbers not exceeding several molecules per platelet at any given time; it is them that cause stochastic appearance of the signals downstream. Application of reduction techniques to simplify the system is demonstrated.

PMID:39970901 | DOI:10.1055/a-2486-6758

Mar Pollut Bull. 2025 Feb 18;213:117689. doi: 10.1016/j.marpolbul.2025.117689. Online ahead of print.

ABSTRACT

Small benthic scavengers and carnivores, such as polychaetes, are very interesting to assess the accumulation and transfer of microplastics (MPs) to higher trophic levels in marine ecosystems. In this study we evaluate the presence, accumulation and impacts of MPs in the North-Atlantic deep-sea polychaete Laetmonice filicornis. Three types of MPs were identified: fishing lines, fibres and fragments, mostly black in colour, followed by red and blue ones. The average number of MPs was 4.10 ± 1.90 particles/g tissue. Fibres were the most abundant. They were composed of Polypropylene, Rayon, Polyethyleneimine Cellulose and Polyester. The histological analysis revealed the presence of microfibres embedded in muscles, peritoneum, nephridia, gonads and blood vessels, which can have a direct impact on vital functions, such as feeding and reproduction. This species occupies both predator and prey roles, bioaccumulate MPs and can transfer them to higher trophic links, representing a significant threat to all marine species, including humans.

PMID:39970794 | DOI:10.1016/j.marpolbul.2025.117689

Plant Dis. 2025 Feb 19. doi: 10.1094/PDIS-11-24-2523-RE. Online ahead of print.

ABSTRACT

Yellow dwarf viruses (YDVs) are transmitted by aphids and can significantly reduce grain yield in cereals worldwide. While barley yellow dwarf virus PAV (BYDV PAV) has long been present in Australia, the YDV species barley virus G (BVG) and barley yellow dwarf virus PAS (BYDV PAS) were reported for the first time more recently. Little data about the transmission and host range of BVG has been published worldwide, while epidemiological information about BVG and BYDV PAS in an Australian context is limited. Therefore, glasshouse experiments were conducted to examine the efficiency of the bird cherry-oat aphid (Rhopalosiphum padi), corn leaf aphid (Rhopalosiphum maidis), rose grain aphid (Metopolophium dirhodum) and Russian wheat aphid (Diuraphis noxia) to transmit BVG, BYDV PAS and BYDV PAV. BYDV PAS and BYDV PAV were transmitted at similar rates by each of the four aphid species. Although BVG was most efficiently transmitted by the corn leaf aphid, it was also transmitted, albeit less efficiently, by the bird cherry-oat aphid. Significantly, in our study, the corn leaf aphid transmitted BVG at a much higher rate (63%) using single-aphid inoculations than had previously been reported by others (7%). Varying levels of susceptibility were observed in host range experiments, and four additional BVG hosts were identified. Russian wheat aphid did not transmit any of the viruses examined. These results have implications for YDV management while also demonstrating the complexity and specificity of the relationships between YDVs, the aphids that transmit them and the plant hosts that they infect.

PMID:39970339 | DOI:10.1094/PDIS-11-24-2523-RE

Nucleic Acids Res. 2025 Feb 8;53(4):gkaf058. doi: 10.1093/nar/gkaf058.

ABSTRACT

Transcription factors (TFs) are often classified as activators or repressors, yet these context-dependent labels are inadequate to predict quantitative profiles that emerge across different promoters. A mechanistic understanding of how different regulatory sequences shape TF function is challenging due to the lack of systematic genetic control in endogenous genes. To address this, we use a library of Escherichia coli strains with precise control of TF copy number, measuring the quantitative regulatory input-output function of 90 TFs on synthetic promoters that isolate the contributions of TF binding sequence, location, and basal promoter strength to gene expression. We interpret the measured regulation of these TFs using a thermodynamic model of gene expression and uncover stabilization of RNA polymerase as a pervasive regulatory mechanism, common to both activating and repressing TFs. This property suggests ways to tune the dynamic range of gene expression through the interplay of stabilizing TF function and RNA polymerase basal occupancy, a phenomenon we confirm by measuring fold change for stabilizing TFs across synthetic promoter sequences spanning over 100-fold basal expression. Our work deconstructs TF function at a mechanistic level, providing foundational principles on how gene expression is realized across different promoter contexts, with implications for decoding the relationship between sequence and gene expression.

PMID:39970288 | DOI:10.1093/nar/gkaf058

Sci Adv. 2025 Feb 21;11(8):eado2830. doi: 10.1126/sciadv.ado2830. Epub 2025 Feb 19.

ABSTRACT

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.

PMID:39970212 | DOI:10.1126/sciadv.ado2830

PLoS Comput Biol. 2025 Feb 19;21(2):e1012364. doi: 10.1371/journal.pcbi.1012364. Online ahead of print.

ABSTRACT

For many infectious diseases, the risk of outbreaks varies seasonally. If a pathogen is usually absent from a host population, a key public health policy question is whether the pathogen's arrival will initiate local transmission, which depends on the season in which arrival occurs. This question can be addressed by estimating the "probability of a major outbreak" (the probability that introduced cases will initiate sustained local transmission). A standard approach for inferring this probability exists for seasonal pathogens (involving calculating the Case Epidemic Risk; CER) based on the mathematical theory of branching processes. Under that theory, the probability of pathogen extinction is estimated, neglecting depletion of susceptible individuals. The CER is then one minus the extinction probability. However, as we show, if transmission cannot occur for long periods of the year (e.g., over winter or over summer), the pathogen will most likely go extinct, leading to a CER that is equal (or very close) to zero even if seasonal outbreaks can occur. This renders the CER uninformative in those scenarios. We therefore devise an alternative approach for inferring outbreak risks for seasonal pathogens (involving calculating the Threshold Epidemic Risk; TER). Estimation of the TER involves calculating the probability that introduced cases will initiate a local outbreak in which a threshold number of cumulative infections is exceeded before outbreak extinction. For simple seasonal epidemic models, such as the stochastic Susceptible-Infectious-Removed model, the TER can be calculated numerically (without model simulations). For more complex models, such as stochastic host-vector models, the TER can be estimated using model simulations. We demonstrate the application of our approach by considering chikungunya virus in northern Italy as a case study. In that context, transmission is most likely in summer, when environmental conditions promote vector abundance. We show that the TER provides more useful assessments of outbreak risks than the CER, enabling practically relevant risk quantification for seasonal pathogens.

PMID:39970184 | DOI:10.1371/journal.pcbi.1012364

Cell Rep. 2025 Feb 18;44(2):115317. doi: 10.1016/j.celrep.2025.115317. Online ahead of print.

ABSTRACT

Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation, called chromosomal instability (CIN). CIN is caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduce the correction efficiency of erroneous K-MT attachments. UMK57, a chemical agonist of the protein MCAK (mitotic centromere-associated kinesin), improves chromosome segregation fidelity in CIN cancer cells by destabilizing K-MT attachments, but cells rapidly develop resistance. To determine the mechanism, we performed unbiased screens, which revealed increased phosphorylation in cells adapted to UMK57 at Aurora kinase A phosphoacceptor sites on BOD1L1 (protein biorientation defective 1-like-1). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression, and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of Taxol or Aurora kinase A inhibitor.

PMID:39970043 | DOI:10.1016/j.celrep.2025.115317

Proc Natl Acad Sci U S A. 2025 Feb 25;122(8):e2405379122. doi: 10.1073/pnas.2405379122. Epub 2025 Feb 19.

ABSTRACT

Natural selection often acts on multiple traits simultaneously. For example, the virus HIV-1 faces pressure to evade host immunity while also preserving replicative fitness. While past work has studied selection during HIV-1 evolution, as in other examples where selection acts on multiple traits, it is challenging to quantitatively separate different contributions to fitness. This task is made more difficult because a single mutation can affect both immune escape and replication. Here, we develop an evolutionary model that disentangles the effects of escaping CD8+ T cell-mediated immunity, which we model as a binary trait, from other contributions to fitness. After validation in simulations, we applied this model to study within-host HIV-1 evolution in a clinical dataset. We observed strong selection for immune escape, sometimes greatly exceeding past estimates, especially early in infection. Conservative estimates suggest that roughly half of HIV-1 fitness gains during the first months to years of infection can be attributed to T cell escape. Our approach is not limited to HIV-1 or viruses and could be adapted to study the evolution of quantitative traits in other contexts.

PMID:39970000 | DOI:10.1073/pnas.2405379122