bluuebunny/crossref_metadata_2025 huggingface dataset:
Clostridium sediminicola sp. nov., a crude oil aggregation-forming anaerobic bacterium isolated from marine sediment
Authors: Hirano Shiori , Terahara Takeshi , Kato Ririka , Mori Koji , Hamada Moriyuki , Miura Takamasa , Matsumoto Ryo , Hayashi Masahiro , Kobayashi Takeshi
Published: January 2025

An erratum of this article has been published full details can be found at

https://doi.org/10.1099/ijsem.0.006671

A crude oil aggregation-forming, strictly anaerobic, Gram-stain-positive, spore-forming, rod-shaped, motile and mesophilic bacterium, named strain SH18-2T, was isolated from marine sediment near Sado Island in the Sea of Japan. The temperature, salinity and pH ranges of this strain for the growth were 15–40 °C (optimum 35 °C), 0.5–6.0% NaCl (w/v; optimum 2.0%) and pH 6.0–8.0 (optimum 7.5), respectively. A phylogenetic analysis of the 16S rRNA gene sequence showed that this strain belongs to the genus Clostridium. It was most closely related to Clostridium grantii A-1T (97.02% homology). The draft genome size was 5616089 bp, with a G+C content of 29.7 mol%. The digital DNA–DNA hybridization values determined using the Genome-to-Genome Distance Calculator and the average nucleotide identity between this strain and C. grantii A-1T were 20.30 and 78.24%, respectively. Whole-organism hydrolysates of strain SH18-2T contained meso-diaminopimelic acid; the major fatty acid was C16:0, and the polar lipid pattern consisted of diphosphatidylglycerol, phosphatidylglycerol, glycolipid and three unidentified polar lipids. From the results of genotypic, phenotypic and chemotaxonomic analyses, SH18-2T (=NBRC 116030T=DSM 115762T) is the type strain and represents a novel species of the genus Clostridium, and the name Clostridium sediminicola sp. nov. is proposed.
Single-cell transcriptomics-guided development of flow cytometric tests predicting chronic myeloid leukemia blast crisis transformation at chronic phase diagnosis
Authors: Yu Mengge , Krishnan Vaidehi , Shyamsundar Pavithra , Lee Kian Leong , Schmidt Florian , Ren Xi , Chuah Charles , Prabhakar Shyam , Saunders Verity , Yeung David , Shanmuganathan Naranie , Yong Agnes S.M. , Hughes Timothy P. , Ong S. Tiong
Published: January 2025

Clinical risk scores in chronic myeloid leukemia (CML) are inadequate for identifying chronic phase (CP) patients at high-risk of blast crisis (BC) progression. The lack of accurate predictive tests hamper timely interventions, including stem cell transplants, that are more effective in early disease. By interrogating a single cell atlas of primary imatinib resistance for a BC-like gene expression signature, we identify aberrant CD42A+megakaryocytic and CD10+CD19+lymphoid progenitor expansion, as well as STAT1- and IFNγ-related inflammatory programs, as consistent features in the bone marrow and peripheral blood of CP patients at high-risk of BC transformation. We develop multi-color flow cytometry-based tests (MFC) to detect these features in CP patients at the time of diagnosis. Validating our MFC panels on a combined Australia-Singapore cohort comprising 28 CP patients, including 14 who underwent transformation, we demonstrate their ability to detect 100% of CP patients who transform with no false positives. Our findings highlight small populations of inflamed hematopoietic stem and progenitor cells, present at CP diagnosis, as powerful harbingers of future BC transformation. The ability of MFC panels to detect these cells at diagnosis support their inclusion as accurate risk-assessment tools to improve management of high-risk patients.
Inhibition of EMT driver PTK6 enhances anti-tumor immune responses against triple-negative breast cancer
Authors: Harada Ibuki , Martinez Criseyda , Ito Koichi , Lee Eunjee , Zhu Jun , Irie Hanna Y
Published: January 2025

The non-receptor tyrosine kinase PTK6 is expressed in 70% of triple negative breast cancers (TNBC) and is an oncogenic driver of epithelial-mesenchymal transition (EMT). EMT promotes metastasis and immune evasion of TNBC. Therefore, targeting EMT drivers could reverse these properties and lead to more favorable outcomes. Treatment of TNBC tumors with a small molecule inhibitor of PTK6 kinase (P21d) suppressed their growthin vivo. Tumor inhibition by P21d is dependent on an induced immune response because: 1) inhibition is observed in immunocompetent, but not immunodeficient, mice; 2) P21d increases tumor-infiltrating CD8+T and NK cells and decreases immunosuppressive myeloid-derived suppressor cells; and 3) tumor inhibition by P21d is abrogated by co-treatment with NK or CD8+T cell-depleting antibodies. These effects on tumor growth and cytotoxic TILs are phenocopied by the knockdown of tumoral PTK6 or SNAIL, which supports EMT inhibition as a mechanism for enhanced anti-tumor immune response. RNA sequencing (RNA-seq) profiling of P21d-treated tumors also revealed changes consistent with activation of the immune response and identified CXCL10 as a critical chemokine induced intratumorally by P21d that promotes recruitment of NK/CD8+ T cells to the tumor site, leading to tumor growth inhibition. Our study highlights the novel tumor immune microenvironmental functions of PTK6 with important consequences for tumor growth that could lead to new immunotherapeutic approaches for TNBC.
Simultaneous Targeting of KRAS and CDK4 Synergistically Suppresses Pancreatic Cancer Cells
Authors: Paulsohn Maj-Britt , Frahnert Klara Henrike , Fang Xin , Schneider Carolin , Tapia Contreras Constanza , Schneider Günter , Hessmann Elisabeth , Dobbelstein Matthias
Published: January 2025

Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule inhibitors of KRAS have been developed, bearing high potential for cancer therapy but considerable risk of resistance development. To avoid cancer cell adaptation, effective combinatorial partners for increasing immediate efficacy remain to be explored. Here, we demonstrate that combining the KRAS inhibitor Sotorasib with the CDK4/6 inhibitor Palbociclib synergistically eliminates pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS G12C mutations. This synergy was particularly pronounced after drug washout, indicating a durable impact. Similar effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, MRTX1133, a KRAS G12D inhibitor, synergized with Palbociclib to suppress KRAS G12D-mutant PDAC-derived cells. Mechanistically, these combinations induced sustained cell cycle arrest through reduced RB phosphorylation, decreased E2F1 levels, and increased CDKN1B/p27 expression. Deletion of CDKN1B largely rescued tumor cell proliferation, underscoring its critical role in mediating the observed synergy. These findings support the therapeutic potential of combining KRAS and CDK4/6 inhibitors for treating PDAC and other Ras-driven cancers.
Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression
Authors: Jeong Jain , Hsu Shao-Jung , Horikami Daiki , Utsumi Teruo , Yang Yilin , Arefyev Nikolai , Zhang Xuchen , Cai Shi-Ying , Boyer James L. , Garcia-Milan Rolando , Tanaka Masatake , McConnell Matthew J. , Huang Hui-Chun , Iwakiri Yasuko
Published: January 2025

The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-β signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.
Tissue-dependent mechanosensing by cells derived from human tumors
Authors: Parihar Kshitiz , Nukpezah Jonathan , Iwamoto Daniel V , Cruz Katrina , Byfield Fitzroy J , Chin LiKang , Murray Maria E , Mendez Melissa G , van Oosten Anne S , Herrmann Anne , Charrier Elisabeth E , Galie Peter A , Donlick Megan , Lee Tongkeun , Janmey Paul A , Radhakrishnan Ravi
Published: January 2025

Alterations of the extracellular matrix (ECM), including both mechanical (such as stiffening of the ECM) and chemical (such as variation of adhesion proteins and deposition of hyaluronic acid (HA)) changes, in malignant tissues have been shown to mediate tumor progression. To survey how cells from different tissue types respond to various changes in ECM mechanics and composition, we measured physical characteristics (adherent area, shape, cell stiffness, and cell speed) of 25 cancer and 5 non-tumorigenic cell lines on 7 different substrate conditions. Our results indicate substantial heterogeneity in how cell mechanics changes within and across tissue types in response to mechanosensitive and chemosensitive changes in ECM. The analysis also underscores the role of HA in ECM with some cell lines showing changes in cell mechanics in response to presence of HA in soft substrate that are similar to those observed on stiff substrate. This pan-cancer investigation also highlights the importance of tissue-type and cell line specificity for inferences made based on comparison between physical properties of cancer and normal cells. Lastly, using unsupervised machine learning, we identify phenotypic classes that characterize the physical plasticity, i.e. the distribution of physical feature values attainable, of a particular cell type in response to different ECM-based conditions.
Effects of the Histone Deacetylase Inhibitor Valproic Acid in Combination with Fear Memory Retrieval before Exposure Therapy for Spider Phobia: A Randomized Controlled Trial
Authors: Schicktanz Nathalie S. , Dechent Frieder , Huber Carlo Andreas , Zimmer Anja , Iseli Galya Clara , Howald Jeanne , Schenker Maya Thalia , Gräff Johannes , Lang Undine , de Quervain Dominique JF , Bentz Dorothée
Published: January 2025

Return of fear after successful exposure therapy for phobia is a common clinical challenge. A previous study on mice demonstrated that the persistent attenuation of remote fear memories can be achieved by combining histone deacetylase inhibitors (HDACis) with fear-memory retrieval prior to extinction training. To evaluate the translational potential of this approach, we conducted a randomized, double-blind placebo-controlled trial. Forty-eight individuals with DSM-IV spider phobia received either HDACi valproic acid (VPA, 500 mg) or a placebo prior to the retrieval of fear memory followed by exposure therapy in virtual reality. No significant group difference was found in terms of behavioral change on the behavioral approach test at 3 months follow-up and baseline (primary outcome). However, the VPA group displayed significantly reduced fear in two self-report questionnaires related to spider phobia (Fear of Spider Questionnaire; Spider Phobia Beliefs Questionnaire) as compared to the placebo group. No group differences were observed for psychophysiological indicators of fear. The favorable impact of a single administration of VPA in combination with fear-memory retrieval prior to exposure therapy suggests that it might be an effective way to enhance symptom improvement at the subjective level in the treatment of phobias. Further studies need to investigate the conditions under which an improvement on the physiological and behavioral levels can be achieved as well.
Sugar-mediated control ofATG101modulates carbon deficiency-induced autophagy in Arabidopsis
Authors: Boycheva Woltering Svetlana , Tanigawa Mirai , Bläske Tobias , Isono Erika
Published: January 2025

Autophagy is a major eukaryotic degradation and recycling pathway, which eliminates damaged cellular components and provides energy and building blocks especially under adverse environmental conditions. While the core autophagy machinery has been extensively studied, autophagy initiation and regulation remain less understood. In this study, we show that genes encoding the core autophagy initiation complex,ATG1,ATG11,ATG13, andATG101, are transcriptionally regulated by sugars. To analyze the expression of these genes, we took advantage ofArabidopsis thalianaaccessions, which display strong variations in their responses to darkness-induced fixed carbon deprivation. One of the components of the initiation complex,ATG101, has multiple sugar-related elements, and was repressed by sugar. Moreover,ATG101was induced stronger upon starvation in carbon starvation-resistant accessions when compared to carbon starvation-sensitive accessions. We identified three single nucleotide polymorphisms in the genomic region ofATG101which are associated with the carbon-starvation phenotype. Further analyses through complementation of theatg101mutant with different variants ofATG101demonstrated that the single nucleotide polymorphism alleles contribute differently toATG101expression regulation, response to sugar, and phenotype recovery. Taken together, our data suggest that modulation ofATG101by sugar is part of a multi-layered mechanism regulating the sensitivity to carbon starvation in Arabidopsis.
Ameliorative Effects ofBrideliaferrugineaExtracts on Cadmium Chloride-Induced Reproductive Hormone Imbalance, Oxidative Stress, Hepatorenal Damage, Hematological Disorders, and Acute Toxicity in Wistar Rats
Authors: Adewuyi Hassan Abdulsalam , Shekari Abednego , Adio Sakariyau Waheed , Oluwatoyin Adebimpe Hameedah , Fagbohun Rokibat Omowunmi , Owoeye Emmanuel Abiodun , Korie George Chibuike , Nasiru Monsurat Ololade , Olusegun Timothy God-Giveth , Ishola Ayomide Babatunde , Gidado Medina Ojuolape
Published: January 2025

Background

Cadmium chloride is a toxic heavy metal that can cause oxidative stress, damage to organs, and disrupt hormonal balance.Brideliaferrugineais a plant with antioxidant and free radical-scavenging properties. The aim of this study was to investigate the protective effects ofBrideliaferrugineaextract against cadmium chloride-induced toxicity in rats.

Methods

This study used a randomized controlled design, with 36 rats divided into 6 groups. The rats were treated with cadmium chloride,Brideliaferrugineaextract, or a combination of both. The study employed various assay methods, including acute toxicity test, reproductive hormone marker assays, oxidative stress marker assays, hepatic marker assays, and hematological parameter assays.

Main findings

The results showed that cadmium chloride induced significant acute toxicity, as evidenced by 33.33% mortality rate and significant body weight loss (-15.67 ± 3.33 g), whereas co-treatment with BFE (100 and 200 mg/kg) reduced mortality to 0% and reversed body weight loss to a gain of 10.00 ± 2.50g and 20.00 ± 2.50g, respectively. CdCl2 group had significantly lower testosterone, LH, and FSH levels compared to the control group (p < 0.05), significantly higher MDA levels and lower SOD and CAT levels compared to the control group (p < 0.05).significantly higherALT, AST, and ALP levels compared to the control group (p < 0.05), and significantly lower Hb, PCV, WBC, and RBC levels compared to the control group (p < 0.05) respectively. Co-administration ofBrideliaferrugineaextract with CdCl2 significantly improved reproductive hormone markers, reduced MDA levels and improved SOD and CAT levels in a dose-dependent manner (p < 0.05). Additionally, ALT, AST, and ALP levels were significantly reduced in a dose-dependent manner (p < 0.05), hematological parameters significantly improved in Hb, PCV, WBC, and RBC levels in a dose-dependent manner (p < 0.05). The highest dose of Brideliaferruginea extract (200 mg/kg) showed the most significant improvement in all parameters (p < 0.01).

Implications

This study suggests thatBrideliaferrugineaextract may be a useful therapeutic agent against heavy metal toxicity. The findings have implications for the development of novel treatments for heavy metal poisoning and highlight the potential of Brideliaferruginea extract as a natural remedy for heavy metal toxicity.
CSMA: an ImageJ Plugin for the Analysis of Wound Healing Assays
Authors: Pham Tri T. , Sagymbayeva Amina , Elebessov Timur , Onzhanova Zhadyra , Molnár Ferdinand
Published: January 2025

Accurate quantification of wound closure in cell migration assays is crucial yet challenging. Still, existing methods often underperform due to omitting cell detection within the wound area, resulting in biased outcomes. To overcome this limitation, we developed the CSMA plugin for ImageJ. CSMA utilizes advanced image processing techniques, including contrast enhancement, edge detection, and morphological operations, to precisely identify and quantify cells in the wound region. The plugin offers user-friendly features and adjustable parameters to accommodate different imaging conditions, ensuring robust performance across diverse experimental setups. Validation against conventional tools confirms CSMA’s superior ability to delineate wound boundaries and provide accurate estimations of area and width at every time point. As applied to SW480-ADH colon cancer cells treated with various compounds, CSMA proves valuable in biomedical research. It represents a significant advancement in wound healing assay analysis, providing researchers with a simple and reliable tool for studying cell migration dynamics with enhanced precision and reproducibility. CSMA is available as an ImageJ plugin and source code athttps://github.com/AminaSagymbayeva/CSMA_WoundHealing.
The 3D affinities of the OT-I TCR to foreign and self-antigens predict their 2D affinities and reveal imperfect antigen discrimination
Authors: Huhn Anna , Kutuzov Mikhail A. , Maclean Keir , Uhl Lion F. K. , Mahale Jagdish M. , Gerard Audrey , van der Merwe P. Anton , Dushek Omer
Published: January 2025

T cells use the T cell antigen receptor (TCR) to discriminate between higher-affinity foreign and lower-affinity self peptide-MHC (pMHC) antigens. The OT-I mouse TCR is widely used to study anti-gen discrimination utilising many pMHCs, including foreign and self antigens. Previous studies sug-gested that OT-I T cells achieve near-perfect discrimination between higher and lower affinity antigens. Moreover, these 3D affinities measured in solution did not correlate with the 2D membrane affinities, suggesting a complex relationship between 3D and 2D affinities. In contrast, other TCRs have shown imperfect antigen discrimination and strong correlations between 3D and 2D affinities. To resolve these discrepancies, we extended a protocol for measuring ultra-low TCR/pMHC affinities to accurately de-termine the 3D affinities of the OT-I TCR binding 19 pMHC complexes. These revised 3D affinities now strongly correlate with the 2D affinities, and accurately predict functional responses. Importantly, we now find that the OT-I TCR exhibits enhanced yet imperfect antigen discrimination, similar to other TCRs, allowing it to detect abnormally high levels of low-affinity self-antigens. Finally, we show that discrimination is highest with low-affinity pMHC ligands, a finding predicted by the kinetic-proofreading model of antigen discrimination. This work underscores the ability of T cells to effectively gauge prox-ies for 3D affinity within the 2D cell-cell interface, with significant implications for the mechanisms underlying antigen discrimination.

Lay abstract

T cells protect the body from infection by distinguishing between foreign and self molecules. They do this using a specialized receptor called the T cell receptor (TCR), which senses differences in how strongly it binds to foreign versus self molecules. Scientists have used a mouse TCR called OT-I to understand this process, concluding that OT-I T cells exhibit near perfect discrimination between foreign and self antigens based on a sharp affinity threshold. However, conflicting results from experiments on other TCRs hinted at a more complicated picture. In this study, we used an improved method to accurately measure OT-I TCR binding affinity to 19 peptides, including foreign and self antigens. In contrast to previous results and like other TCRs, we found that OT-I T cells display enhanced but im-perfect discrimination, enabling them to be activated by high levels of self antigen. The new data also revealed that the ability of T cells to discriminate antigens is particularly high at low affinities. These findings reconcile apparent discrepancies between the OT-I TCR and other TCRs, and have implications for understanding diseases where T cells often respond to self antigen, such as autoimmunity and cancer.

Graphical abstract
FaRIF at the Core of Strawberry Fruit Ripening: Deciphering its Targets and Interaction Networks
Authors: Martín-Pizarro Carmen , Franco-Zorrilla José M. , Perotti María Florencia , Lozano-Durán Rosa , Qin Guozheng , Posé David
Published: January 2025

Ripening Inducing Factor (RIF) is a key NAC transcription factor regulating strawberry fruit ripening. Previous studies usingRIF-RNAi and overexpression lines inFragaria × ananassaand CRISPR knock-out lines inF. vescahave established the role of RIF in controlling ABA biosynthesis and signaling, cell wall remodeling, and secondary metabolism.

In this study, we deciphered FaRIF’s transcriptional regulatory network by combining ChIP-seq-based identification of its direct targets with an analysis ofFaRIF-RNAi transcriptome data. These analyses revealed FaRIF’s direct role in multiple aspects of strawberry fruit ripening, including the regulation of ripening-related transcription factors, phytohormone content and signaling, primary and secondary metabolism, and cell wall degradation. Additionally, using the TurboID-based proximity labeling approach, we have identified FaRIF interactors, including proteins involved in mRNA and protein homeostasis, as well as several NAC transcription factors. Among these, FaNAC034 was found to synergistically enhance FaRIF’s transcriptional activity.

This integrative analysis, combining transcriptome analysis,in vivoChIP-seq, and proximity labeling, broadens our knowledge of FaRIF-mediated transcriptional networks and interaction partners, providing valuable insights into the molecular mechanisms underlying strawberry fruit ripening regulation by this transcription factor.
Mechanisms of dexamethasone-induced bone toxicity in developing bone: a single-cell perspective
Authors: Warmink Kelly , Lijnzaad Philip , Vermaat Tristan C.W. , Jansen Lisa , van Gend Marloes C.C. , Zhang Baojie , Balwierz Aleksandra , Proost Natalie , van de Ven Marieke , Merks Johannes H.M. , Margaritis Thanasis , Janda Claudia Y.
Published: January 2025

Abstract

Glucocorticoids, such as dexamethasone, are essential for treating severe childhood conditions, including cancer, organ transplantation, and inflammatory disorders. However, their long-term use can impair bone development, posing risks to pediatric bone health, which is vital for lifelong skeletal integrity. A mechanistic insight on how glucocorticoids negatively impact bone could improve decision-making in patient care to improve the quality of life for pediatric cancer patients and survivors. In this study, we aimed to elucidate the molecular mechanisms underlying dexamethasone-induced bone toxicity in developing bones using single-cell transcriptomics. We treated skeletally immature C57BL/6JRj mice with dexamethasone for 28 days, and assessed the bone architecture with micro-computed tomography, and characterized bone and bone marrow cells from the femurs using single-cell RNA sequencing. Our findings revealed a marked reduction in osteoblast and chondrocyte cell populations and impaired function of pre-osteoblasts. Additionally, dexamethasone adversely affected B cell subsets, significantly depleting early B cell progenitors while allowing some further developed immature B cells to persist. These cellular changes were accompanied by reduced longitudinal bone growth, compromised bone architecture, and increased bone fragility at the highest doses of dexamethasone. Interestingly, unlike observations in adults, dexamethasone did not enhance osteoclast activity in our model. Overall, our study suggests that the adverse effects of dexamethasone on bone development are primarily due to its impact on osteoblastic, chondroblastic and B cell lineages, disrupting the critical signaling crosstalk between the cells necessary for bone development and hematopoiesis.

Layman summary

Glucocorticoids, like dexamethasone, are vital for treating severe childhood illnesses but can harm bone development when used long-term. This study investigated how dexamethasone affects bone health in young mice. Using advanced techniques, we found that dexamethasone reduced key bone-building cells (osteoblasts and chondrocytes) and weakened their function. It also disrupted immune cell development in the bone marrow, especially early B cells. These changes led to weaker, more fragile bones without increasing bone breakdown, unlike in adults. The findings highlight the need to carefully balance treatment benefits and risks for children to protect their bone health and overall well-being.
2D, or not 2D? Investigating Vertical Signal Integrity of Tissue Slices
Authors: Tiesmeyer Sebastian , Müller-Bötticher Niklas , Malt Alexander , Long Brian , Marco-Salas Sergio , Kiessling Paul , Horn Paul , Guillot Adrien , Kuemmerle Louis B , Ma Leyao , Tacke Frank , Theis Fabian , Kuppe Christoph , Nillson Mats , Eils Roland , Ishaque Naveed
Published: January 2025

Imaging-based spatially resolved transcriptomics can localise transcripts within cells in 3D. Cell segmentation precedes assignment of transcripts to cells and annotation of cell function. However, cell segmentation is usually performed in 2D, thus unable to deal with spatial doublets arising from overlapping cells, resulting in segmented cells containing transcripts originating from multiple cell-types. Here we present a computational tool called ovrlpy that identifies overlapping cells, tissue folds and inaccurate cell-segmentation.
Somatic evolution of stem cell mutations in long-lived plants
Authors: Johannes Frank
Published: January 2025

Long-lived perennial plants accumulate numerous somatic mutations with age. Mutations originating in stem cells at the shoot apex often become fixed in large sectors of the plant body due to cell lineage drift during repeated branching. Understanding the somatic evolution of such mutations requires knowledge of the effective stem cell population size, the cellular bottleneck strength during branch initiation, and the mutation rate. Here we show that these parameters can be estimated directly from cell-layer-specific DNA sequencing data, thus filling a gap where no otherin vivomethod exists.
A fast numerical integration scheme for clonal expansion processes on graphs
Authors: Paterson Chay , Gao Miaomiao , Hellier Joshua , Luebeck Georg , Wedge David , Bozic Ivana
Published: January 2025

Compound birth-death processes are widely used to model the age-incidence curves of many cancers [1]. There are efficient schemes for directly computing the relevant probability distributions in the context of linear multi-stage clonal expansion (MSCE) models [2]. However, these schemes have not been generalised to models on arbitrary graphs, forcing the use of either full stochastic simulations or mean-field approximations, which can become inaccurate at late times or old ages [3, 4]. Here, we present a numerical integration scheme for directly computing survival probabilities of a first-order birth-death process on an arbitrary directed graph, without the use of stochastic simulations. As a concrete application, we show that this new numerical method can be used to infer the parameters of an example graphical model from simulated data.
Clustering Digestive Tract Tumors Using Transcriptomic and Mutation Data
Authors: Tally Dwayne G. , Bombina Polina , Reed Jake , Kinne Jeffrey , Abruzzo Lynne V. , Coombes Kevin R. , Abrams Zachary B.
Published: January 2025

Digestive tract cancers, like most other cancers, are usually categorized based on cell or tissue of origin. Molecular clustering based on the transcriptome often produces the same classification. We developed a new method, Newmanization, to reduce underlying tissue signals from transcriptomic analysis. To test our method, we downloaded data on 1635 samples of digestive tract cancers from The Cancer Genome Atlas. The available data includes transcriptomic data, by RNA-Seq, as well as binary mutation allele frequency data by whole exome sequencing. We compared, using silhouette widths and visualization by dimension reduction plots, the effectiveness of Newmanized transcriptome and mutation data to separate digestive tract cancers. The Newmanized transcriptome clusters have clearer separation and larger average silhouette widths. Feature analysis of each cluster for Newmanized transcriptomic data and mutation data revealed that clusters determined with Newmanized data contained more mRNAs present at higher frequencies than clusters defined by mutation data. This suggests that the Newmanized method holds great potential for advancing personalized transcriptomic medicine.
Condensate screening identifies YM155 as β-catenin condensate inhibitor in colorectal cancer
Authors: Manzato Caterina , Sirati Nafiseh , Knol Bronwen A. , Kuiken Hendrik J. , Morris Ben , Fleming Cassio , Beijersbergen Roderick L. , Schuijers Jurian
Published: January 2025

β-catenin is a transcriptional cofactor crucial in forming biomolecular condensates that drive WNT target gene transcription. Its pathological accumulation in the nucleus is a critical step in WNT-driven cancers, such as colorectal cancer. Disrupting β-catenin condensates is a promising cancer treatment strategy, but no clinical applications currently exist. In this study, we developed a Nanobody Enabled Condensate Observation (NECO) screening platform to identify small molecules that modulate β-catenin condensates. The platform revealed compounds that either enhanced or reduced β-catenin transcriptional condensates. Among them, YM155 (sepantronium bromide) was identified as an inhibitor, disrupting essential weak interactions for condensate formation. This disruption effectively inhibits the proliferation of WNT-driven colorectal cancer organoids. These findings show that the NECO platform can identify small molecules that target β-catenin condensates and suggest YM155 as a potential anti-cancer agent for colorectal cancer.
It takes two: Aberrant repair and low-grade inflammation characterizes bronchiolitis obliterans syndrome after lung transplantation in serum proteomic analysis
Authors: van der Ploeg Eline A. , Faiz Alen , Teitsma Greta J. , Brotons Alejandro Sánchez , Govorukhina Natalia , Sand Jannie M.B. , Leeming Diana J. , Melgert Barbro N. , Horvatovich Peter , Burgess Janette K. , Tji Gan C.
Published: January 2025

Aim

The obstructive phenotype of chronic lung allograft dysfunction, bronchiolitis obliterans syndrome (BOS), is diagnosed after lung transplantation (LTx) when irreversible airway obstruction is already present. This study aimed to investigate the fibrotic response and inflammation signals in serum of BOS patients.

Methods

LTx patients transplanted at the University Medical Center Groningen between 2004 and 2017 were screened. Nineteen patients with BOS were selected and matched to 19 non-BOS patients. Only patients for whom lung function and longitudinal serum samples post-LTx were available were included. Enzyme-linked immunosorbent assays were performed for neoepitopes of collagen types I, III, and VI and osteoprotegerin (OPG) in serum. Additionally, serum samples were analyzed by label free liquid chromatography with tandem mass spectrometry proteomics analysis.

Results

Collagen neoepitopes did not differ significantly between BOS and non-BOS patients at any timepoint. OPG was significantly higher in non-BOS compared to BOS six months before BOS onset (p<0.04). In proteomics analysis, proteins indicating cell repair and proliferation, namely human type II keratin-6 and centromere protein F (both FDR<0.1), were significantly lower three months before BOS onset in BOS compared to non-BOS patients. C-reactive protein (FDR<0.05) and SERPINA3 (FDR<0.05) amongst others, were higher in end-stage BOS compared to non-BOS patients.

Conclusion

Differences in expression of proteins that reflect the complex interplay between fibrosis and inflammation in BOS were identified. These proteins should be investigated and validated in larger cohorts and may aid in expanding knowledge about the development of BOS.
Comparative analysis ofXenopusmesonephric transcriptomics: Conservation of the developmental lineage of nephron stages
Authors: Corkins Mark E. , Romero-Mora Adrian , Achieng MaryAnne A. , Lindström Nils O. , Miller Rachel K.
Published: January 2025

The mammalian kidney develops in three sequential stages referred to as the pronephros, mesonephros, and metanephros, each developing from the preceding form. All three phases of kidney development utilize epithelized tubules called nephrons, which function to take in filtrate from the blood or coelom and selectively reabsorb solutes the organism needs, leaving waste products to be excreted as urine. The pronephros are heavily studied in aquatic organisms such as zebrafish and Xenopus, as they develop quickly and are functional. The metanephros is a preferred mammalian kidney model, as it best recapitulates human disease. However, very little is known about the mesonephric stage of kidney development in any organism. The pronephros extend to form the mesonephric duct, which ultimately develops into the Wolffian duct in male amniotes. Meanwhile, in organisms that lay their eggs in aquatic environments, the mesonephric kidney is the final form that is generated. Therefore, further understanding of the development and physiology of these kidneys will provide insight into the urogenital system as well as its evolutionary conservation. To gain a better understanding of its structure and cell types, we analyzed the developing mesonephros by in situ and single-cell mRNA sequencing of cells the that make up the developing mesonephros. By comparing these data to those published for theXenopuspronephros and mammalian metanephros, we were able to evaluate nephron conservation between the three kidney stages.
TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+T cells
Authors: Lee Hoyoung , Kim So-Young , Kim Sang-Hoon , Yu Hosun , Jeong Seongju , Kim Kyung Hwan , Kim Chang Gon , Koh June-Young , Kim Hyung-Don , Han Ji Won , Park Su-Hyung , Eun Hyuk Soo , Shin Eui-Cheol
Published: January 2025

Here we investigated the regulatory mechanisms of TCR-independent bystander activation and NK-like cytotoxicity of human memory CD8+T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8+T-cell activation, including increased NKG2D expression and upregulation of genes related to NK cytotoxicity and IFN response. Moreover, ionomycin suppressed IL-15-induced bystander activation and NK-like cytotoxicity, indicating that Ca2+-calcineurin signaling is responsible for TCR-mediated suppression of IL-15-induced bystander activation. In detail, NFATc1 suppressed IL-15- induced bystander activation via binding to AP-1 that is necessary for the IL-15-induced upregulation of NK cytotoxicity-related genes. Consistent with these results, calcineurin inhibitors enhanced IL-15-induced NKG2D expression in the presence of TCR signals. Additionally, we defined genes upregulated by IL-15 and downregulated by concurrent TCR signals as an IL-15-induced bystander activation gene set, and found that this gene signature was upregulated in bystander CD8+T cells from patients with hepatitis A virus infection. This study paves the way for further investigation of bystander CD8+T-cell activation in various pathological conditions, and its regulation.

Graphical abstract
A qualitative study of how maternal morbidities impact women’s quality of life during pregnancy and postpartum in five countries in sub-Saharan Africa and South Asia
Authors: Abdulai Martha , Adhikary Priyanka , Baumann Sasha G. , Ejaz Muslima , Priya Jenifer Oviya , Spelke M. Bridget , Akelo Victor , Asante Kwaku Poku , Berhane Bitanya M. , Bisht Shruti , Boamah-Kaali Ellen , Diaz-Guzman Gabriela , Cherian Anne George , Hoodbhoy Zahra , Kasaro Margaret P. , Khan Amna , Kuttamperoor Janae , Lall Dorothy , Manohari Gifta Priya , Mazumder Sarmila , McDonnell Karen , Mehrihajmir Mahya , Mutale Wilbroad , Mwebia Winnie K. , Nisar Imran , Ochola Kennedy , Otieno Peter , Ouma Gregory , Patel Piya , Phiri Winifreda , Sharma Neeraj , Smith Emily R. , Tawiah Charlotte , Vallone Natalie J. , Sylvetsky Allison C.
Published: January 2025

Aim

Maternal morbidities present a major burden to the health and well-being of childbearing women. However, their impacts on women’s quality of life (QoL) are not well understood. This work aims to describe the extent to which the morbidities women experience during pregnancy and postpartum affect their QoL and identify any protective or risk factors.

Methods

This qualitative study included pregnant and postpartum women in Kenya, Ghana, Zambia, Pakistan, and India. Data were collected between November 2023 and June 2024. Participants were selected via purposive sampling, with consideration of age, trimester, and time since delivery. A total of 23 focus group discussions with 118 pregnant and 88 late (≥6 months) postpartum participants and 48 in-depth interviews with early (≤6 weeks) postpartum participants were conducted using semi-structured guides developed by the research team. Data was analyzed using a collaborative inductive thematic approach.

Results

Four overarching themes were identified across pregnancy and the postpartum period: (1) physical and emotional challenges pose a barrier to daily activities; (2) lack of social support detracts from women’s QoL; (3) receipt of social support mitigates adverse impacts of pregnancy and postpartum challenges on QoL; and (4) economic challenges exacerbate declines in women’s QoL during pregnancy and postpartum.

Conclusions

Bodily discomfort and fatigue were near-universal experiences. Physical and emotional morbidities related to childbearing limited women’s ability to complete daily tasks and adversely impacted their perceived QoL. Social and financial support from the baby’s father, family and/or in-laws, community members, and healthcare providers are important to mitigate the impacts of pregnancy and postpartum challenges on women’s health and well-being.
Attractive Targeted Sugar Baits for malaria control in western Kenya (ATSB-Kenya) – Effect of ATSBs on epidemiologic and entomologic indicators: a Phase III, open-label, cluster-randomised, controlled trial
Authors: Ogwang Caroline , Samuels Aaron M , McDermott Daniel P , Kamau Alice , Lesosky Maia , Obiet Kizito , Janssen Julia M , Odongo Wycliffe , Gimnig John E , Gutman Julie R , Schultz Jonathan S , Towett Oliver , Seda Brian , Chepkirui Mercy , Muchoki Margaret , Omondi Seline , Kosgei Jackline , Polo Brian , Aduwo Frank , Otieno Kephas , Donnelly Martin J , Kariuki Simon , Ochomo Eric , Kuile Feiko ter , Staedke Sarah G
Published: January 2025

Attractive targeted sugar baits (ATSBs) are a novel malaria control tool designed to target mosquitoes outdoors. We conducted a cluster-randomised trial to evaluate the impact of ATSBs on malaria indicators in Kenya. Seventy clusters (>100 households/cluster) in Siaya county were randomly assigned (1:1) to intervention or control. Pyrethroid-only long-lasting insecticidal nets were distributed to all clusters, aiming for universal coverage. Two ATSBs containing dinotefuran were hung outside household structures in intervention clusters. ATSBs were monitored every two months and replaced every six months over two years. Three consecutive cohorts of randomly selected children (1-<15 years) were enrolled, aiming to accrue 1,260 person-years over two years of follow-up. Incidence of clinical malaria (fever with a positive malaria test) was the primary outcome. A multilevel Poisson regression model was applied, with clusters as a random intercept and study arm as a fixed effect. Secondary outcomes were malaria prevalence in community residents (≥1 month), and parity of mosquitos captured through human landing catches. In March 2022, ATSBs were delivered to 33,180 of 33,419 (99.3%) household structures in intervention clusters. Overall, 268,268 ATSBs were deployed over two years. Of 2,962 cohort children enrolled (intervention=1,497; control=1,465), 2,869 (96.9%) were included in the primary analysis (intervention=1,461; control=1,408), contributing 1,445 person-years of follow-up. Malaria incidence was 1.32 episodes per person-years in the intervention arm versus 1.20 in the control (unadjusted incidence rate ratio 1.11; 95% CI: 0.75-1.65; p=0.598). Of 7,488 community residents surveyed(intervention=3,760; control=3,728), 1,474 (39.2%) intervention and 1,461 (39.2%) control participants tested positive for malaria (unadjusted odds ratio [OR] 0.98; 95% CI: 0.60-1.59; p=0.93). Of 6,457 female anopheles mosquitoes collected (intervention=4,058; control=2,399), 3,579 (88.2%) intervention and 1,973 (82.2%) control mosquitoes were parous (OR 1.34; 95% CI: 0.91-1.99; p=0.14). In Kenya, we found no evidence that ATSBs reduced clinical malaria incidence, malaria prevalence, or vector parity.

Trial registration

Clinicaltrials.gov (NCT05219565), 22 January 2022;https://clinicaltrials.gov/study/NCT05219565
Arrow heads at Obi-Rakhmat (Uzbekistan) 80 ka ago
Authors: Plisson Hugues , Kharevich Alëna V. , Kharevich Vladimir M. , Chistiakov Pavel V. , Zotkina Lydia V. , Baumann Malvina , Pubert Eric , Kolobova Ksenya A. , Krivoshapkin Andrei I.
Published: January 2025

When they are occasionally found in Middle Palaeolithic Neanderthal settlements, lithic weapons heads are large and do not differ in size, shaping or type from those used for activities other than hunting, such as plant gathering or butchery. The presence in a same assemblage of various types of armatures, some of which are microlithic and designed for this purpose, has only been documented in Modern Humans sites.

Recent studies show that light projectile points, which were to become the structuring element of Upper Palaeolithic lithic industries, were already present in its formative stages. However, they remain marginal in debates regarding the Middle to Upper Paleolithic transition.

We present here the first results of a search for weapon heads in the oldest layers of the Obi-Rakhmat rock shelter, at around 80 ka. This site, located in the western foothills of the Tian Shan Mountains, northeastern Uzbekistan, has yielded a blade-based lithic industry which is forming part of the continuity of the Levantine Early Middle Paleolithic but with several innovative traits. The assemblage is based on a systematic blade production (regular thick narrow blades from unipolar and bipolar sub-prismatic and narrow-faced cores, thin and wide blades from flat-faced Levallois-like cores) along with shorter pieces from convergent or centripetal Levallois cores, and bladelets from burin-cores and other small cores.

Three types of projectile armature are identified from their impact marks: retouched points, bladelets and raw micropoints which were so far unseen due to their fragmentary state. The micropoints are too narrow for having been fitted to anything other than arrow shafts. They are similar to the armatures described in a pioneer settlement by Sapiens in the Rhône Valley, France, 25,000 years later.
Repurposing Metal-Based Therapeutics for Human Metapneumovirus (HMPV): An Integrative Computational Approach
Authors: Dubey Amit , Kumar Manish , Tufail Aisha , Dwivedi Vivek Dhar
Published: January 2025

Human metapneumovirus (HMPV) poses a significant global health challenge, with limited therapeutic options available. This study employs a comprehensive computational framework to repurpose metal-based drugs as potential HMPV inhibitors. A library of compounds was systematically evaluated using virtual screening, high-precision molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT) calculations, molecular electrostatic potential (MESP) mapping, and pharmacophore modeling. Key candidates, including Auranofin, Silver Sulfadiazine, and Gallium Nitrate, demonstrated high binding affinities (ΔGbinding: -68.5 to -62.7 kcal/mol) and favorable stability metrics (RMSD: 2.1–2.4 Å). ADME-toxicity (ADMET) profiling highlighted Auranofin’s robust bioavailability (80%) and extended half-life (8.5 hours), while Ribavirin and Favipiravir emerged as safe controls with minimal toxicity. Quantum chemical analyses reinforced the compounds’ electronic stability and reactivity. This integrative study provides a promising avenue for repurposing existing therapeutics, bridging computational insights with translational potential to combat HMPV.
Strategies for resolving cellular phylogenies from sequential lineage tracing data
Authors: Mulberry Nicola , Stadler Tanja
Published: January 2025

A combination of recent advancements in molecular recording devices and sequencing technologies has made it possible to generate lineage tracing data on the order of thousands of cells. Dynamic lineage recorders are able to generate random, heritable mutations which accumulate continuously on the timescale of developmental processes; this genetic information is then recovered using single-cell RNA sequencing. These data have the potential to hold rich phylogenetic information due to the irreversible nature of the editing process, a key feature of the employed CRISPR-based systems that deviates from traditional assumptions about molecular mutation processes, and recent technologies have furthermore made it possible for mutations to be acquired sequentially. Understanding the information content of these recorders remains an open area of investigation. Here, we model a sequentially-edited recording system and analyse the experimental conditions over which exact phylogenetic reconstruction occurs with high probability. We find, using simulation and theory, explicit parameter regimes over which simple and efficient distance-based reconstruction methods can accurately resolve the cellular phylogeny. We furthermore illustrate how our theoretical results could be used to help inform experimental design.

Highlights

Uncovering cellular phylogenies is a key goal in developmental biology.

State-of-the-art lineage tracing tools generate genetic sequences with irreversible and ordered mutations which can be recovered at the single-cell resolution.

We analyze these experimental systems and assess when accurate reconstruction of the cellular phylogeny is possible.