bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatal paraquat poisoning: a case report and literature review on rapid deterioration and therapeutic challenges
Authors: Barma Aachal , Poudel Aashis , Rawal Gunjana , Karn Mitesh , Kc Unika , Ojha Liladhar , Bajgai Dinesh , Mandal Manisha
Published: February 2025

Introduction and importance:

Paraquat (PQ) poisoning is a life-threatening condition with a high-mortality rate. As it lacks a specific antidote, treatment is mainly supportive, focusing on reducing oxidative damage and organ dysfunction. Despite aggressive intervention, the condition can rapidly progress to multiorgan failure. This report presents a fatal case of PQ poisoning, highlighting its clinical course and management challenges.

Case presentation:

A 45-year-old female ingested 10 mL of 20% PQ, presenting with vomiting, dizziness, and generalized body aches. At presentation, she was alert, with stable vital signs and no significant findings. Immediate treatment, including gastric lavage, activated charcoal, corticosteroids, antioxidants, and monitoring of renal and hepatic function, was initiated. On Day 2, her condition deteriorated with jaundice, respiratory distress, and PQ-induced tongue ulcers. Lab results showed worsening renal and hepatic dysfunction. She received cyclophosphamide, N-acetylcysteine, and heparin-free hemodialysis, but her condition continued to decline, leading to multiorgan failure. She succumbed to her condition on the fourth day.

Clinical discussion:

PQ toxicity causes oxidative stress, resulting in rapid progression to multiorgan failure. Early decontamination and supportive care are key, but no curative treatment exists. The rapid progression and limited effectiveness of current therapies make management difficult.

Conclusion:

PQ poisoning remains a critical medical emergency with a high-mortality rate. Timely recognition, aggressive supportive care, and further research into novel detoxification and therapeutic strategies are essential to improving survival outcomes. Additionally, public health measures, including stricter regulations and increased awareness regarding PQ’s toxicity, are crucial in preventing future cases.
Immunoglobulin Therapy and Standards of Practice
Authors: Clarke Amy E. , Sobolevsky Luba
Published: February 2025

Immunoglobulin (Ig) therapy is vital for managing immunodeficiency and autoimmune disorders, offering replacement and immunomodulatory benefits. This article provides an evidence-based guide to safe and effective Ig therapy including guidance for home-based administration. Key topics include managing adverse reactions, clinician training, patient education, and quality improvement. A patient case study highlights practical applications, supporting home care clinicians in delivering high-quality home care aligned with national standards.
Comparative Study of Inflammatory and Fibrotic Reactions Induced by Silicone Implants with Different Hardness
Authors: Lee Da Woon , Jang Si-Hyong , Kim Hyun , Kim Taek Kyun , Byeon Je Yeon , Choi Hwan Jun
Published: February 2025

Background:

Silicone nasal implants have been widely used in rhinoplasty. However, research on the correlation between implant hardness and the development of fibrosis and inflammation is lacking. This study investigated how the hardness of silicone implants influences fibrosis and inflammation through an experimental investigation.

Methods:

Three types of nasal silicone implants with varying hardness levels were implanted bilaterally on the backs of 15 Wistar rats. Ten weeks post-implantation, clinical aspects, such as differences in immune reactions and formation of peri-implant capsules were analyzed. The intra-tissue response of the host was assessed by qRT-PCR using 11 markers. Specific markers were investigated by immunohistochemical (IHC) staining. Pathological grading was performed to investigate inflammation and fibrosis in the peri-implant tissues. Quantification and statistical analysis of these parameters were conducted to derive scores for intergroup comparisons.

Results:

Histological analysis of the 45 capsules obtained revealed lower levels of fibrosis and acute inflammation in the group with lower hardness. This result was confirmed by IHC staining. Hematoxylin and eosin staining showed that the capsule thickness was less in the low-hardness group. Additionally, inflammation resolved quickly in the low-hardness group, and mature fibrotic tissue was observed.

Conclusions:

When silicone implants are stably positioned within the body, less-rigid implants exhibit lower inflammatory or fibrotic responses. This is directly related to the adverse effects associated with capsule formation. These findings contribute to our understanding of the behavior of heterotopic materials in the nasal dorsum and their effects on the skin and soft tissue envelope.
Hexanoic acid improves metabolic health in mice fed high-fat diet.
Authors: Ikeda Takako , Nishimoto Yuki , Ichikawa Daisuke , Matsunaga Tomoka , Kawauchi Ami , Kimura Ikuo
Published: February 2025

Background: Overweight and obesity is currently a worldwide problem with undesirable health consequences such as type 2 diabetes. Therefore, much attention has been paid to preventing obesity through diet. Free fatty acids (FFAs) are an important energy source, and they also serve as signaling molecules in many biological processes leading to an increased energy expenditure and insulin secretion. Short-chain fatty acids (SCFAs) such as acetic, propionic and butyric acid are the bioactive metabolites produced by gut microbes, and their beneficial effects on host metabolism are well-studied. In addition, medium-chain fatty acids (MCFAs) such as octanoic and decanoic acid also play a positive role in regulating lipid and glucose metabolisms. However, the effects of hexanoic acid on metabolism are poorly understood. Therefore, this study investigated the role of hexanoic acid on lipid and glucose metabolism in mice. Methods: Male C57BL/6J mice were fed normal chow diet, high-fat diet (HFD), HFD-containing 5% butyric acid or HFD-containing 5% hexanoic acid for 4 weeks, and the effects of hexanoic acid on lipid and glucose metabolism were examined. Results: Butyric acid and hexanoic acid prevented body weight gain and fat accumulation in white adipose tissues under HFD-feeding. In addition, both FFAs suppressed the elevated plasma levels of non-esterified fatty acid (NEFA) and hepatic triglyceride content induced by HFD. The expression levels of genes involved in fatty acid biosynthesis were decreased in white adipose tissues by oral supplementation of butyric acid or hexanoic acid. Mice fed HFD also exhibited hyperglycemia and hyperinsulinemia, and these impaired glucose metabolisms improved by hexanoic acid. Hexanoic acid increased the expression levels of genes associated with gluconeogenesis, and improved insulin sensitivity in mice fed HFD. Conclusions: This study highlights the importance of hexanoic acid in improvement of lipid and glucose metabolisms. Thus, our findings provide insight into the development of functional foods which prevent obesity-related disease such as type 2 diabetes.
Drug repurposing reveals Posaconazole as a CYP11A1 inhibitor enhancing anti-tumour immunity
Authors: Pramanik Jhuma , Shaji Sanu K. , Zaman Megan , Brown Bethany , Zhang Baojie , Yamashita-Kanemaru Yumi , Homer Natalie Z. M. , Hussein Hosni , Zhao Qiuchen , Okkenhaug Klaus , Roychoudhuri Rahul , Mukhopadhyay Abhik , Mahata Bidesh
Published: February 2025

Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumour growth and suppressing anti-tumour immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking in silico structure-based drug repurposing approach, we found Posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that Posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilising the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that Posaconazole restricts metastatic cancer growth by stimulating anti-tumour immunity. These findings highlight Posaconazole's potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathological conditions associated with local steroid production, such as steroidogenic tumours.
Association Between Dietary Vitamin B1 and the Risk of Endometriosis: A Cross-Sectional Study Based on NHANES 2003–2006
Authors: Zhang Jing , Zhou Zhigang , Guo Huiwen
Published: February 2025

Endometriosis is a chronic gynecological condition influenced by inflammation and oxidative stress. Dietary vitamin B1 plays a role in reducing oxidative stress, which may influence endometriosis risk. However, limited research explores this association. Objective To investigate the association between dietary vitamin B1 intake and the risk of endometriosis, using NHANES 2003–2006 data. Vitamins B2 and B6 are included as reference comparisons. Methods Data from 2,462 participants in NHANES 2003–2006 were analyzed. Logistic regression models were used to examine the association between vitamin B1 intake and endometriosis risk, with adjustments for covariates. Subgroup analyses and restricted cubic spline (RCS) regressions were applied to assess non-linear relationships. Vitamins B2 and B6 served as reference nutrients for comparison. Results Vitamin B1: Higher intake of dietary vitamin B1 was significantly associated with reduced risk of endometriosis (OR = 0.76, 95% CI: 0.58–0.99, P = 0.044 in Model 4). Vitamin B2 and B6: No significant associations were observed (P > 0.05).RCS regression demonstrated a non-linear relationship for vitamin B1, with a protective effect observed at intake levels > 1.84 mg/day. Conclusion Higher dietary vitamin B1 intake is associated with a reduced risk of endometriosis. While B2 and B6 showed no significant associations, their trends provide additional insight for future research.
A computational dynamic model of combination treatment for type II inhibitors with asciminib
Authors: Roadnight Sheehan J. , de Wijn Astrid S. , Friedman Ran
Published: February 2025

Despite continuous strides forward in drug development, resistance to treatment looms large in the battle against cancer as well as communicable diseases. Chronic myeloid leukaemia (CML) is treated with targeted therapy and treatment is personalised when resistance arises. It has been extensively studied and is used as a model for targeted therapy. In this work, we examine combination treatments of type II Abl1 inhibitors and asciminib (an allosteric regulator) through a computational model at patient relevant concentrations. Due to the separate binding sites of type II inhibitors and asciminib, we propose their combination treatment as potentially robust to resistance. We find that the simultaneous cobinding of type II inhibitors and asciminib is high in synergetic combinations. As an aid to designing and comparing combination treatments, we put forward an equation that expands on the effective ratio of IC50(ERIC). Unlike usual comparisons of IC50values, ERIC takes takes patient plasma concentrations into account. The product of two ERIC values (ERICcombo) creates comparable approximations of the effectiveness of combination treatments with low levels of synergy or antagonism at different concentrations. Its simple formulation is done without experiments and requires less computation and input data than the current standard of ZIP values. As such, the new scheme is a useful complement to experiments that deal with synergy in drug use.
Establishment of an efficient one-step enzymatic synthesis of cyclic-2,3-diphosphoglycerate
Authors: Stracke Christina , Meyer Benjamin H. , DeRose Simone A. , Ferrandi Erica E. , Kublanov Ilya , Isupov Michail N. , Harmer Nicholas , Monti Daniela , Littlechild Jennifer , Mueller Felix , Snoep Jacky L. , Braesen Christopher , Siebers Bettina
Published: February 2025

Extremolytes, unique compatible solutes produced by extremophiles, protect biological structures like membranes, proteins, and DNA under extreme conditions, including extremes of temperature and osmotic stress. These compounds hold significant potential for applications in pharmaceuticals, healthcare, cosmetics, and life sciences. However, despite their promise, only a few extremolytes, such as ectoine and hydroxyectoine, are commercially established, primarily due to the lack of efficient production strategies for other compounds. Cyclic 2,3-diphosphoglycerate (cDPG), a unique metabolite found in certain hyperthermophilic methanogenic Archaea, plays a key role in thermoprotection and is synthesized from 2-phosphoglycerate (2PG) through a two-step enzymatic process involving 2-phosphoglycerate kinase (2PGK) and cyclic-2,3-diphosphoglycerate synthetase (cDPGS). In this study, we present the development of an efficientin vitroenzymatic approach for the production of cDPG directly from 2,3-diphosphoglycerate (2,3DPG), leveraging the activity of the cDPGS from Methanothermus fervidus (MfcDPGS). We optimized the heterologous production of MfcDPGS inEscherichia coliby refining codon usage and expression conditions. The purification process was significantly streamlined through an optimized heat precipitation step, coupled with effective stabilization of MfcDPGS for both usage and storage by incorporating KCl, Mg2+, reducing agents and omission of an affinity tag. The recombinant MfcDPGS showed a Vmax of 38.2 U mg-1, with KM values of 1.52 mM for 2,3DPG and 0.55 mM for ATP. The enzyme efficiently catalyzed the complete conversion of 2,3DPG to cDPG. Remarkably, even at a scale of 100 mM, it achieved full conversion of 37.6 mg of 2,3DPG to cDPG within 180 minutes, using just 0.5 U of recombinant MfcDPGS at 55°C. These results highlight that MfcDPGS can be easily produced, rapidly purified, and sufficiently stabilized while delivering excellent conversion efficiency for cDPG synthesis as value-added product. Additionally, a kinetic model for MfcDPGS activity was developed, providing a crucial tool to simulate and scale up cDPG production for industrial applications. This streamlined process offers significant advantages for the scalable synthesis of cDPG, paving the way for further biochemical and industrial applications of this extremolyte.
Modulation of intestinal bile acids influences colonic mucosal responses
Authors: Wortmann Esther , Groll Tanja , Strigli Anne , Peuker Kenneth , Volet Colin , Arps Leona , Bernier-Latmani Rizlan , Zeissig Sebastian , Steiger Katja , Middelhoff Moritz , Clavel Thomas
Published: February 2025

Background: Elevated levels of secondary bile acids produced by the gut microbiome, in particular deoxycholic acid (DCA), influence epithelial cell proliferation and accelerate the development of colorectal cancer (CRC) under adverse dietary conditions, such as long-term, high fat intake. However, their effects on the intestinal epithelium have not been studied in detail. Aim: To determine gut epithelial responses to bile acid modulation in vivo and in situ. Methods: We performed targeted colonization of gnotobiotic mice followed by single-cell RNA sequencing (scRNA-Seq) of colonic epithelial cells combined with immunostaining of human biopsies from: (i) an observational patient cohort with hyperproliferative polyps or cancer; (ii) an interventional study with bile acid-scavenging drugs. Results: Colonization of mice with a synthetic bacterial community together with the 7α-dehydroxylating species Extibacter muris resulted in DCA production. ScRNA-Seq of colonic epithelial cells revealed increased cell density of bile acid-sensitive enterocytes but fewer stem cells, goblet cells, and transit amplifying cells in mice exposed to DCA. This was associated with increased expression of pyruvate dehydrogenase kinase (Pdk4) and decreased expression of mucin (Muc2). PDK expression was also increased in human hyperplastic polyps and adenomas, whilst MUC2 expression was reduced in adenomas and carcinomas compared to normal mucosa. In addition, human exposure to bile acid sequestrants was associated with enhanced epithelial proliferation. Conclusion: This study provides insight into intestinal epithelial cell responses to bile acids and their potential clinical relevance.
Donor-Specific Digital Twin for Living Donor Liver Transplant Recovery
Authors: Halder Suvankar , Lawrence Michael C , Testa Giuliano , Periwal Vipul
Published: February 2025

Liver resection initiates a meticulously coordinated hyperplasia process characterized by regulated cell proliferation that drives liver regeneration. This process concludes with the complete restoration of liver mass, showcasing the precision and robustness of this homeostasis. The remarkable capacity of the liver to regenerate rapidly into a fully functional organ has been crucial to the success of living donor liver transplantation (LDLT). In healthy livers, hepatocytes typically remain in a quiescent state (G0). However, following partial hepatectomy, these cells transition to the G1 phase to re-enter the cell cycle. Surgical resection induces various stresses, including physical injury, altered blood flow, and increased metabolic demands. These all trigger the activation and suppression of numerous genes involved in tissue repair, regeneration, and functional recovery. Both coding and noncoding RNAs detectable in the bloodstream during this process provide valuable insights into the gene responses driving liver recovery. This study integrates clinical gene expression data into a previously developed mathematical model of liver regeneration, which tracks transitions among quiescent, primed, and proliferating hepatocytes to construct virtual, patient-specific liver models. Using whole transcriptome RNA sequencing data from 12 healthy LDLT donors, collected at 14 time points over a year, we identified liver resection-specific gene expression patterns through Weighted Gene Co-expression Network Analysis (WGCNA). These patterns were organized into distinct clusters with unique transcriptional dynamics and mapped to model variables using deep learning techniques. Consequently, we developed a Personalized Progressive Mechanistic Digital Twin (PePMDT) for the livers of LDLT donors. The resulting PePMDT predicts individual patient recovery trajectories by leveraging blood-derived gene expression data to simulate regenerative responses. By transforming gene expression profiles into dynamic model variables, this approach bridges clinical data and mathematical modeling, providing a robust platform for personalized medicine. This study highlights the transformative potential of data-driven frameworks like PePMDT in advancing precision medicine and optimizing recovery outcomes for LDLT donors.
Topical application of the cold-mimetic L-menthol decreases wheel running without affecting the beneficial effects of voluntary exercise in mice
Authors: Bellucci Annalaura , Baranowski Bradley , Jeromson Stewart , Akcan Michael , Trang Serena , Arbeau Meagan , Alfares Hadil , Eisner Katelyn , Wright David
Published: February 2025

Topical application of L-menthol, a pharmacological cold-mimetic and agonist of the cold-sensing receptor TRPM8 (Transient Receptor Potential Cation Channel Subfamily M Member 8), has been shown to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain in both obese and lean male mice, without affecting energy intake. While these findings suggest that L-menthol could offer a novel approach to prevent weight gain, its potential to enhance the benefits of exercise on whole-body metabolic health remains unexplored. In this study, we investigated whether daily topical L-menthol application, combined with voluntary wheel running, could enhance exercise-induced improvements in metabolic health in male and female C57BL/6J mice housed at thermoneutrality (29C). Our results demonstrated that although L-menthol treatment reduced voluntary wheel running distance there was still a main effect of exercise to reduce fat mass, weight gain and improve glucose tolerance. Indirect calorimetry revealed that L-menthol increased total energy expenditure, potentially explaining improvements in metabolic health despite reductions in voluntary wheel running. These findings suggest that although L-menthol does not enhance the effects of voluntary exercise, it remains a promising strategy for improving metabolic health.
Local graph-motif features improve gene interaction network prediction
Authors: Leon Victor Julio , Matelsky Jordan K , Ernlund Amanda , Kitchell Lindsey M , Rawls Kristopher D , Bishop Caitlyn , Reilly Elizabeth
Published: February 2025

Gene interaction networks specify how genes interact to produce an organism's phenotype. These networks are often incomplete due to absent or unobserved information. Predicting these missing links is critical for many applications, including genome-wide association studies and phenotype prediction. Efforts have previously applied graph neural networks (GNNs) to this missing-link prediction problem, but these techniques too have limitations when the sparsity of the networks is very high. Here, we apply a novel feature engineering technique that uses local graph motif incidence to enhance the feature set for variational graph autoencoders (VGAE). We compare the performance of our technique against state-of-the-art approaches, and then progressively hide more and more of the original graph edges. Our results show that VGAEs with our local-area motif prevalence (LAMP) features outperform state-of-the-art node embeddings for a wide range of missing edges on both a benchmark and a biological dataset. We also observe that this combined VGAE and LAMP technique has the potential to facilitate the search for novel genetic interactions in an experimental adaptive sampling context with far fewer samples. Improvements to gene interaction imputation can lower the barrier to new pharmaceutical and epidemiological discoveries by revealing hidden gene interactions that steer the development of potential drug targets.
Genetics in the ocean's twilight zone: Population structure of the Mueller's pearlside across its distribution range
Authors: Quintela María , Mateos-Rivera Alejandro , Lille-Langøy Roger , Besnier François , Tsagarakis Konstantinos , Rodriguez-Ezpeleta Naiara , Bao Miguel , Wiech Martin , Giulietti Lucilla , Rábade-Uberos Sonia , Saborido-Rey Fran , Chlaida Malika , Strand Espen , Knutar Sofie , García-Seoane Eva , Melle Webjørn , Axelsen Bjørn Erik , Glover Kevin A.
Published: February 2025

The large estimates of mesopelagic fish biomass have fuelled harvesting interests in the relatively untouched ocean's twilight zone. The Mueller's pearlside, one of the most abundant species inhabiting the north Atlantic mesopelagic layer, is a candidate to such fisheries despite its enormous ecological importance and the insufficient knowledge about its population genetic structure. To shed light on the latter, 863 individuals sampled across the North Atlantic and Mediterranean were genotyped using 170 genome-wide SNPs. Analyses revealed habitat-driven differentiation in three units: Mediterranean Sea, oceanic samples, and Norwegian fjords. These groups were not completely isolated to each other as a cline of Mediterranean admixture was detected in the Eastern Atlantic façade up to latitude 47 °N in an otherwise genetically homogeneous oceanic cluster. Temperature seemed to modulate the differentiation patterns, and in the Mediterranean added to the complicated topography of the Greek Seas to shape genetic structure. In the Norwegian coastline, sills did not hamper genetic exchange among fjords ranging 200 km apart, probably due to the position of the species in the water column together with its swimming capacity. This genetic information should be combined with demographic properties to outline the management of this species prior to any eventual fishery attempt.
SCOIGET: Predicting Spatial Tumor Evolution Pattern by Inferring Spatial Copy Number Variation Distributions
Authors: Zhang Yujia , Yang Yitao , Kong Yan , Zhong Bingxu , Nakai Kenta , Lu Hui
Published: February 2025

Constructing a comprehensive spatiotemporal map of tumor heterogeneity is essential for understanding tumor evolution, with copy number variation (CNV) as a significant feature. Existing studies often rely on tools originally developed for single-cell data, which fail to utilize spatial information. Our study aims to develop a model that fully leverages spatial omics data to elucidate spatio-temporal changes in tumor evolution. Here, we introduce SCOIGET (Spatial COpy number Inference by Graph on Evolution of Tumor), a novel framework using graph neural networks with graph attention layers to learn spatial neighborhood features of gene expression and infer copy number variations. This approach integrates spatial multi-omics features to create a comprehensive spatial map of tumor heterogeneity. Notably, SCOIGET achieves a substantial reduction in error metrics (e.g., mean squared error, cosine similarity, and distance measures) and produces superior clustering performance as indicated by higher Silhouette Scores compared to existing methods. Our model significantly enhances the efficiency and accuracy of tumor evolution depiction, capturing detailed spatial and temporal changes within the tumor microenvironment. It is versatile and applicable to various downstream tasks, demonstrating strong generalizability across different spatial omics technologies and cancer types. This robust performance improves research efficiency and provides valuable insights into tumor progression. In conclusion, SCOIGET offers an innovative solution by integrating multiple features and advanced algorithms, providing a detailed and accurate representation of tumor heterogeneity and evolution, aiding in the development of personalized cancer treatment strategies.
Comprehensive LC-MS/MS Data Acquisition in Metabolomics via Maximum Bipartite Matching
Authors: McBride Ross , Weidt Stefan , Wandy Joe , Davies Vinny , Daly Rónán , Bryson Kevin
Published: February 2025

Background: In untargeted metabolomics studies, liquid chromatography tandem mass spectrometry (LC-MS/MS) is a powerful analytical platform. The fragmentation spectra produced can be used as ``molecular fingerprints" to identify unknown metabolites. However, the high number of analytes that may be co-eluting limits the number of fragmentation spectra that can be collected and potentially identified, presenting a serious bottleneck for many studies. There is a need for new fragmentation strategies which are comprehensive, interpretable and robust, meaning they produce high-quality fragmentation spectra for as many analytes as possible while operating within the constraints of notoriously noisy mass spectrometry data. Results: We present a data acquisition workflow which uses a bipartite graph to represent the relationship between opportunities for fragmentation and desired fragmentation targets. This method allows a schedule for data acquisition to be optimally allocated by a standard algorithm. We augment this existing technique by allowing it to solve for multiple samples collectively, allowing it to optimise target intensity (and hence spectral quality) via the use of a weighted matching and by assigning leftover scans redundantly to improve robustness. We also show how this workflow can be used flexibly to generate inclusion windows for Data-Dependent Acquisition (DDA) methods. Our experiments show that several thousand peaks identified in a realistic biological sample can be targeted using only two LC-MS/MS runs. We also further investigate the trade-off between offline workflows and DDA methods by exposing our target list of peaks to realistic variation across samples. We find in those circumstances that our new method has performance (measured by number of peaks targeted comparable to state-of-the-art DDA methods). However, this competitive performance is only possible with our additions to the base maximum matching technique, which provide extra resistance against inter-sample variations. Conclusions: We have proposed a workflow for LC-MS/MS data acquisition which can be used flexibly for entirely pre-scheduled acquisition or which may generate inclusion windows for online DDA methods. Our results show that the maximum matching workflow with our improvements is state-of-the-art where pre-scheduling is concerned, and in future this foundation may be developed to build more powerful DDA methods which can action the promise of truly comprehensive data acquisition.
Human memory CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader pathogen-specific responses
Authors: Stetsenko Volodymyr , Gail Daniel P , Reba Scott , Suzart Vinicius G , Sandhu Avinaash K , Sette Alessandro , Dezfulian Mohammad Haj , Arlehamn Cecilia S Lindestam , Carpenter Stephen M
Published: February 2025

Recognition of macrophages infected with Mycobacterium tuberculosis (Mtb) is essential for CD4+ T cells to prevent tuberculosis (TB). Yet not all antigen-specific T cells recognize infected macrophages in human and murine models. Using monocyte-derived macrophages (MDMs) and autologous memory CD4+ T cells from individuals with latent Mtb infection (LTBI), we quantify T cell activation in response to infected macrophages. T cell antigen receptor (TCR) sequencing revealed >70% of unique and >90% of total Mtb-specific TCR clonotypes in stable LTBI are linked to recognition of infected macrophages, while a subset required exogenous antigen exposure, suggesting incomplete recognition. Clonotypes specific for multiple Mtb antigens and other pathogens were identified, indicating Mtb-specific and non-specific activation. Single-cell transcriptomics demonstrates Mtb-specific T cells express signature effector functions dominated by IFNg, TNF, IL-2, and GM-CSF or chemokine production and signaling. We propose TB vaccines that elicit T cells capable of recognizing infected macrophages and expressing these canonical effector functions will offer protection against TB.
Grammar acquisition in preschool children is related to white matter maturation of the dorsal language network
Authors: Klein Cheslie C. , Berger Philipp , Wiesmann Charlotte Grosse , Friederici Angela D.
Published: February 2025

In preschool years, children take important steps in grammar acquisition, which are essential to learning their native language. A central aspect is the acquisition of the morpho-syntactic rule system, which forms an intersection between words and sentences. In adults, rule-based linguistic processes are supported by the dorsal fiber pathway to BA44, the arcuate fascicle. This pathway matures relatively late in development, raising the question of whether it already supports grammar processes in the early preschool years, or whether early grammar acquisition is supported by different, earlier-maturing fiber pathways. In two independent samples of 3- to 5-year-old children (N = 90 and N = 30), we examined the association between the maturation of fiber pathways of the language network and children's noun plural assignment as an index of their morpho-syntactic abilities. This revealed consistent differences between 3-year-olds and 4- to 5-year-olds. The 4- and 5-year-olds, but not 3-year-olds, showed a relation of morpho-syntax with both the dorsal pathway to BA44, supporting syntactic processes, and the dorsal pathway to BA6, supporting phonological processes in adults. Our results suggest that, in contrast to adults, preschool-aged children rely on both dorsal fiber pathways for morpho-syntax. This difference might point to different processing strategies reflecting the transition from phonology-based statistical learning to rule-based learning in grammar acquisition.
IL-1R1 Blockade Enhances CD40 Agonist-Mediated Immune Responses but Fails to Increase Efficacy or Mitigate Hepatotoxicity in Pancreatic Cancer
Authors: Boda Akash , Bandey Irfan N , CHOWDHURY SAIKAT , Aggarwal Sadhna , Reddy Mekala venugopala , Fowlkes Natalie Wall , Roszik Jason , Curran Michael A , Morris Van Karlyle , Kopetz Scott , Singh Manisha
Published: February 2025

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of only 10% in the United States. While immune checkpoint blockade (ICB) has shown efficacy in many solid tumors, PDAC remains largely unresponsive. Agonistic CD40 antibodies can activate PDAC-associated myeloid cells, enhancing innate and adaptive anti-tumor immunity. However, clinical trials with agonistic CD40 antibodies have demonstrated only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances CD40 agonist efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b+Ly6C+Ly6G+). Since PMN-MDSCs also cause liver toxicity. This study investigates the impact of IL-1R1 blockade on the efficacy and toxicity of CD40 agonist therapy in PDAC. We found that treatment with an agonistic CD40 antibody induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. The transcriptomic profile revealed that IL-1R1 blockade as monotherapy downregulated innate and adaptive immune response and exacerbated tumor growth. However, the combination therapy of agonistic CD40 antibody and IL-1R1 blockade upregulated several immune-related pathways (GO enrichment analysis), including JAK-STAT signaling, antigen processing, and presentation, natural killer cell mediated cytotoxicity, boosted innate and adaptive immune responses, compared to CD40 agonist treatment alone. Paradoxically, despite these immunostimulatory effects, IL-1R1 blockade failed to improve the overall anti-tumor efficacy of CD40 agonist therapy and exacerbated liver toxicity. Liver toxicity was assessed by serum ALT and AST levels, and transcriptomic profiling of the liver revealed several pathways related to immune infiltration, liver metabolism, viral carcinogenesis and alcoholic liver disease were associated with hepatotoxicity. To further investigate the role of PMN-MDSCs in PDAC and understand the failure of anti-IL-1R1 therapy, we depleted these cells using an anti-Ly6G antibody in mice treated with an agonistic CD40 antibody. Unexpectedly, Ly6G depletion reduced the efficacy of CD40 agonist therapy, suggesting that, contrary to expectations, Ly6G⁺ immune cells (PMN-MDSCs or neutrophils) exhibit an anti-tumor rather than an immunosuppressive role in PDAC. Our findings underscore the complex role of IL-1 signaling in modulating immune responses in PDAC and caution against pursuing IL-1R1 blockade, either as a monotherapy or in combination with CD40 agonist antibodies, in future clinical trials for PDAC.
RAB1A is a novel vulnerability in uveal melanoma revealed by dual inhibition of MNK1/2 and mTOR.
Authors: Flores Gonzalez Raul Ernesto , Goncalves Christophe , Wirasinghe Noah , Gaudeault St-Laurent Veronique , Noda Ferro Jesus M. , Dany-Coutant Kelly Simone , Mitchel Andrew , Guettler Elizabeth , Gonzalez Moreno Daniel Rodolfo , Preston Samuel , Cai Feiyang , Gagnon Natascha , Jean Steve , Landreville Solange , Miller Wilson , Del Rincon Sonia Victoria
Published: February 2025

Uveal melanoma (UM) is an eye cancer that is fatal upon metastasis to the liver. Most treatments trialed in UM fail to provide therapeutic benefit, thus there is an urgent need for novel treatment strategies. The MAPK and PI3K signaling pathways, key molecular drivers found to be hyper-activated in UM, converge on the MNK1/2-eIF4E and mTORC1/2-4EBP axes. Here, we demonstrate that the pharmacologic inhibition of MNK1/2 in combination with an mTOR inhibitor impairs clonogenic outgrowth and UM cell invasion. Proteomic analyses reveal that combined MNK1/2 and mTOR inhibition disrupts Golgi homeostasis and protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. Experimental UM liver metastasis assays show that knockdown of RAB1A blocks metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. This study identifies protein vesicle transport as an unrecognized vulnerability in UM and supports a mechanistic rationale for targeting MNK1/2 and mTOR in metastatic UM.
Stress drives plasticity in leaf maturation transcriptional dynamics
Authors: Swift Joseph , Wu Xuelin , Xu Jiaying , Jain Tanvi , Illouz-Eliaz Natanella , Nery Joseph R. , Chory Joanne , Ecker Joseph R.
Published: February 2025

Leaf development is dynamic, adapting to environmental stress to optimize resource use. For example, in response to drought,Arabidopsisrestricts leaf growth to enhance water use efficiency. While this plastic response is well described at the physiological level, the underlying transcriptional changes that facilitate adjustments in leaf development in response to stress remain poorly described. By constructing a ∼1 million single-nuclei transcriptome atlas, we demonstrate that drought stress limits leaf growth by advancing transcriptional responses related to maturation and aging. Notably, we find that these transcriptional changes scale with environmental stress, and help explain how shoot size can decline proportionally with stress intensity. Leveraging these insights, we increased leaf growth under stress by cell-type targeted upregulation ofFERRIC REDUCTION OXIDASE 6in the mesophyll.
Expanding the Tubulin Code: TTLL11 Polyglutamylase Drives Elongation of Primary Tubulin Chains
Authors: Campbell Jana , Vosahlikova Miroslava , Ismail Samar , Volnikova Margareta , Motlova Lucia , Kudlacova Julia , Ustinova Kseniya , Snajdr Ivan , Novakova Zora , Basta Miroslav , Gutsche Irina , Desfosses Amboise , Barinka Cyril
Published: February 2025

Microtubules (MTs) undergo diverse post-translational modifications that regulate their structural and functional properties. Among these, polyglutamylation - a dominant and conserved modification targeting the unstructured tubulin C-terminal tails - plays a pivotal role in defining the tubulin code. Here, we uncovered a novel mechanism by which tubulin tyrosine ligase-like 11 (TTLL11) expands and diversifies the code. Cryo-electron microscopy revealed a unique bipartite MT recognition strategy wherein TTLL11 binding and catalytic domains engage adjacent MT protofilaments. Biochemical assays identified previously unknown polyglutamylation patterns, showing that TTLL11 directly extends the primary polypeptide chains of alpha and beta tubulin, challenging the prevailing paradigms emphasizing lateral branching. Moreover, cell-based and in vivo data firmly established a crosstalk between TTLL11-mediated polyglutamylation and other tubulin-modifying processes, notably the detyrosination/tyrosination cycle. This discovery unveils an unrecognized layer of complexity within the tubulin code and offers new insights into the molecular basis of functional specialization of cytoskeleton across diverse cellular contexts.
Cutting through the clutter: minimizing redundancy in GO enrichment analysis with evoGO
Authors: Strielkov Ievgen , Buinovskaja Greta , Uvarovskii Alexey , Galatenko Vladimir
Published: February 2025

Gene Ontology (GO) enrichment analysis is a powerful tool for elucidating underlying biological processes in high-throughput transcriptomic and proteomic studies. However, the redundancy of identified enriched GO terms, caused by the hierarchical nature of GO, significantly complicates the prioritization of relevant terms and makes drawing concise conclusions challenging. To address this problem, we developed evoGO, a novel method that aims to improve the specificity and relevance of enrichment results by considering the GO hierarchy during the analysis. Built on the foundation of conventional overrepresentation analysis (ORA), evoGO reduces the impact of differentially expressed genes on the significance of a given GO term if those genes already contribute to a higher significance of any descendant GO term. The effectiveness of the algorithm was evaluated against other advanced ORA-based GO enrichment analysis methods (topGO, clusterProfiler, and SetRank) using synthetic and real-life datasets. In the synthetic benchmarks, evoGO reduced the number of enriched terms identified by ORA on average by 30% while recovering the highest fraction (96%) of the true positives. When applied to real-life data, evoGO most efficiently prioritized tissue-specific GO terms in the analyses aimed to capture the biological processes inherent to various human tissues. Furthermore, evoGO eliminated the fewest enriched GO terms that had no significantly enriched relatives and thus should not be considered redundant. Finally, evoGO was one of the fastest of the tested methods and, unlike competitors, maintained consistent execution times across both benchmarks. In conclusion, our findings demonstrate that among tested ORA-based approaches, evoGO stands out as an effective and fast method for minimizing redundancy in GO enrichment analysis results while reliably preserving biologically relevant information. We believe that evoGO could be a valuable tool for conducting downstream analyses, particularly in the context of high-throughput transcriptomic and proteomic screening studies. The evoGO method has been implemented as an R package, which is available on GitHub.
Early and late RNA eQTL are driven by different genetic mechanisms
Authors: Sakaue Saori ,   Accelerating Medicines Partnership®: RA/SLE Network, Raychaudhuri Soumya
Published: February 2025

Understanding the genetic regulation of RNA abundance is essential to defining disease mechanisms. However, conventional expression quantitative loci (eQTL) studies quantify RNA molecules across the transcript lifecycle. While most eQTL likely affect transcription by altering promoter or enhancer function within the nucleus, it is also possible that they modulate any processes after transcription, including chemical modifications and RNA stability in the cytosol. To elucidate distinct eQTL mechanisms of early versus late RNA, we compared eQTL from mature cellular RNA and nascent nuclear RNA in the brain and the kidney. Across tissues, we identified different causal variants for cellular and nuclear eQTL for the sameeGene. Cellular eQTL were enriched in transcribed regions (P=3.3×10-126), suggesting the importance of post-transcriptional regulation. Conversely, nuclear eQTL were enriched in distal regulatory elements (P=7.0×10-32), highlighting the role of DNA transcriptional regulation. For example, we identified stop-gain eQTL variants likely acting through nonsense-mediated decay in cellular eQTL that had no effect in nuclear eQTL. Cellular eQTL were enriched for loci with multiple causal variants in linkage disequilibrium within the transcribed regions, where they may in concert affect RNA stability. We also identified examples of nuclear eQTL variants within enhancers that had no effect in cellular eQTL. We show that such eQTL (e.g.,TUBGCP4) sometimes uniquely colocalize with disease alleles (schizophrenia). This study reveals key differences in the genetic mechanisms of cellular and nuclear eQTL.
Sericanthe etugeiandS. onanae(Coffeeae Rubiaceae) new cloud forest tree species Endangered in Southwest Cameroon & Bioko (Equatorial Guinea)
Authors: Cheek Martin , Onana Jean Michel , Sonké Bonaventure
Published: February 2025

Two new species of cloudforest tree are described and illustrated from the Cross-Sanaga Interval within the Lower Guinea Domain.Sericanthe etugeiCheek from South West and Littoral Regions of Cameroon is species from the Cameroon Highlands, andSericanthe onanaeCheek from South West Region, Cameroon, and Bioko (Equatorial Guinea).

Sericanthe etugeiis similar toSericanthe leonardii(N. Hallé) Robbr. of DRC (Kivu) and Rwanda, differing in the stipular awn 0.25 mm long (vs 1 – 4 mm), the adaxial leaf midrib and secondary nerves glabrous (vs hairy), the tertiary nerves conspicuously scalariform with the naked eye (vs not visible). The species is also similar toSericanthe testuivar.testui,differing in being a tree (vs liana), with stems not decorticating (vs decorticating), the calyx truncate in bud (vs closed) and in the pubescent ovary (vs glabrous).

Sericanthe onanaeis similar toS. mpassaSonké & Robbr. of lowland forest in Gabon, differing from that species in that the leaves have an acumen (0.5 – )0.7 – 0.8(– 1.2) cm long vs 0.3 – 0.5 cm, secondary nerves are 7 – 10 (– 12) on each side of the midrib (vs 4 – 6 inS. mpassa), and that the stipules are 5 – 6.5( – 7) × 3 – 5(– 6) mm ( vs 2.5 mm long) and truncate (vs overtopped by an awn c. 1 mm long). It is also similar toS. jacfelicis(N. Halle) Robbr., differing in that the leaves are smaller (<15 cm long vs 16 – 20 cm long), the abaxial surface of the leaf blade has 7 – 10( –12) lateral nerves on each side of the midrib (vs 5 –7) and has a glossy surface and papery texture (vs matt, coriaceous), the petioles are hairy (vs glabrous), the stipules are 5 – 6.5( – 7) mm long, truncate, lacking an awn or arista, (vs 3 –4 mm long, with an arista 0.5 – 1 mm long). These two new species are both provisionally assessed as Endangered EN B2ab(iii) with the 2012 IUCN standard.

The new species are briefly discussed in the context of other newly discovered submontane species from the Cross-Sanaga Interval. We speculate that the seeds of these species may be primate-dispersed.
Super Quantum Neuroelectromagnetic Dynamics of Action and Percept Potentials
Authors: Kanjua Jolly
Published: February 2025

The spatiotemporal selectivity of neurons to sensory stimuli that underlie the center and surround receptive fields represents the anticommutative and, thus, symmetry that defines sensorimotor transformation. However, owing to the nonabelian nature of the irresponsiveness of neurons to sensory stimuli characterized by inexcitations, symmetry and, thus, transformation does not become apparent. Hence, a neuroscientific model that describes the precise mechanism of the nonabelian gauge group in the brain is unknown. Using quantum field theory, we show visuomotor transformation of natural images in which the superposition of opposite parallel cortical columns creates visual fields and annihilates motor fields. The creation and annihilation operators, magnetic and electric charged particles, are opposed inertia systems that act on each other by raising and lowering each other’s particles, leading to momentum–energy trade-offs, in our case, retinotopic gain and retinomotion loss, and vice versa. The magnetic charged particlesK−,Cl+,Na−, intrinsic to a magnetic neuron, nabla, are predicted to exist opposite parallel to the electrically charged particlesNa+,Cl−,K+of the electrical pyramidal neuron in the neocortex. The implication is that the physical neocortex or electric brain is in concert with a nonphysical complex neocortex or magnetic brain that is hardly detectable but much alive and proactive.
Caging-group-free photoactivatable fluorophores with far-red emission
Authors: Lincoln Richard , Butkevich Alexey N , Gürth Clara-Marie , Fischer Alena , Emmerich Anna R , Fidlin Maximilian , Bossi Mariano L , Hell Stefan W
Published: February 2025

State of the art super-resolution microscopy methods profit greatly when combined with photoactivatable or photoswitchable fluorophores with far-red emission, but the majority of these fluorophores require specialized buffers or rely on photolabile protecting groups that limit their biocompatibility. We report here a caging-group-free strategy for photoactivatable dyes based on 1-vinyl-10-silaxanthone derivatives containing 9-acylimino or 9-(alkoxycarbonyl)imino groups, enabling minimally-sized photoactivatable dyes with >680 nm emission. The 9-(alkoxycarbonyl)imino silaxanthones are particularly suitable for live-cell labelling, undergoing byproduct-free photoactivation to yield bright and photostable fluorophores that can be readily imaged by STED, PALM, or MINFLUX nanoscopy techniques. The labels derived from these photoactivatable dyes open up new possibilities for multiplexed imaging.