bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting ARNT attenuates chemoresistance through destabilizing p38α-MAPK signaling in glioblastoma
Authors: Alafate Wahafu , Lv Gen , Zheng Jiantao , Cai Haiping , Wu Wei , Yang Yong , Du Shichao , Zhou Dong , Wang Peng 
Published: May 2024

AbstractGlioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.
ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy
Authors: Dong Nguyen Quan , Ehlers Justis P. , Boyer David S. , Jin Xidong , Giani Andrea , Ehrlich Michael S. ,   On behalf of the ROBIN study investigators, Brucker Alexander , Hu Allen , Fawzi Amani , Antoszyk Andrew , Berger Brian , Jhaveri Chirag , Bailey Claire , Brown David , Kunimoto Derek , Ghanchi Faruque , Bandello Francesco , Menon Geeta , Sen Harsha , Talks James , Figueira João , Barranco Jose Juan Escobar , Donate Lopez Juan , Habib Maged , Erke Maja Gran , Weger Martin , Cunningham Matthew , Varano Monica , Manjunatha Nonavinakere , Hahn Paul , Calvo Pilar , Dugel Pravin , Maturi Raj , Rosen Richard , Silva Rufino , Pagliarini Sergio , Sivaprasad Sobha , Androudi Sofia , Patel Sunil ,   Vall d’Hebron University Hospital,   CHLC - Hospital Santo António dos Capuchos
Published: May 2024

Abstract
Objective
To evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR).

Methods
ROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks.

Results
Seventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group.

Conclusions
BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.
Pretreatment-free SERS sensing of microplastics using a self-attention-based neural network on hierarchically porous Ag foams
Authors: Guselnikova Olga , Trelin Andrii , Kang Yunqing , Postnikov Pavel , Kobashi Makoto , Suzuki Asuka , Shrestha Lok Kumar , Henzie Joel , Yamauchi Yusuke 
Published: May 2024

AbstractLow-cost detection systems are needed for the identification of microplastics (MPs) in environmental samples. However, their rapid identification is hindered by the need for complex isolation and pre-treatment methods. This study describes a comprehensive sensing platform to identify MPs in environmental samples without requiring independent separation or pre-treatment protocols. It leverages the physicochemical properties of macroporous-mesoporous silver (Ag) substrates templated with self-assembled polymeric micelles to concurrently separate and analyze multiple MP targets using surface-enhanced Raman spectroscopy (SERS). The hydrophobic layer on Ag aids in stabilizing the nanostructures in the environment and mitigates biofouling. To monitor complex samples with multiple MPs and to demultiplex numerous overlapping patterns, we develop a neural network (NN) algorithm called SpecATNet that employs a self-attention mechanism to resolve the complex dependencies and patterns in SERS data to identify six common types of MPs: polystyrene, polyethylene, polymethylmethacrylate, polytetrafluoroethylene, nylon, and polyethylene terephthalate. SpecATNet uses multi-label classification to analyze multi-component mixtures even in the presence of various interference agents. The combination of macroporous-mesoporous Ag substrates and self-attention-based NN technology holds potential to enable field monitoring of MPs by generating rich datasets that machines can interpret and analyze.
Gut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Authors: Mohr Alex E. , Sweazea Karen L. , Bowes Devin A. , Jasbi Paniz , Whisner Corrie M. , Sears Dorothy D. , Krajmalnik-Brown Rosa , Jin Yan , Gu Haiwei , Klein-Seetharaman Judith , Arciero Karen M. , Gumpricht Eric , Arciero Paul J. 
Published: May 2024

AbstractThe gut microbiome (GM) modulates body weight/composition and gastrointestinal functioning; therefore, approaches targeting resident gut microbes have attracted considerable interest. Intermittent fasting (IF) and protein pacing (P) regimens are effective in facilitating weight loss (WL) and enhancing body composition. However, the interrelationships between IF- and P-induced WL and the GM are unknown. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks. Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P (p < 0.05), whereas metabolites associated with a longevity-related metabolic pathway increase with CR (p < 0.05). Differences indicate GM and metabolomic factors play a role in WL maintenance and body composition. This novel work provides insight into the GM and metabolomic profile of participants following an IF-P or CR diet and highlights important differences in microbial assembly associated with WL and body composition responsiveness. These data may inform future GM-focused precision nutrition recommendations using larger sample sizes of longer duration. Trial registration, March 6, 2020 (ClinicalTrials.gov as NCT04327141), based on a previous randomized intervention trial.
Human movement and environmental barriers shape the emergence of dengue
Authors: Harish Vinyas , Colón-González Felipe J. , Moreira Filipe R. R. , Gibb Rory , Kraemer Moritz U. G. , Davis Megan , Reiner Robert C. , Pigott David M. , Perkins T. Alex , Weiss Daniel J. , Bogoch Isaac I. , Vazquez-Prokopec Gonzalo , Saide Pablo Manrique , Barbosa Gerson L. , Sabino Ester C. , Khan Kamran , Faria Nuno R. , Hay Simon I. , Correa-Morales Fabián , Chiaravalloti-Neto Francisco , Brady Oliver J. 
Published: May 2024

AbstractUnderstanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.
TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene
Authors: Kabirova Evelyn , Ryzhkova Anastasiya , Lukyanchikova Varvara , Khabarova Anna , Korablev Alexey , Shnaider Tatyana , Nuriddinov Miroslav , Belokopytova Polina , Smirnov Alexander , Khotskin Nikita V. , Kontsevaya Galina , Serova Irina , Battulin Nariman 
Published: May 2024

AbstractTopologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation — a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.
Regiodivergent biosynthesis of bridged bicyclononanes
Authors: Ernst Lukas , Lyu Hui , Liu Pi , Paetz Christian , Sayed Hesham M. B. , Meents Tomke , Ma Hongwu , Beerhues Ludger , El-Awaad Islam , Liu Benye 
Published: May 2024

AbstractMedicinal compounds from plants include bicyclo[3.3.1]nonane derivatives, the majority of which are polycyclic polyprenylated acylphloroglucinols (PPAPs). Prototype molecules are hyperforin, the antidepressant constituent of St. John’s wort, and garcinol, a potential anticancer compound. Their complex structures have inspired innovative chemical syntheses, however, their biosynthesis in plants is still enigmatic. PPAPs are divided into two subclasses, named type A and B. Here we identify both types in Hypericum sampsonii plants and isolate two enzymes that regiodivergently convert a common precursor to pivotal type A and B products. Molecular modelling and substrate docking studies reveal inverted substrate binding modes in the two active site cavities. We identify amino acids that stabilize these alternative binding scenarios and use reciprocal mutagenesis to interconvert the enzymatic activities. Our studies elucidate the unique biochemistry that yields type A and B bicyclo[3.3.1]nonane cores in plants, thereby providing key building blocks for biotechnological efforts to sustainably produce these complex compounds for preclinical development.
SARS-CoV-2-specific immune responses converge in kidney disease patients and controls with hybrid immunity
Authors: Aguilar-Bretones Muriel , den Hartog Yvette , van Dijk Laura L. A. , Malahe S. Reshwan K. , Dieterich Marjolein , Mora Héctor Tejeda , Mueller Yvonne M. , Koopmans Marion P. G. , Reinders Marlies E. J. , Baan Carla C. , van Nierop Gijsbert P. , de Vries Rory D. ,   RECOVAC Consortium, Abrahams Alferso C. , Baas Marije C. , Hemmelder Marc H. , Bouwmans Pim , ten Dam Marc A. G. J. , Gommers Lennert , de Vries Aiko P. J. 
Published: May 2024

AbstractHealthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens.
Mycobacterium tuberculosis produces d-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice
Authors: Cheng Hongyu , Ji Zhe , Wang Yang , Li Shenzhi , Tang Tianqi , Wang Fei , Peng Cheng , Wu Xiangyang , Cheng Yuanna , Liu Zhonghua , Ma Mingtong , Wang Jie , Huang Xiaochen , Wang Lin , Qin Lianhua , Liu Haipeng , Chen Jianxia , Zheng Ruijuan , Feng Carl G. , Cai Xia , Qu Di , Ye Lilin , Yang Hua , Ge Baoxue 
Published: May 2024

AbstractAdaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce d-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, d-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, d-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.
Long non-coding RNAs expression and regulation across different brain regions in primates
Authors: Navandar Mohit , Vennin Constance , Lutz Beat , Gerber Susanne 
Published: May 2024

AbstractHuman and non-human primates have strikingly similar genomes, but they strongly differ in many brain-based processes (e.g., behaviour and cognition). While the functions of protein-coding genes have been extensively studied, rather little is known about the role of non-coding RNAs such as long non-coding RNAs (lncRNAs). Here, we predicted lncRNAs and analysed their expression pattern across different brain regions of human and non-human primates (chimpanzee, gorilla, and gibbon). Our analysis identified shared orthologous and non-orthologous lncRNAs, showing striking differences in the genomic features. Differential expression analysis of the shared orthologous lncRNAs from humans and chimpanzees revealed distinct expression patterns in subcortical regions (striatum, hippocampus) and neocortical areas while retaining a homogeneous expression in the cerebellum. Co-expression analysis of lncRNAs and protein-coding genes revealed massive proportions of co-expressed pairs in neocortical regions of humans compared to chimpanzees. Network analysis of co-expressed pairs revealed the distinctive role of the hub-acting orthologous lncRNAs in a region- and species-specific manner. Overall, our study provides novel insight into lncRNA driven gene regulatory landscape, neural regulation, brain evolution, and constitutes a resource for primate’s brain lncRNAs.
EpCAM-CD24+ circulating cells associated with poor prognosis in breast cancer patients
Authors: Perelmuter V. M. , Grigoryeva E. S. , Savelieva O. E. , Alifanov V. V. , Andruhova E. S. , Zavyalova M. V. , Bragina O. D. , Garbukov E. Yu. , Menyailo M. E. , Khozyainova A. A. , Denisov E. V. , Cherdyntseva N. V. , Tashireva L. A. 
Published: May 2024

AbstractFollowing the discovery of circulating tumor cells (CTCs) in the peripheral blood of cancer patients, CTCs were initially postulated to hold promise as a valuable prognostic tool through liquid biopsy. However, a decade and a half of accumulated data have revealed significant complexities in the investigation of CTCs. A challenging aspect lies in the reduced expression or complete loss of key epithelial markers during the epithelial-mesenchymal transition (EMT). This likely hampers the identification of a pathogenetically significant subset of CTCs. Nevertheless, there is a growing body of evidence regarding the prognostic value of such molecules as CD24 expressing in the primary breast tumor. Herewith, the exact relevance of CD24 expression on CTCs remains unclear. We used two epithelial markers (EpCAM and cytokeratin 7/8) to assess the count of CTCs in 57 breast cancer patients, both with (M0mts) and without metastasis (M0) during the follow-up period, as well as in M1 breast cancer patients. However, the investigation of these epithelial markers proved ineffective in identifying cell population expressing different combinations of EpCAM and cytokeratin 7/8 with prognostic significance for breast cancer metastases. Surprisingly, we found CD24+ circulating cells (CCs) in peripheral blood of breast cancer patients which have no epithelial markers (EpCAM and cytokeratin 7/8) but was strongly associated with distant metastasis. Namely, the count of CD45-EpCAM-CK7/8-CD24+ N-cadherin—CCs was elevated in both groups of patients, those with existing metastasis and those who developed metastases during the follow-up period. Simultaneously, an elevation in these cell counts beyond the established threshold of 218.3 cells per 1 mL of blood in patients prior to any treatment predicted a 12-fold risk of metastases, along with a threefold decrease in distant metastasis-free survival over a 90-month follow-up period. The origin of CD45-EpCAM-CK7/8-CD24+ N-cadherin—CCs remains unclear. In our opinion their existence can be explained by two most probable hypotheses. These cells could exhibit a terminal EMT phenotype, or it might be immature cells originating from the bone marrow. Nonetheless, if this hypothesis holds true, it's worth noting that the mentioned CCs do not align with any of the recognized stages of monocyte or neutrophil maturation, primarily due to the presence of CD45 expression in the myeloid cells. The results suggest the presence in the peripheral blood of patients with metastasis (both during the follow-up period and prior to inclusion in the study) of a cell population with a currently unspecified origin, possibly arising from both myeloid and tumor sources, as confirmed by the presence of aneuploidy.
A forensic genetic investigation reveals a captive origin for a wild alien population of raccoons in Italy
Authors: Garofalo Luisa , Cappai Nadia , Mencucci Marco , Mori Emiliano , Attili Lorenzo , Lorenzini Rita 
Published: May 2024

AbstractInvasive alien species have extensively impacted the ecosystems, where they may affect the native biodiversity. The North American raccoon Procyon lotor is one of the most successful invaders in Europe since its introduction in the early twentieth century. In Italy, a wild population was first established in the North at the beginning of the 2000s following a local introduction event. A further self-sustaining population was reported ten years later in Central Italy. To support an official investigation by the authorities, who suspected a captive origin of the free-ranging raccoons in Central Italy, we used nuclear and mitochondrial DNA markers, combined with different statistical approaches, to characterise their gene pool and trace the source of the founders. Results revealed that founders came from a private zoo-park from which they had inadvertently escaped, soon establishing a reproductive population in the wild. Additionally, our mitochondrial DNA data were used to supplement the haplotype variability known to date in captive and wild raccoons from Europe, Asia and their native range. The comparisons allowed us to update previous networks based on the control region with a new mitochondrial lineage, which had not been detected so far.