bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children’s Oncology Group Report
Authors: DelRocco N. J. , Loh M. L. , Borowitz M. J. , Gupta S. , Rabin K. R. , Zweidler-McKay P. , Maloney K. W. , Mattano L. A. , Larsen E. , Angiolillo A. , Schore R. J. , Burke M. J. , Salzer W. L. , Wood B. L. , Carroll A. J. , Heerema N. A. , Reshmi S. C. , Gastier-Foster J. M. , Harvey R. , Chen I. M. , Roberts K. G. , Mullighan C. G. , Willman C. , Winick N. , Carroll W. L. , Rau R. E. , Teachey D. T. , Hunger S. P. , Raetz E. A. , Devidas M. , Kairalla J. A. 
Published: February 2024

AbstractCurrent strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.
Tau depletion in human neurons mitigates Aβ-driven toxicity
Authors: Ng Bryan , Vowles Jane , Bertherat Féodora , Abey Ajantha , Kilfeather Peter , Beccano-Kelly Dayne , Stefana M. Irina , O’Brien Darragh P. , Bengoa-Vergniory Nora , Carling Phillippa J. , Todd John A. , Caffrey Tara M. , Connor-Robson Natalie , Cowley Sally A. , Wade-Martins Richard 
Published: February 2024

AbstractAlzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt−/− mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Social activity mediates locus coeruleus tangle-related cognition in older adults
Authors: Zide Benjamin S. , Donovan Nancy J. , Lee Soyoung , Nag Sukriti , Bennett David A. , Jacobs Heidi I. L. 
Published: February 2024

AbstractThe locus coeruleus-noradrenaline system regulates brain-wide neural activity involved in cognition and behavior. Integrity of this subcortical neuromodulatory system is proposed to be a substrate of cognitive reserve that may be strengthened by lifetime cognitive and social activity. Conversely, accumulation of tau tangles in the brainstem locus coeruleus nuclei is recently studied as a very early marker of Alzheimer’s disease (AD) pathogenesis and cognitive vulnerability, even among older adults without cognitive impairment or significant cerebral AD pathologies. This clinical-pathologic study examined whether locus coeruleus tangle density was cross-sectionally associated with lower antemortem cognitive performance and social activity among 142 cognitively unimpaired and impaired older adults and whether social activity, a putative reserve factor, mediated the association of tangle density and cognition. We found that greater locus coeruleus tangle density was associated with lower social activity for the whole sample and in the cognitively unimpaired group alone and these associations were independent of age, sex, education, depressive symptoms, and burden of cerebral amyloid and tau. The association of locus coeruleus tangle density with lower cognitive performance was partially mediated by level of social activity. These findings implicate the locus coeruleus-noradrenaline system in late-life social function and support that locus coeruleus tangle pathology is associated with lower levels of social activity, independent of cerebral AD pathologies, and specifically among older adults who are cognitively unimpaired. Early brainstem pathology may impact social function, and level of social function, in turn, influences cognition, prior to canonical stages of AD.
RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases
Authors: Heim Tanya E. , Hankins Margaret L. , Belayneh Rebekah , Douglas Nerone , Dinh Vu , Kovvur Murali , Boone David N. , Ukani Vrutika , Bhogal Sumail , Patel Vaidehi , Moniz Taylor M. A. , Bailey Kelly M. , John Ivy , Schoedel Karen , Weiss Kurt R. , Watters Rebecca J. 
Published: February 2024

AbstractOne-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65–70%, patients with LM experience poor survival rates of only 19–30%. Unacceptably, this situation that has remained unchanged for 30 years. Thus, there is an urgent need to elucidate the mechanisms of metastatic spread in OS and to identify targetable molecular pathways that enable more effective treatments for patients with LM. We aimed to identify OS-specific gene alterations using RNA-sequencing of extremity and LM human tissues. Samples of extremity and LM tumors, including 4 matched sets, were obtained from patients with OS. Our data demonstrate aberrant regulation of the androgen receptor (AR) pathway in LM and predicts aldehyde dehydrogenase 1A1 (ALDH1A1) as a downstream target. Identification of AR pathway upregulation in human LM tissue samples may provide a target for novel therapeutics for patients with LM resistant to conventional chemotherapy.
Loss of macrophage TSC1 exacerbates sterile inflammatory liver injury through inhibiting the AKT/MST1/NRF2 signaling pathway
Authors: Ni Ming , Qiu Jiannan , liu Guoqing , Sun Xiaohu , Zhu Wenjie , Wu Peng , Chen Zheng , Qiu Jiajing , Wu Ziming , Zhang Yang , Zhang Feng , Li Changyong , Gao Yuan , Zhou Jun , Zhu Qiang 
Published: February 2024

AbstractTuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients.
CD24 induced cellular quiescence-like state and chemoresistance in ovarian cancer cells via miR-130a/301a-dependent CDK19 downregulation
Authors: Jang Yeonsue , Kang Suki , Han Hyun Ho , Kim Baek Gil , Cho Nam Hoon 
Published: February 2024

AbstractCancer stem-like cell (CSC) is thought to be responsible for ovarian cancer recurrence. CD24 serves as a CSC marker for ovarian cancer and regulates the expression of miRNAs, which are regulators of CSC phenotypes. Therefore, CD24-regulated miRNAs may play roles in manifesting the CSC phenotypes in ovarian cancer cells. Our miRNA transcriptome analysis showed that 94 miRNAs were up or down-regulated in a CD24-high clone from an ovarian cancer patient compared to a CD24-low one. The CD24-dependent expression trend of the top 7 upregulated miRNAs (miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, 34b*) was confirmed in other 8 clones (4 clones for each group). CD24 overexpression upregulated the expression of miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, and 34b* in TOV112D (CD24-low) cells compared to the control, while CD24 knockdown downregulated the expression of miR-199a-3p, 199a-5p, 130a, 301a, and 34b* in OV90 (CD24-high) cells. miR-130a and 301a targeted CDK19, which induced a cellular quiescence-like state (increased G0/G1 phase cell population, decreased cell proliferation, decreased colony formation, and decreased RNA synthesis) and resistance to platinum-based chemotherapeutic agents. CD24 regulated the expression of miR-130a and 301a via STAT4 and YY1 phosphorylation mediated by Src and FAK. miR-130a and 301a were positively correlated in expression with CD24 in ovarian cancer patient tissues and negatively correlated with CDK19. Our results showed that CD24 expression may induce a cellular quiescence-like state and resistance to platinum-based chemotherapeutic agents in ovarian cancer via miR-130a and 301a upregulation. CD24-miR-130a/301a-CDK19 signaling axis could be a prognostic marker for or a potential therapeutic target against ovarian cancer recurrence.
Melt adsorption of poly(tert-butyl methacrylate) and poly(ethyl methacrylate) on silica studied with chip nanocalorimetry
Authors: Ishihara Minato , Watanabe Tomoya , Hirata Toyoaki , Sasaki Takashi 
Published: February 2024

AbstractIrreversible adsorption of polymer chains from a melt on a substrate surface can be strongly affected by interfacial interactions. In this study, we examined the adsorption of two polymers, poly(tert-butyl methacrylate) (PtBMA) and poly(ethyl methacrylate) (PEMA), on a silica surface at temperatures above their glass transition temperatures. The degree of adsorption γ(t) over time was evaluated with variations of storage heat capacity determined with alternating current chip nanocalorimetry (in-situ measurement of a buried interface). γ(t) revealed two-step profiles for both polymers. At the second stage of adsorption (regime II), the slope of a plot of γ(t) vs. log t increased as adsorption proceeded; this trend has not been reported for other polymers and may be characteristic of the present polymers. The trend observed in regime II suggested that the unadsorbed free chains near the interface became less mobile and were incorporated into the adsorbed layer via interactions with the tails of the chains directly attached to the substrate surface. The increasing slope in regime II was more prominent for PtBMA than for PEMA. In addition, a difference was observed for PtBMA and PEMA in the atomic force microscopy images of the exposed adsorption layer surfaces.
Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway
Authors: McRonald Fiona E. , Pethick Joanna , Santaniello Francesco , Shand Brian , Tyson Adele , Tulloch Oliver , Goel Shilpi , Lüchtenborg Margreet , Borthwick Gillian M. , Turnbull Clare , Shaw Adam C. , Monahan Kevin J. , Frayling Ian M. , Hardy Steven , Burn John 
Published: February 2024

AbstractIt is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years’ data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.
Diversity and evolution of the vertebrate chemoreceptor gene repertoire
Authors: Policarpo Maxime , Baldwin Maude W. , Casane Didier , Salzburger Walter 
Published: February 2024

AbstractChemoreception – the ability to smell and taste – is an essential sensory modality of most animals. The number and type of chemical stimuli that animals can perceive depends primarily on the diversity of chemoreceptors they possess and express. In vertebrates, six families of G protein-coupled receptors form the core of their chemosensory system, the olfactory/pheromone receptor gene families OR, TAAR, V1R and V2R, and the taste receptors T1R and T2R. Here, we study the vertebrate chemoreceptor gene repertoire and its evolutionary history. Through the examination of 1,527 vertebrate genomes, we uncover substantial differences in the number and composition of chemoreceptors across vertebrates. We show that the chemoreceptor gene families are co-evolving, highly dynamic, and characterized by lineage-specific expansions (for example, OR in tetrapods; TAAR, T1R in teleosts; V1R in mammals; V2R, T2R in amphibians) and losses. Overall, amphibians, followed by mammals, are the vertebrate clades with the largest chemoreceptor repertoires. While marine tetrapods feature a convergent reduction of chemoreceptor numbers, the number of OR genes correlates with habitat in mammals and birds and with migratory behavior in birds, and the taste receptor repertoire correlates with diet in mammals and with aquatic environment in fish.
Structured information extraction from scientific text with large language models
Authors: Dagdelen John , Dunn Alexander , Lee Sanghoon , Walker Nicholas , Rosen Andrew S. , Ceder Gerbrand , Persson Kristin A. , Jain Anubhav 
Published: February 2024

AbstractExtracting structured knowledge from scientific text remains a challenging task for machine learning models. Here, we present a simple approach to joint named entity recognition and relation extraction and demonstrate how pretrained large language models (GPT-3, Llama-2) can be fine-tuned to extract useful records of complex scientific knowledge. We test three representative tasks in materials chemistry: linking dopants and host materials, cataloging metal-organic frameworks, and general composition/phase/morphology/application information extraction. Records are extracted from single sentences or entire paragraphs, and the output can be returned as simple English sentences or a more structured format such as a list of JSON objects. This approach represents a simple, accessible, and highly flexible route to obtaining large databases of structured specialized scientific knowledge extracted from research papers.
Tissue-location-specific transcription programs drive tumor dependencies in colon cancer
Authors: Yang Lijing , Tu Lei , Bisht Shilpa , Mao Yiqing , Petkovich Daniel , Thursby Sara-Jayne , Liang Jinxiao , Patel Nibedita , Yen Ray-Whay Chiu , Largent Tina , Zahnow Cynthia , Brock Malcolm , Gabrielson Kathy , Salimian Kevan J. , Baylin Stephen B. , Easwaran Hariharan 
Published: February 2024

AbstractCancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.
PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment
Authors: Darrous Liza , Hemani Gibran , Davey Smith George , Kutalik Zoltán 
Published: February 2024

AbstractMendelian Randomisation (MR) estimates causal effects between risk factors and complex outcomes using genetic instruments. Pleiotropy, heritable confounders, and heterogeneous causal effects violate MR assumptions and can lead to biases. To alleviate these, we propose an approach employing a Phenome-Wide association Clustering of the MR instruments (PWC-MR) and apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU): $$\widehat{\alpha }$$

α

̂

= −0.19 [−0.22, −0.16]. First, we cluster 324 BMI-associated genetic instruments based on their association with 407 traits in the UK Biobank, which yields six distinct groups. Subsequent cluster-specific MR reveals heterogeneous causal effect estimates on EDU. A cluster enriched for socio-economic indicators yields the largest BMI-on-EDU causal effect estimate ($$\widehat{\alpha }$$

α

̂

= −0.49 [−0.56, −0.42]) whereas a cluster enriched for body-mass specific traits provides a more likely estimate ($$\widehat{\alpha }$$

α

̂

= −0.09 [−0.13, −0.05]). Follow-up analyses confirms these findings: within-sibling MR ($$\widehat{\alpha }$$

α

̂

= −0.05 [−0.09, −0.01]); MR for childhood BMI on EDU ($$\widehat{\alpha }$$

α

̂

= −0.03 [−0.06, −0.002]); step-wise multivariable MR ($$\widehat{\alpha }$$

α

̂

= −0.05 [−0.07, −0.02]) where socio-economic indicators are jointly modelled. Here we show how the in-depth examination of the BMI-EDU causal relationship demonstrates the utility of our PWC-MR approach in revealing distinct pleiotropic pathways and confounder mechanisms.
Computational redesign of a hydrolase for nearly complete PET depolymerization at industrially relevant high-solids loading
Authors: Cui Yinglu , Chen Yanchun , Sun Jinyuan , Zhu Tong , Pang Hua , Li Chunli , Geng Wen-Chao , Wu Bian 
Published: February 2024

AbstractBiotechnological plastic recycling has emerged as a suitable option for addressing the pollution crisis. A major breakthrough in the biodegradation of poly(ethylene terephthalate) (PET) is achieved by using a LCC variant, which permits 90% conversion at an industrial level. Despite the achievements, its applications have been hampered by the remaining 10% of nonbiodegradable PET. Herein, we address current challenges by employing a computational strategy to engineer a hydrolase from the bacterium HR29. The redesigned variant, TurboPETase, outperforms other well-known PET hydrolases. Nearly complete depolymerization is accomplished in 8 h at a solids loading of 200 g kg−1. Kinetic and structural analysis suggest that the improved performance may be attributed to a more flexible PET-binding groove that facilitates the targeting of more specific attack sites. Collectively, our results constitute a significant advance in understanding and engineering of industrially applicable polyester hydrolases, and provide guidance for further efforts on other polymer types.