bluuebunny/crossref_metadata_2025_split huggingface dataset:
The potential clinical utility of Whole Genome Sequencing for patients with cancer: evaluation of a regional implementation of the 100,000 Genomes Project
Authors: Leung Elaine Y. L. , Robbins Helen L. , Zaman Shafquat , Lal Neeraj , Morton Dion , Dew Lisa , Williams Anthony P. , Wallis Yvonne , Bell Jennie , Raghavan Manoj , Middleton Gary , Beggs Andrew D. 
Published: October 2024

Abstract
Background
The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom.

Methods
A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results.

Results
After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491).

Conclusions
The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients.
The impact of interfacial quality and nanoscale performance disorder on the stability of alloyed perovskite solar cells
Authors: Frohna Kyle , Chosy Cullen , Al-Ashouri Amran , Scheler Florian , Chiang Yu-Hsien , Dubajic Milos , Parker Julia E. , Walker Jessica M. , Zimmermann Lea , Selby Thomas A. , Lu Yang , Roose Bart , Albrecht Steve , Anaya Miguel , Stranks Samuel D. 
Published: October 2024

Abstract
Microscopy provides a proxy for assessing the operation of perovskite solar cells, yet most works in the literature have focused on bare perovskite thin films, missing charge transport and recombination losses present in full devices. Here we demonstrate a multimodal operando microscopy toolkit to measure and spatially correlate nanoscale charge transport losses, recombination losses and chemical composition. By applying this toolkit to the same scan areas of state-of-the-art, alloyed perovskite cells before and after extended operation, we show that devices with the highest macroscopic performance have the lowest initial performance spatial heterogeneity—a crucial link that is missed in conventional microscopy. We show that engineering stable interfaces is critical to achieving robust devices. Once the interfaces are stabilized, we show that compositional engineering to homogenize charge extraction and to minimize variations in local power conversion efficiency is critical to improve performance and stability. We find that in our device space, perovskites can tolerate spatial disorder in chemistry, but not charge extraction.
Vertical bedrock shifts reveal summer water storage in Greenland ice sheet
Authors: Ran Jiangjun , Ditmar Pavel , van den Broeke Michiel R. , Liu Lin , Klees Roland , Khan Shfaqat Abbas , Moon Twila , Li Jiancheng , Bevis Michael , Zhong Min , Fettweis Xavier , Liu Junguo , Noël Brice , Shum C. K. , Chen Jianli , Jiang Liming , van Dam Tonie 
Published: October 2024

AbstractThe Greenland ice sheet (GrIS) is at present the largest single contributor to global-mass-induced sea-level rise, primarily because of Arctic amplification on an increasingly warmer Earth1–5. However, the processes of englacial water accumulation, storage and ultimate release remain poorly constrained. Here we show that a noticeable amount of the summertime meltwater mass is temporally buffered along the entire GrIS periphery, peaking in July and gradually reducing thereafter. Our results arise from quantifying the spatiotemporal behaviour of the total mass of water leaving the GrIS by analysing bedrock elastic deformation measured by Global Navigation Satellite System (GNSS) stations. The buffered meltwater causes a subsidence of the bedrock close to GNSS stations of at most approximately 5 mm during the melt season. Regionally, the duration of meltwater storage ranges from 4.5 weeks in the southeast to 9 weeks elsewhere. We also show that the meltwater runoff modelled from regional climate models may contain systematic errors, requiring further scaling of up to about 20% for the warmest years. These results reveal a high potential for GNSS data to constrain poorly known hydrological processes in Greenland, forming the basis for improved projections of future GrIS melt behaviour and the associated sea-level rise6.
Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake
Authors: Tan Han L. , Yin Luping , Tan Yuqi , Ivanov Jessica , Plucinska Kaja , Ilanges Anoj , Herb Brian R. , Wang Putianqi , Kosse Christin , Cohen Paul , Lin Dayu , Friedman Jeffrey M. 
Published: October 2024

AbstractLeptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3–5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.
Clonal dynamics after allogeneic haematopoietic cell transplantation
Authors: Spencer Chapman Michael , Wilk C. Matthias , Boettcher Steffen , Mitchell Emily , Dawson Kevin , Williams Nicholas , Müller Jan , Kovtonyuk Larisa , Jung Hyunchul , Caiado Francisco , Roberts Kirsty , O’Neill Laura , Kent David G. , Green Anthony R. , Nangalia Jyoti , Manz Markus G. , Campbell Peter J. 
Published: October 2024

Abstract
Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor1,2. Here, to quantify dynamics of long-term stem cell engraftment, we sequenced genomes from 2,824 single-cell-derived haematopoietic colonies of ten donor–recipient pairs taken 9–31 years after HLA-matched sibling HCT3. With younger donors (18–47 years at transplant), 5,000–30,000 stem cells had engrafted and were still contributing to haematopoiesis at the time of sampling; estimates were tenfold lower with older donors (50–66 years). Engrafted cells made multilineage contributions to myeloid, B lymphoid and T lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to around 10–15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. A transplant-related population bottleneck could not explain these differences; instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In pruning selection, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant—their selective advantage derived from preferential mobilization, collection, survival ex vivo or initial homing. In growth selection, cell divisions underpinning clonal expansion occurred in the recipient’s marrow after engraftment, most pronounced in clones with multiple driver mutations. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.
Progressive plasticity during colorectal cancer metastasis
Authors: Moorman Andrew , Benitez Elizabeth K. , Cambulli Francesco , Jiang Qingwen , Mahmoud Ahmed , Lumish Melissa , Hartner Saskia , Balkaran Sasha , Bermeo Jonathan , Asawa Simran , Firat Canan , Saxena Asha , Wu Fan , Luthra Anisha , Burdziak Cassandra , Xie Yubin , Sgambati Valeria , Luckett Kathleen , Li Yanyun , Yi Zhifan , Masilionis Ignas , Soares Kevin , Pappou Emmanouil , Yaeger Rona , Kingham T. Peter , Jarnagin William , Paty Philip B. , Weiser Martin R. , Mazutis Linas , D’Angelica Michael , Shia Jinru , Garcia-Aguilar Julio , Nawy Tal , Hollmann Travis J. , Chaligné Ronan , Sanchez-Vega Francisco , Sharma Roshan , Pe’er Dana , Ganesh Karuna 
Published: October 2024

Abstract
As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3–5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.
Tissue spaces are reservoirs of antigenic diversity for Trypanosoma brucei
Authors: Beaver Alexander K. , Keneskhanova Zhibek , Cosentino Raúl O. , Weiss Brian L. , Awuoche Erick O. , Smallenberger Gretchen M. , Buenconsejo Gracyn Y. , Crilly Nathan P. , Smith Jaclyn E. , Hakim Jill M. C. , Zhang Bailin , Bobb Bryce , Rijo-Ferreira Filipa , Figueiredo Luisa M. , Aksoy Serap , Siegel T. Nicolai , Mugnier Monica R. 
Published: October 2024

AbstractThe protozoan parasite Trypanosoma brucei evades clearance by the host immune system through antigenic variation of its dense variant surface glycoprotein (VSG) coat, periodically ‘switching’ expression of the VSG using a large genomic repertoire of VSG-encoding genes1–6. Recent studies of antigenic variation in vivo have focused near exclusively on parasites in the bloodstream6–8, but research has shown that many, if not most, parasites reside in the interstitial spaces of tissues9–13. We sought to explore the dynamics of antigenic variation in extravascular parasite populations using VSG-seq7, a high-throughput sequencing approach for profiling VSGs expressed in populations of T. brucei. Here we show that tissues, not the blood, are the primary reservoir of antigenic diversity during both needle- and tsetse bite-initiated T. brucei infections, with more than 75% of VSGs found exclusively within extravascular spaces. We found that this increased diversity is correlated with slower parasite clearance in tissue spaces. Together, these data support a model in which the slower immune response in extravascular spaces provides more time to generate the antigenic diversity needed to maintain a chronic infection. Our findings reveal the important role that extravascular spaces can have in pathogen diversification.
A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features
Authors: Klughammer Johanna , Abravanel Daniel L. , Segerstolpe Åsa , Blosser Timothy R. , Goltsev Yury , Cui Yi , Goodwin Daniel R. , Sinha Anubhav , Ashenberg Orr , Slyper Michal , Vigneau Sébastien , Jané‐Valbuena Judit , Alon Shahar , Caraccio Chiara , Chen Judy , Cohen Ofir , Cullen Nicole , DelloStritto Laura K. , Dionne Danielle , Files Janet , Frangieh Allison , Helvie Karla , Hughes Melissa E. , Inga Stephanie , Kanodia Abhay , Lako Ana , MacKichan Colin , Mages Simon , Moriel Noa , Murray Evan , Napolitano Sara , Nguyen Kyleen , Nitzan Mor , Ortiz Rebecca , Patel Miraj , Pfaff Kathleen L. , Porter Caroline B. M. , Rotem Asaf , Strauss Sarah , Strasser Robert , Thorner Aaron R. , Turner Madison , Wakiro Isaac , Waldman Julia , Wu Jingyi , Gómez Tejeda Zañudo Jorge , Zhang Diane , Lin Nancy U. , Tolaney Sara M. , Winer Eric P. , Boyden Edward S. , Chen Fei , Nolan Garry P. , Rodig Scott J. , Zhuang Xiaowei , Rozenblatt-Rosen Orit , Johnson Bruce E. , Regev Aviv , Wagle Nikhil 
Published: October 2024

AbstractAlthough metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.
Human prolyl hydroxylase domain 2 reacts with O2 and 2-oxoglutarate to enable formation of inactive Fe(III).2OG.hypoxia-inducible-factor α complexes
Authors: Fiorini Giorgia , Marshall Stephen A. , Figg William D. , Myers William K. , Brewitz Lennart , Schofield Christopher J. 
Published: October 2024

AbstractHypoxia inducible transcription factors (HIFs) mediate the hypoxic response in metazoans. When sufficient O2 is present, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases (human PHD1-3) promote HIFα degradation via prolyl-hydroxylation. We report crystallographic, spectroscopic, and biochemical characterization of stable and inactive PHD2.Fe(III).2OG complexes. Aerobic incubation of PHD2 with Fe(II) and 2OG enables formation of PHD2.Fe(III).2OG complexes which bind HIF1-2α to give inactive PHD2.Fe(III).2OG.HIF1-2α complexes. The Fe(III) oxidation state in the inactive complexes was shown by EPR spectroscopy. L-Ascorbate hinders formation of the PHD2.Fe(III).2OG.(+/-HIFα) complexes and slowly regenerates them to give the catalytically active PHD2.Fe(II).2OG complex. Crystallographic comparison of the PHD2.Fe(III).2OG.HIF2α complex with the analogous anaerobic Fe(II) complex reveals near identical structures. Exposure of the anaerobic PHD2.Fe(II).2OG.HIF2α crystals to O2 enables in crystallo hydroxylation. The resulting PHD2.product structure, manifests conformational changes compared to the substrate structures. The results have implications for the role of the PHDs in hypoxia sensing and open new opportunities for inhibition of the PHDs and other 2OG dependent oxygenases by promoting formation of stable Fe(III) complexes.
Exploring the role of different cell types on cortical folding in the developing human brain through computational modeling
Authors: Zarzor Mohammad Saeed , Ma Qiang , Almurey Median , Kainz Bernhard , Budday Silvia 
Published: October 2024

AbstractThe human brain’s distinctive folding pattern has attracted the attention of researchers from different fields. Neuroscientists have provided insights into the role of four fundamental cell types crucial during embryonic development: radial glial cells, intermediate progenitor cells, outer radial glial cells, and neurons. Understanding the mechanisms by which these cell types influence the number of cortical neurons and the emerging cortical folding pattern necessitates accounting for the mechanical forces that drive the cortical folding process. Our research aims to explore the correlation between biological processes and mechanical forces through computational modeling. We introduce cell-density fields, characterized by a system of advection-diffusion equations, designed to replicate the characteristic behaviors of various cell types in the developing brain. Concurrently, we adopt the theory of finite growth to describe cortex expansion driven by increasing cell density. Our model serves as an adjustable tool for understanding how the behavior of individual cell types reflects normal and abnormal folding patterns. Through comparison with magnetic resonance images of the fetal brain, we explore the correlation between morphological changes and underlying cellular mechanisms. Moreover, our model sheds light on the spatiotemporal relationships among different cell types in the human brain and enables cellular deconvolution of histological sections.
Tandem dye-sensitized solar cells achieve 12.89% efficiency using novel organic sensitizers
Authors: Badawy Safa A. , Abdel-Latif Ehab , Elmorsy Mohamed R. 
Published: October 2024

AbstractThis study presents a significant advancement in tandem dye-sensitized solar cells (T-DSSCs) through the strategic synthesis of novel triazatruxene (TAT) sensitizers MS-1 and MS-2. These organic sensitizers demonstrate exceptional light-harvesting capacity and overall performance, pushing the boundaries of power conversion efficiency (PCE) in DSSCs. The MS-1-based DSSCs achieved an impressive PCE of 12.81%, while MS-2 sensitizers reached a notable 10.92%. These efficiencies represent significant improvements over the conventional N719 dye (7.60%), demonstrating the potential of metal-free organic sensitizers in DSSC technology. The key to these noteworthy results lies in the molecular design of the organic sensitizers. The triazatruxene donor segment in the MS-1 and MS-2 dyes, featuring a rigid structure and efficient intramolecular charge transfer (ICT), proved to be a game-changer for photovoltaic properties. Building on these results, we explored an innovative parallel tandem cell (PT-DSSC) configuration. By connecting separate cells containing N719 and MS-1 sensitizers, we achieved a record efficiency of 12.89% with enhanced short-circuit current density (JSC) and open-circuit voltage (VOC)compared to single-dye cells. This study highlights the potential of molecular engineering in organic sensitizers and device optimization to enhance DSSC performance, paving the way for further advancements in solar cell technology.
FCGR3A V158F gene polymorphism and trastuzumab response in HER2-positive breast cancer patients
Authors: Abdel-Wahed Marwa A. , Sabbour Ghada Sadek , Hamed Amira I. , EL Kady Mohammed Sabry , Mohammed Shaimaa Khalil , Shaaban Menat Allah Ali Mahmoud 
Published: October 2024

AbstractBreast cancer is considered a multifactorial disease, with genetic factors playing an important role in diagnosis and treatment. FCGR3A encodes the receptor for the Fc portion of immunoglobulin G that has been linked to the trastuzumab response. Our study aimed to investigate the association of FCGR3A-V158F gene polymorphism with breast cancer and to evaluate the impact of FCGR3A-V158F gene polymorphism on trastuzumab response in HER2-positive breast cancer patients. The study was conducted on eighty breast cancer patients who were collected from the Department of Oncology at Ain Shams University Hospitals; in addition, twenty age-matched healthy subjects were taken as a healthy control group. Patients were further sub-classified according to their responses. The study showed that there were no statistically significant differences between patients and controls regarding FCGR3A-V158F gene polymorphism genotypes. However, there was a significant association between the concordance of this polymorphism and the response to trastuzumab therapy among the patient’s group. V/V is associated with better treatment response and overall survival (OS) compared to F/V and F/F alleles. Assessment of FCGR3A-V158F gene polymorphism might be useful in making a treatment decision in HER2-positive breast cancer patients.
Binaural beats at 0.25 Hz shorten the latency to slow-wave sleep during daytime naps
Authors: Fan Zhiwei , Zhu Yunyao , Suzuki Chihiro , Suzuki Yoko , Watanabe Yumi , Watanabe Takahiro , Abe Takashi 
Published: October 2024

AbstractBinaural beats can entrain neural oscillations and modulate behavioral states. However, the effect of binaural beats, particularly those with slow frequencies (< 1 Hz), on sleep remains poorly understood. We hypothesized that 0.25-Hz beats can entrain neural oscillations and enhance slow-wave sleep by shortening its latency or increasing its duration. To investigate this, we included 12 healthy participants (six women; mean age, 25.4 ± 2.6 years) who underwent four 90-min afternoon nap sessions, comprising a sham condition (without acoustic stimulation) and three binaural-beat conditions (0, 0.25, or 1 Hz) with a 250-Hz carrier tone. The acoustic stimuli, delivered through earphones, were sustained throughout the 90-min nap period. Both N2- and N3- latencies were shorter in the 0.25-Hz binaural beats condition than in the sham condition. We observed no significant results regarding neural entrainment at slow frequencies, such as 0.25 and 1 Hz, and the modulation of sleep oscillations, including delta and sigma activity, by binaural beats. In conclusion, this study demonstrated the potential of binaural beats at slow frequencies, specifically 0.25 Hz, for inducing slow-wave sleep in generally healthy populations.