bluuebunny/crossref_metadata_2025_split huggingface dataset:
Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology
Authors: Yang Jingjing , Griffin Anthony , Qiang Zhe , Ren Jie 
Published: November 2022

AbstractCancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.
Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway
Authors: Süß Sandra T. , Olbricht Linda M. , Herlitze Stefan , Spoida Katharina 
Published: November 2022

AbstractSerotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD). Although in recent years, a considerable amount of evidence supports 5-HT2CRs facilitating effect on anxiety behavior, the involvement in learned fear responses and fear extinction is rather unexplored. Here, we used a 5-HT2CR knock-out mouse line (2CKO) to gain new insights into the involvement of 5-HT2CRs in the neuronal fear circuitry. Using a cued fear conditioning paradigm, our results revealed that global loss of 5-HT2CRs exclusively accelerates fear extinction, without affecting fear acquisition and fear expression. To investigate the neuronal substrates underlying the extinction enhancing effect, we mapped the immediate-early gene product cFos, a marker for neuronal activity, in the dorsal raphe nucleus (DRN), amygdala and bed nucleus of the stria terminalis (BNST). Surprisingly, besides extinction-associated changes, our results revealed alterations in neuronal activity even under basal home cage conditions in specific subregions of the DRN and the BNST in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in an extinction-supporting direction due to 5-HT2CR knock-out. Finally, the assessment of DRN-BNST connectivity using antero- and retrograde tracing techniques uncovered a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (DRC) to the anterodorsal portion of the BNST (BNSTad). This serotonergic DRC-BNSTad pathway showed increased neuronal activity in 2CKO mice. Thus, our results provide new insights for the fear extinction network by revealing a specific serotonergic DRC-BNSTad pathway underlying a 5-HT2CR-sensitive mechanism with high significance in the treatment of PTSD.
Folate receptor alpha in ovarian cancer tissue and patient serum is associated with disease burden and treatment outcomes
Authors: Bax Heather J. , Chauhan Jitesh , Stavraka Chara , Santaolalla Aida , Osborn Gabriel , Khiabany Atousa , Grandits Melanie , López-Abente Jacobo , Palhares Lais C. G. F. , Chan Wah Hak Charleen , Robinson Alexandra , Pope Amy , Woodman Natalie , Naceur-Lombardelli Cristina , Malas Sadek , Coumbe Jack E. M. , Nakamura Mano , Laddach Roman , Mele Silvia , Crescioli Silvia , Black Anna M. , Lombardi Sara , Canevari Silvana , Figini Mariangela , Sayasneh Ahmad , Tsoka Sophia , FitzGerald Kevin , Gillett Cheryl , Pinder Sarah , Van Hemelrijck Mieke , Kristeleit Rebecca , Ghosh Sharmistha , Montes Ana , Spicer James , Karagiannis Sophia N. , Josephs Debra H. 
Published: November 2022

Abstract
Background
Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker.

Methods
We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay.

Results
Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses.

Conclusions
sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.
UK Biobank: a globally important resource for cancer research
Authors: Conroy Megan C. , Lacey Ben , Bešević Jelena , Omiyale Wemimo , Feng Qi , Effingham Mark , Sellers Jonathan , Sheard Simon , Pancholi Mahesh , Gregory Gareth , Busby John , Collins Rory , Allen Naomi E. 
Published: November 2022

AbstractUK Biobank is a large-scale prospective study with deep phenotyping and genomic data. Its open-access policy allows researchers worldwide, from academia or industry, to perform health research in the public interest. Between 2006 and 2010, the study recruited 502,000 adults aged 40–69 years from the general population of the United Kingdom. At enrolment, participants provided information on a wide range of factors, physical measurements were taken, and biological samples (blood, urine and saliva) were collected for long-term storage. Participants have now been followed up for over a decade with more than 52,000 incident cancer cases recorded. The study continues to be enhanced with repeat assessments, web-based questionnaires, multi-modal imaging, and conversion of the stored biological samples to genomic and other ‘–omic’ data. The study has already demonstrated its value in enabling research into the determinants of cancer, and future planned enhancements will make the resource even more valuable to cancer researchers. Over 26,000 researchers worldwide are currently using the data, performing a wide range of cancer research. UK Biobank is uniquely placed to transform our understanding of the causes of cancer development and progression, and drive improvements in cancer treatment and prevention over the coming decades.
Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice
Authors: Farini A. , Tripodi L. , Villa C. , Napolitano F. , Strati F. , Molinaro D. , Facciotti F. , Cassani B. , Torrente Y. 
Published: November 2022

AbstractMuscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.
Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities
Authors: Yamada Yosuke , Belharazem-Vitacolonnna Djeda , Bohnenberger Hanibal , Weiß Christel , Matsui Naoko , Kriegsmann Mark , Kriegsmann Katharina , Sinn Peter , Simon-Keller Katja , Hamilton Gerhard , Graeter Thomas , Preissler Gerhard , Ott German , Schölch Sebastian , Nakajima Naoki , Yoshizawa Akihiko , Haga Hironori , Date Hiroshi , Thomas Roman K. , Petrini Iacopo , Giaccone Giuseppe , Ströbel Philipp , Marx Alexander 
Published: November 2022

AbstractTuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.
Onboard early detection and mitigation of lithium plating in fast-charging batteries
Authors: Huang Wenxiao , Ye Yusheng , Chen Hao , Vilá Rafael A. , Xiang Andrew , Wang Hongxia , Liu Fang , Yu Zhiao , Xu Jinwei , Zhang Zewen , Xu Rong , Wu Yecun , Chou Lien-Yang , Wang Hansen , Xu Junwei , Boyle David Tomas , Li Yuzhang , Cui Yi 
Published: November 2022

AbstractFast-charging is considered as one of the most desired features needed for lithium-ion batteries to accelerate the mainstream adoption of electric vehicles. However, current battery charging protocols mainly consist of conservative rate steps to avoid potential hazardous lithium plating and its associated parasitic reactions. A highly sensitive onboard detection method could enable battery fast-charging without reaching the lithium plating regime. Here, we demonstrate a novel differential pressure sensing method to precisely detect the lithium plating event. By measuring the real-time change of cell pressure per unit of charge (dP/dQ) and comparing it with the threshold defined by the maximum of dP/dQ during lithium-ion intercalation into the negative electrode, the onset of lithium plating before its extensive growth can be detected with high precision. In addition, we show that by integrating this differential pressure sensing into the battery management system (BMS), a dynamic self-regulated charging protocol can be realized to effectively extinguish the lithium plating triggered by low temperature (0 °C) while the conventional static charging protocol leads to catastrophic lithium plating at the same condition. We propose that differential pressure sensing could serve as an early nondestructive diagnosis method to guide the development of fast-charging battery technologies.
Multi-omics signatures of the human early life exposome
Authors: Maitre Léa , Bustamante Mariona , Hernández-Ferrer Carles , Thiel Denise , Lau Chung-Ho E. , Siskos Alexandros P. , Vives-Usano Marta , Ruiz-Arenas Carlos , Pelegrí-Sisó Dolors , Robinson Oliver , Mason Dan , Wright John , Cadiou Solène , Slama Rémy , Heude Barbara , Casas Maribel , Sunyer Jordi , Papadopoulou Eleni Z. , Gutzkow Kristine B. , Andrusaityte Sandra , Grazuleviciene Regina , Vafeiadi Marina , Chatzi Leda , Sakhi Amrit K. , Thomsen Cathrine , Tamayo Ibon , Nieuwenhuijsen Mark , Urquiza Jose , Borràs Eva , Sabidó Eduard , Quintela Inés , Carracedo Ángel , Estivill Xavier , Coen Muireann , González Juan R. , Keun Hector C. , Vrijheid Martine 
Published: November 2022

AbstractEnvironmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations (https://helixomics.isglobal.org/) will serve to guide future investigation into the biological imprints of the early life exposome.
Disparate impacts on online information access during the Covid-19 pandemic
Authors: Suh Jina , Horvitz Eric , White Ryen W. , Althoff Tim 
Published: November 2022

AbstractThe COVID-19 pandemic has stimulated important changes in online information access as digital engagement became necessary to meet the demand for health, economic, and educational resources. Our analysis of 55 billion everyday web search interactions during the pandemic across 25,150 US ZIP codes reveals that the extent to which different communities of internet users enlist digital resources varies based on socioeconomic and environmental factors. For example, we find that ZIP codes with lower income intensified their access to health information to a smaller extent than ZIP codes with higher income. We show that ZIP codes with higher proportions of Black or Hispanic residents intensified their access to unemployment resources to a greater extent, while revealing patterns of unemployment site visits unseen by the claims data. Such differences frame important questions on the relationship between differential information search behaviors and the downstream real-world implications on more and less advantaged populations.
Deep learning to decompose macromolecules into independent Markovian domains
Authors: Mardt Andreas , Hempel Tim , Clementi Cecilia , Noé Frank 
Published: November 2022

AbstractThe increasing interest in modeling the dynamics of ever larger proteins has revealed a fundamental problem with models that describe the molecular system as being in a global configuration state. This notion limits our ability to gather sufficient statistics of state probabilities or state-to-state transitions because for large molecular systems the number of metastable states grows exponentially with size. In this manuscript, we approach this challenge by introducing a method that combines our recent progress on independent Markov decomposition (IMD) with VAMPnets, a deep learning approach to Markov modeling. We establish a training objective that quantifies how well a given decomposition of the molecular system into independent subdomains with Markovian dynamics approximates the overall dynamics. By constructing an end-to-end learning framework, the decomposition into such subdomains and their individual Markov state models are simultaneously learned, providing a data-efficient and easily interpretable summary of the complex system dynamics. While learning the dynamical coupling between Markovian subdomains is still an open issue, the present results are a significant step towards learning Ising models of large molecular complexes from simulation data.
Melting of generalized Wigner crystals in transition metal dichalcogenide heterobilayer Moiré systems
Authors: Matty Michael , Kim Eun-Ah 
Published: November 2022

AbstractMoiré superlattice systems such as transition metal dichalcogenide heterobilayers have garnered significant recent interest due to their promising utility as tunable solid state simulators. Recent experiments on a WSe2/WS2 heterobilayer detected incompressible charge ordered states that one can view as generalized Wigner crystals. The tunability of the transition metal dichalcogenide heterobilayer Moiré system presents an opportunity to study the rich set of possible phases upon melting these charge-ordered states. Here we use Monte Carlo simulations to study these intermediate phases in between incompressible charge-ordered states in the strong coupling limit. We find two distinct stripe solid states to be each preceded by distinct types of nematic states. In particular, we discover microscopic mechanisms that stabilize each of the nematic states, whose order parameter transforms as the two-dimensional E representation of the Moiré lattice point group. Our results provide a testable experimental prediction of where both types of nematic occur, and elucidate the microscopic mechanism driving their formation.
Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity
Authors: McEvoy Eoin , Sneh Tal , Moeendarbary Emad , Javanmardi Yousef , Efimova Nadia , Yang Changsong , Marino-Bravante Gloria E. , Chen Xingyu , Escribano Jorge , Spill Fabian , Garcia-Aznar José Manuel , Weeraratna Ashani T. , Svitkina Tatyana M. , Kamm Roger D. , Shenoy Vivek B. 
Published: November 2022

AbstractThe formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.
Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state
Authors: Maiti Atanu , Hedger Adam K. , Myint Wazo , Balachandran Vanivilasini , Watts Jonathan K. , Schiffer Celia A. , Matsuo Hiroshi 
Published: November 2022

AbstractAPOBEC3 proteins (A3s) are enzymes that catalyze the deamination of cytidine to uridine in single-stranded DNA (ssDNA) substrates, thus playing a key role in innate antiviral immunity. However, the APOBEC3 family has also been linked to many mutational signatures in cancer cells, which has led to an intense interest to develop inhibitors of A3’s catalytic activity as therapeutics as well as tools to study A3’s biochemistry, structure, and cellular function. Recent studies have shown that ssDNA containing 2′-deoxy-zebularine (dZ-ssDNA) is an inhibitor of A3s such as A3A, A3B, and A3G, although the atomic determinants of this activity have remained unknown. To fill this knowledge gap, we determined a 1.5 Å resolution structure of a dZ-ssDNA inhibitor bound to active A3G. The crystal structure revealed that the activated dZ-H2O mimics the transition state by coordinating the active site Zn2+ and engaging in additional stabilizing interactions, such as the one with the catalytic residue E259. Therefore, this structure allowed us to capture a snapshot of the A3’s transition state and suggests that developing transition-state mimicking inhibitors may provide a new opportunity to design more targeted molecules for A3s in the future.