bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consequences of Continental Core Complexes on Rifting Patterns: Insights From Multichannel Seismic Data From the Northern Margin of the South China Sea
Authors: Xu Yancheng , Ren Jianye , Zhao Yanghui , Zheng Jinyun , Lei Chao , Zhu Dingwei 
Published: April 2024

AbstractCore complex type structures are common in continental margins. Recent studies have proposed exhumation of deeper crustal and mantle levels during extension of the continental margin along the Northern South China Sea (NSCS) in a core complex mode. Here, we present high‐resolution seismic profiles across different sections of the NSCS that allow us to observe two types of core complex systems. The Kaiping Rift and eastern Baiyun Rift are characterized by a sub‐horizontal Moho and exhumation of ductile deeper crust beneath an extremely thinned brittle upper crust. The central Baiyun Rift in contrast is marked by homogeneous thinning of the entire crust that is floored by mantle unroofing with a concave‐down Moho geometry. While the former type, referred to as crustal core complexes, coincides with relatively intense syn‐rift magmatism, the latter, referred to as mantle core complexes, is marked by limited magmatism. Consistently, basin subsidence rates are lower over crustal core complexes than mantle core complexes. Compared to mantle core complexes at the magma‐poor Iberian margin, the widely distributed crustal core complexes in the NSCS indicate higher geotherms and more intense magmatism during extension of the continental lithosphere. We propose that the continental core complexes observed at the NSCS represent a typical outcome of extension of a gravitationally unstable lithosphere.
Glacier Retreat in Eastern Himalaya Drives Catastrophic Glacier Hazard Chain
Authors: Li Yao , Cui Yifei , Hu Xie , Lu Zhong , Guo Jian , Wang Yu , Wang Hao , Wang Shuofan , Zhou Xinzhi 
Published: April 2024

AbstractCryospheric responses to climate warming include glacier retreat, altitude‐dependent thermal instability, and abundant meltwater, which increase the frequency of catastrophic glacier hazard chain (CGHC) events. Here we investigated the formation mechanism of a special CGHC event in 2018, in the Sedongpu Glacier, Eastern Himalayas, China. Based on the multi‐source remote sensing, seismic signal analysis, and numerical simulation, we conducted long‐term retrospective analysis and co‐event process reconstruction. The results show that the event could be divided into two phases. First, the hanging glacier with a volume of 8.5 × 106 m3 collapsed onto the downstream trunk glacier. Next, ∼1.17 × 108 m3 eroded materials from the impacted glacier transformed into debris flow and traveled downstream 8 km. During the cascading process, ice‐rock avalanche momentum and glacier velocity are key factors in determining CGHC formation and eventual volume. Our study helps better understand the domino effects of the CGHC disaster.
Continental Crust Rejuvenation Across the Paleo‐Mesoarchean Transition Resulted From Elevated Mantle Geotherms
Authors: Lu Gui‐Mei , Xu Yi‐Gang , Wang Wei , Spencer Christopher J. , Huang Guangyu , Roberts Nick M. W. 
Published: April 2024

AbstractThe increase in initial Hf isotopes identified in early Mesoarchean detrital zircon is commonly interpreted as a reflection of the geodynamic transition from stagnant‐lid to mobile‐lid tectonics. However, given the lack of petrogenetic context, interpreting detrital zircon may lead to spurious conclusions. In this contribution, we use zircon U‐Pb‐Hf‐O isotopic and bulk rock compositions of newly identified 3.05–2.9 Ga granitoids from the SW Yangtze Block to posit petrogenesis within an isotopically juvenile magmatic system. A statistical analysis of these data with a global igneous zircon Lu‐Hf isotopic compilation reveals an increase in average initial radiogenic Hf isotopes during the Paleoarchean to Mesoarchean transition. We posit that the Earth's continental crust underwent a global rejuvenation across the Paleo‐Mesoarchean transition. This rejuvenation can be explained by an independently observed increase in mantle temperatures resulting from mantle thermal evolution and does not require a change in tectonic style.
Genome-wide DNA methylation-analysis of blastic plasmacytoid dendritic cell neoplasm identifies distinct molecular features
Authors: Künstner Axel , Schwarting Julian , Witte Hanno M. , Xing Pengwei , Bernard Veronica , Stölting Stephanie , Lohneis Philipp , Janke Florian , Salehi Maede , Chen Xingqi , Kusch Kathrin , Sültmann Holger , Chteinberg Emil , Fischer Anja , Siebert Reiner , von Bubnoff Nikolas , Merz Hartmut , Busch Hauke , Feller Alfred C. , Gebauer Niklas 
Published: April 2024

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.
Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia
Authors: Bell Hayden L. , Blair Helen J. , Jepson Gosling Samantha J. , Galler Martin , Astley Daniel , Moorman Anthony V. , Heidenreich Olaf , Veal Gareth J. , van Delft Frederik W. , Lunec John , Irving Julie A. E. 
Published: April 2024

AbstractDue to the rarity of TP53 mutations in acute lymphoblastic leukemia (ALL), p53 re-activation by antagonism of the p53-MDM2 interaction represents a potential therapeutic strategy for the majority of ALL. Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy. Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal to prognostically-poor, primary-derived and primary patient blasts in ex vivo coculture, and reduced leukemia burden in two very high-risk ALL xenograft models at drug concentrations safely attained in patients; in fact, the navitoclax plasma concentrations were equivalent to those attained in contemporary “low-dose” navitoclax clinical trials. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.
AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects
Authors: Soler-Cedeño Omar , Alton Hannah , Bi Guo-Hua , Linz Emily , Ji Lipin , Makriyannis Alexandros , Xi Zheng-Xiong 
Published: April 2024

AbstractPreclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist with inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As a result, efforts have shifted towards developing novel neutral CB1R antagonists without an inverse agonist profile for treating substance use disorders. Here, we assessed AM6527, a CB1R neutral antagonist, in addiction animal models. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it under progressive-ratio reinforcement schedules. Additionally, AM6527 dose-dependently inhibited heroin self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and oral sucrose self-administration under a fixed-ratio reinforcement schedule, as well as cocaine- or heroin-triggered reinstatement of drug-seeking behavior in rats. However, chronic AM6527 administration for five consecutive days significantly inhibited heroin self-administration only during the initial two days, indicating tolerance development. Notably, AM6527 did not produce rewarding or aversive effects by itself in classical electrical intracranial self-stimulation and conditioned place preference tests. However, in optical intracranial self-stimulation (oICSS) maintained by optogenetic stimulation of midbrain dopamine neurons in DAT-cre mice, both AM6527 and rimonabant dose-dependently inhibited dopamine-dependent oICSS behavior. Together, these findings suggest that AM6527 effectively reduces drug-taking and seeking behaviors without rimonabant-like adverse effects. Thus, AM6527 warrants further investigation as a potential pharmacotherapy for opioid and cocaine use disorders.
NRF2 activation by cysteine as a survival mechanism for triple-negative breast cancer cells
Authors: Bottoni Laura , Minetti Alberto , Realini Giulia , Pio Elena , Giustarini Daniela , Rossi Ranieri , Rocchio Chiara , Franci Lorenzo , Salvini Laura , Catona Orazio , D’Aurizio Romina , Rasa Mahdi , Giurisato Emanuele , Neri Francesco , Orlandini Maurizio , Chiariello Mario , Galvagni Federico 
Published: April 2024

AbstractTriple-negative breast cancer (TNBC) is a very aggressive and heterogeneous group of tumors. In order to develop effective therapeutic strategies, it is therefore essential to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy. TNBC cells are highly dependent on exogenous cystine, provided by overexpression of the cystine/glutamate antiporter SLC7A11/xCT, to fuel glutathione synthesis and promote an oxidative stress response consistent with their high metabolic demands. Here we show that TNBC cells of the mesenchymal stem-like subtype (MSL) utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to defend against oxidative stress. Mechanistically, we demonstrate that NRF2 activation is mediated by direct cysteinylation of the inhibitor KEAP1. Furthermore, we show that cystine-mediated NRF2 activation induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Remarkably, in survival analysis, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, expression of exogenous OSGIN1, similarly to expression of exogenous NRF2, can prevent cystine depletion-dependent death of MSL TNBC cells. The results suggest that the cystine/NRF2/OSGIN1 axis is a potential target for effective treatment of MSL TNBCs.
Robotic technology (ROBERT®) to enhance muscle strength in the hip flexor muscles following spinal cord injury: a feasibility study
Authors: Sørensen S. L. , Poulsen I. , Harvey L. A. , Biering-Sørensen F. , Nielsen J. F. 
Published: April 2024

Abstract
Study design
Feasibility study.

Objective
To determine the feasibility of conducting a large trial designed to determine whether the ROBERT® can be used to increase the strength of the hip flexor muscles after spinal cord injury (SCI). The ROBERT® is a robotic device that provides assisted active movement while supporting the weight of the leg. Focus was on recruitment capability, suitability, and acceptability of the intervention and outcome measure.

Setting
Specialised SCI centre in Denmark.

Methods
All first-time admitted patients were screened to assess participant recruitment capability. Four people with SCI < 3 months tested a protocol consisting of 60 repetitions of hip flexion in supine conducted with the assistance of the ROBERT® three times a week for 4 weeks. Feasibility was assessed based on adherence to the protocol and completion rate and from the participants’ perspectives. Maximal voluntary contraction (MVC) was accessed at baseline and four weeks.

Results
The recruitment rate was 8% (7 months). The four participants completed 44 out of 48 sessions (92%). No adverse events occurred. One physiotherapist was required to set-up and supervise each session. The active exercise time varied from 7.5 to 17 min. The participants found the ROBERT® a good supplement to their usual rehabilitation. We were able to measure MVC in even very weak hip flexor muscles with a dynamometer MicroFET2 fixed to a frame.

Conclusion
The ROBERT® was feasible and acceptable. The participants perceived it as a supplement, not a replacement to usual physiotherapy. However, recruitment to the study was slow.

Trial registration
ClinicalTrials.gov NCT05558254. Registered 28th September 2022.
Higher-order functional brain networks and anterior cingulate glutamate + glutamine (Glx) in antipsychotic-naïve first episode psychosis patients
Authors: Maximo Jose O. , Briend Frederic , Armstrong William P. , Kraguljac Nina V. , Lahti Adrienne C. 
Published: April 2024

AbstractHuman connectome studies have provided abundant data consistent with the hypothesis that functional dysconnectivity is predominant in psychosis spectrum disorders. Converging lines of evidence also suggest an interaction between dorsal anterior cingulate cortex (dACC) cortical glutamate with higher-order functional brain networks (FC) such as the default mode (DMN), dorsal attention (DAN), and executive control networks (ECN) in healthy controls (HC) and this mechanism may be impaired in psychosis. Data from 70 antipsychotic-medication naïve first-episode psychosis (FEP) and 52 HC were analyzed. 3T Proton magnetic resonance spectroscopy (1H-MRS) data were acquired from a voxel in the dACC and assessed correlations (positive FC) and anticorrelations (negative FC) of the DMN, DAN, and ECN. We then performed regressions to assess associations between glutamate + glutamine (Glx) with positive and negative FC of these same networks and compared them between groups. We found alterations in positive and negative FC in all networks (HC > FEP). A relationship between dACC Glx and positive and negative FC was found in both groups, but when comparing these relationships between groups, we found contrasting associations between these variables in FEP patients compared to HC. We demonstrated that both positive and negative FC in three higher-order resting state networks are already altered in antipsychotic-naïve FEP, underscoring the importance of also considering anticorrelations for optimal characterization of large-scale functional brain networks as these represent biological processes as well. Our data also adds to the growing body of evidence supporting the role of dACC cortical Glx as a mechanism underlying alterations in functional brain network connectivity. Overall, the implications for these findings are imperative as this particular mechanism may differ in untreated or chronic psychotic patients; therefore, understanding this mechanism prior to treatment could better inform clinicians.Clinical trial registration: Trajectories of Treatment Response as Window into the Heterogeneity of Psychosis: A Longitudinal Multimodal Imaging Study, NCT03442101. Glutamate, Brain Connectivity and Duration of Untreated Psychosis (DUP), NCT02034253.
Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models
Authors: Arshad Maryam , Azad Abul , Chan Phoebe Yuen Ka , Vigneswara Vasanthy , Feldinger Katharina , Nafi Siti Norasikin Mohd , Laporte-Maguire Eloise , De Santo Carmela , Zuo Jianmin , Shaaban Abeer M. , Kong Anthony 
Published: April 2024

Abstract
Background
Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear.

Methods
We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays.

Results
Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab.

Conclusion
This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.
Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice
Authors: Yang Long , Xu Hao-Ran , Zhang Xuan , Shi Yan , Shi Jia-Xin , Chen Qian-Qian , Shen Xiao-Rong , He Ya-Ping , Tang Jia-Nan , Gu Wen-Wen , Wang Jian 
Published: April 2024

AbstractDecidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1β, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.
Prevalence of presenting bilateral visual impairment associated with refractive error – findings from the See4School, pre-school vision screening programme in NHS Scotland
Authors: Pentland Lee , Conway Miriam Louise 
Published: April 2024

Abstract
Background/objectives
The See4School programme in Scotland is a pre-school vision screening initiative delivered by orthoptists on a national scale. The primary objective of any vision screening programme is to identify amblyopia, given the common understanding that this condition is unlikely to be detected either at home or through conventional healthcare channels. The target condition is not bilateral visual impairment, as it is believed that most children will be identified within the first year of life either through observations at home or as part of the diagnosis of another related disorder. This belief persists even though bilateral visual impairment is likely to have a more detrimental impact on a child’s day-to-day life, including their education. If this hypothesis were accurate, the occurrence of bilateral visual impairment detected through the Scottish vision screening programme would be minimal as children already under the hospital eye service are not invited for testing. The overarching aim of this study was therefore to determine the prevalence of presenting bilateral visual impairment associated with refractive error detected via the Scottish preschool screening programme.

Subjects/methods
Retrospective anonymised data from vision screening referrals in Scotland from 2013–2016 were collected. Children underwent an assessment using a crowded logMAR vision test and a small number of orthoptic tests.

Results
During the 3-year period, out of 165,489 eligible children, 141,237 (85.35%) received the vision screening assessment. Among them, 27,010 (19.12%) failed at least one part of the screening and were subsequently referred into the diagnostic pathway, where they received a full sight test. The prevalence of bilateral visual impairment associated with refractive error and detected via the vision screening programme (≥ 0.3LogMAR) was reported to range between 1.47% (1.37–1.59) and 2.42% (2.29–2.57).

Conclusions
It is estimated that up to 2.42% (2.29–2.57) of children living Scotland have poorer than driving standard of vision (6/12) in their pre-school year, primarily due to undetected refractive error. Reduced vision has the potential to impact a child’s their day-to-day life including their future educational, health and social outcomes.