bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogenous late Miocene extension in the northern Walker Lane (California-Nevada, USA) demonstrates vertically decoupled crustal extension
Authors: Say Michael C. , Zuza Andrew V. 
Published: September 2021

AbstractThe spatial distribution and kinematics of intracontinental deformation provide insight into the dominant mode of continental tectonics: rigid-body motion versus continuum flow. The discrete San Andreas fault defines the western North America plate boundary, but transtensional deformation is distributed hundreds of kilometers eastward across the Walker Lane–Basin and Range provinces. In particular, distributed Basin and Range extension has been encroaching westward onto the relatively stable Sierra Nevada block since the Miocene, but the timing and style of distributed deformation overprinting the stable Sierra Nevada crust remains poorly resolved. Here we bracket the timing, magnitude, and kinematics of overprinting Walker Lane and Basin and Range deformation in the Pine Nut Mountains, Nevada (USA), which are the westernmost structural and topographic expression of the Basin and Range, with new geologic mapping and 40Ar/39Ar geochronology. Structural mapping suggests that north-striking normal faults developed during the initiation of Basin and Range extension and were later reactivated as northeast-striking oblique-slip faults following the onset of Walker Lane transtensional deformation. Conformable volcanic and sedimentary rocks, with new ages spanning ca. 14.2 Ma to 6.8 Ma, were tilted 30°–36° northwest by east-dipping normal faults. This relationship demonstrates that dip-slip deformation initiated after ca. 6.8 Ma. A retrodeformed cross section across the range suggests that the range experienced 14% extension. Subsequently, Walker Lane transtension initiated, and clockwise rotation of the Carson domain may have been accommodated by northeast-striking left-slip faults. Our work better defines strain patterns at the western extent of the Basin and Range province across an approximately 150-km-long east-west transect that reveals domains of low strain (∼15%) in the Carson Range–Pine Nut Mountains and Gillis Range surrounding high-magnitude extension (∼150%–180%) in the Singatse and Wassuk Ranges. There is no evidence for irregular crustal thickness variations across this same transect—either in the Mesozoic, prior to extension, or today—which suggests that strain must be accommodated differently at decoupled crustal levels to result in smooth, homogenous crustal thickness values despite the significantly heterogeneous extensional evolution. This example across an ∼150 km transect demonstrates that the use of upper-crust extension estimates to constrain pre-extension crustal thickness, assuming pure shear as commonly done for the Mesozoic Nevadaplano orogenic plateau, may not be reliable.
Child maltreatment, early life socioeconomic disadvantage and all-cause mortality in mid-adulthood: findings from a prospective British birth cohort
Authors: Rogers Nina T , Power Christine , Pinto Pereira Snehal M 
Published: September 2021

ObjectivesEarly-life adversities (ELAs) such as child maltreatment (neglect and abuse) and socioeconomic disadvantage have been associated with adult mortality. However, evidence is sparse for specific types of ELA. We aimed to establish whether specific ELAs (ie, different types of child maltreatment and socioeconomic disadvantage) were associated independently with all-cause mortality in mid-adulthood and to examine potential intermediary pathways.DesignProspective cohort study.Setting1958 British birth cohort: a longitudinal, population-based sample of individuals born in Great Britain during a single week in March 1958.Participants9310 males and females with data on child maltreatment and mortality (44/45–58 years).Outcome measuresMortality follow-up from 2002/2003 to 2016 when participants were aged 44/45–58 years. Death was ascertained via the NHS Central Register (N=296) or cohort maintenance activities (N=16).ResultsPrevalence of ELAs ranged from 1.6% (sexual abuse) to 11% (psychological abuse). Several, but not all, ELAs were associated with increased risk of premature death, independent of covariates and other adversities; adjusted HRs were 2.64 (95% CI 1.52 to 4.59) for sexual abuse, 1.93 (95% CI 1.45 to 2.58) for socioeconomic disadvantage, 1.73 (95% CI 1.11 to 2.71) for physical abuse and 1.43 (95% CI 1.03 to 1.98) for neglect. After adjustment for covariates and other adversities, no associations with mortality were observed for psychological and witnessing abuse. Regarding potential intermediaries (including adult socioeconomic factors, behaviours, adiposity, mental health and cardiometabolic markers), most associations attenuated after accounting for adult health behaviours (particularly smoking). In addition, early-life socioeconomic disadvantage and neglect associations attenuated after accounting for adult socioeconomic factors. The association for sexual abuse and premature mortality was largely unaffected by potential intermediaries.ConclusionsAssociations with premature mortality varied by type of ELA: associations for sexual and physical abuse, neglect and socioeconomic disadvantage were independent of each other. Different types of ELAs could influence premature mortality via different pathways; this requires further research.
Effect of prenotification on the response rate of a postal survey of emergency physicians: a randomised, controlled, assessor-blind trial
Authors: Hickey Michael , McIntyre Lauralyn , Taljaard Monica , Abdulaziz Kasim , Yadav Krishan , Hickey Carly , Perry Jeffrey J 
Published: September 2021

ObjectivesResponse rates to physician surveys are typically low. The objective of this study was to determine the effect of a prenotification letter on the response rate of a postal survey of emergency physicians.DesignThis was a substudy of a national, cross-sectional postal survey sent to emergency physicians in Canada. We randomised participants to either receive a postal prenotification letter prior to the survey, or to no prenotification letter.ParticipantsA random sample of 500 emergency physicians in Canada. Participants were selected from the Canadian Medical Directory, a national medical directory which lists more than 99% of practising physicians in Canada.InterventionsUsing computer-generated randomisation, physicians were randomised in a concealed fashion to receive a prenotification letter approximately 1 week prior to the survey, or to not receive a prenotification letter. All physicians received an unconditional incentive of a $3 coffee card with the survey instrument. In both groups, non-respondents were sent reminder surveys approximately every 14 days and a special contact using Xpresspost during the final contact attempt.OutcomeThe primary outcome was the survey response rate.Results201 of 447 eligible physicians returned the survey (45.0%). Of 231 eligible physicians contacted in the prenotification group, 80 (34.6%) returned the survey and among 237 eligible physicians contacted in the no-prenotification group, 121 (51.1%) returned the survey (absolute difference in proportions 16.5%, 95% CI 2.5 to 30.5, p=0.01).ConclusionInclusion of a prenotification letter resulted in a lower response rate in this postal survey of emergency physicians. Given the added costs, time and effort required to send a prenotification letter, this study suggests that it may be more effective to omit the prenotification letter in physician postal surveys.
Comparison of deliberate self-harm incidents attended by Helicopter Emergency Medical Services before and during the first wave of COVID-19 in the East of England
Authors: Stevens Joanna , Price James , Hazlerigg Antonia , McLachlan Sarah , Barnard Ed Benjamin Graham 
Published: September 2021

IntroductionThere is significant interest in the mental health impact of the COVID-19 pandemic. Helicopter Emergency Medical Services (HEMS) attend the most seriously unwell and injured patients in the community; their data therefore present an early opportunity to examine self-harm trends. The primary aim was to compare the incidence of deliberate self-harm incident (DSH-I) encounters by HEMS before and during the first wave of COVID-19.MethodsData were obtained from all three East of England HEMS: total number of activations and stand-downs, number of DSH-I activations and stand-downs, self-harm mechanism and number of ‘severe’ DSH-I patient encounters, in two 61-day periods: 1 March to 30 April in 2019 (control) and 2020 (COVID-19). Severe DSH-I was defined as cardiac arrest and/or died prehospital. Proportions were compared with a Fisher’s exact test.ResultsThere were a total of 1725 HEMS activations: n=981 (control) and n=744 (COVID-19), a decrease of 24.2% during COVID-19. DSH-I patient encounters increased by 65.4%: n=26 (control) and n=43 (COVID-19). The proportion of encounters that were DSH-I and severe DSH-I both significantly increased during COVID-19: p=0.002 and p=0.001, respectively. The absolute number of hangings and falls from height both approximately tripled during COVID-19, whereas the number of other mechanisms remained almost constant.ConclusionDespite a reduction in overall HEMS patient encounters, there were significant increases in both the proportion of DSH-Is and their severity attended by HEMS during the first wave of the COVID-19 pandemic in the East of England.
From adaptive resolution to molecular dynamics of open systems
Authors: Cortes-Huerto Robinson , Praprotnik Matej , Kremer Kurt , Delle Site Luigi 
Published: September 2021

Abstract
We provide an overview of the Adaptive Resolution Simulation method (AdResS) based on discussing its basic principles and presenting its current numerical and theoretical developments. Examples of applications to systems of interest to soft matter, chemical physics, and condensed matter illustrate the method’s advantages and limitations in its practical use and thus settle the challenge for further future numerical and theoretical developments.

Graphic abstract
Study on the optical spectra of the oxygen vacancy in ZnWO4crystal
Authors: Lian Gaiping , Liu Tingyu , Yu Le 
Published: September 2021

ZnWO4is easy to color, which will reduce the luminous efficiency of the crystal and limit the application of the crystal. In order to study the origin of the color in the crystal, in this paper, the effects of the oxygen vacancy on the optical properties for the ZnWO4crystal have been studied based on the density functional theory (DFT). The hybrid functional method (HSE) and the finite-size correction scheme (FNV) are used to correct the band edge problem and eliminate the artificial interaction of the charged defects, respectively. On the basis of the corrected defect formation energy, we obtain the optical spectra of the [Formula: see text] and [Formula: see text] centers containing electron-phonon coupling. The calculated absorption and luminescence peaks are at 2.54 eV and 0.79 eV for the [Formula: see text] center and at 2.98 eV and 1.09 eV for the [Formula: see text] center, respectively. The calculated absorption band of the [Formula: see text] center is close to the experimental value of 2.48 eV (500 nm), so we speculate that the coloring of the ZnWO4crystal is related to the [Formula: see text] center. Meanwhile, the existence of oxygen vacancy makes ZnWO4crystal to have self-absorption and to increase decay time, which greatly affects the scintillation properties of the crystal.
Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment
Authors: Hashimoto Masakazu , Konda John David , Perrino Stephanie , Celia Fernandez Maria , Lowy Andrew M. , Brodt Pnina 
Published: September 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti–PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.
Phosphoproteomics Identifies PI3K Inhibitor–selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance
Authors: Cintas Célia , Douche Thibault , Dantes Zahra , Mouton-Barbosa Emmanuelle , Bousquet Marie-Pierre , Cayron Coralie , Therville Nicole , Pont Frédéric , Ramos-Delgado Fernanda , Guyon Camille , Garmy-Susini Barbara , Cappello Paola , Burlet-Schiltz Odile , Hirsch Emilio , Gomez-Brouchet Anne , Thibault Benoît , Reichert Maximilian , Guillermet-Guibert Julie 
Published: September 2021

Abstract
The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kβ, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
Heme Sequestration as an Effective Strategy for the Suppression of Tumor Growth and Progression
Authors: Wang Tianyuan , Ashrafi Adnin , Konduri Purna Chaitanya , Ghosh Poorva , Dey Sanchareeka , Modareszadeh Parsa , Salamat Narges , Alemi Parinaz Sadat , Berisha Eranda , Zhang Li 
Published: September 2021

AbstractHeme is an essential nutritional, metabolic, and signaling molecule in living organisms. Pathogenic microbes extract heme from hosts to obtain metallonutrient, while heme fuels mitochondrial respiration and ATP generation in lung tumor cells. Here, we generated small heme-sequestering proteins (HeSPs) based on bacterial hemophores. These HeSPs contain neutral mutations in the heme-binding pocket and hybrid sequences from hemophores of different bacteria. We showed that HeSPs bind to heme and effectively extracted heme from hemoglobin. They strongly inhibited heme uptake and cell proliferation and induced apoptosis in non–small cell lung cancer (NSCLC) cells, while their effects on nontumorigenic cell lines representing normal lung cells were not significant. HeSPs strongly suppressed the growth of human NSCLC tumor xenografts in mice. HeSPs decreased oxygen consumption rates and ATP levels in tumor cells isolated from treated mice, while they did not affect liver and blood cell functions. IHC, along with data from Western blotting and functional assays, revealed that HeSPs reduced the levels of key proteins involved in heme uptake, as well as the consumption of major fuels for tumor cells, glucose, and glutamine. Further, we found that HeSPs reduced the levels of angiogenic and vascular markers, as well as vessel density in tumor tissues. Together, these results demonstrate that HeSPs act via multiple mechanisms, including the inhibition of oxidative phosphorylation, to suppress tumor growth and progression. Evidently, heme sequestration can be a powerful strategy for suppressing lung tumors and likely drug-resistant tumors that rely on oxidative phosphorylation for survival.
Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors
Authors: Sheikh Tahir N. , Chen Xiao , Xu Xinjing , McGuire John T. , Ingham Matthew , Lu Chao , Schwartz Gary K. 
Published: September 2021

Abstract
Chondrosarcomas are inherently resistant to chemotherapy and radiotherapy, pointing to an unmet need for new treatment options. Immune checkpoint inhibitors, which have shown remarkable promise in multiple solid cancer types, have limited efficacy in chondrosarcomas. Mutations in IDH1/2 genes, which result in progressive increases in DNA and histone methylation, are observed in 50% of conventional chondrosarcomas, suggesting that epigenetic dysregulation represents a potential barrier for tumor progression and target for therapeutic intervention. Here, we demonstrated that combined treatment of FDA-approved inhibitors of DNA methyltransferases (DNMTs) 5-aza-2′-deoxycytidine (5-aza), and histone deacetylases (HDACs) suberanilohydroxamic acid (SAHA) impaired the proliferation of chondrosarcoma cell lines in vitro and in xenograft studies. Transcriptomic analysis reveals that chondrosarcoma cells treated with 5-aza and SAHA markedly elevated the expression of IFN-stimulated genes including PD-L1, indicating that these epigenetic drugs induced a potent innate immune response. We demonstrated that 5-aza and SAHA resulted in both genomic and epigenomic instability, as shown by elevated DNA damage response and derepression of retrotransposons, respectively, which in turn activated pattern recognition receptors (PRRs) and the downstream IFN signaling pathways. Importantly, the cytotoxic effects of 5-aza and SAHA can be rescued by depletion of PRRs such as cGAS and MAVS, and potentiated by depletion of the RNA-editing enzyme ADAR1. Together, our results demonstrate preclinical activity of combined DNMT and HDAC inhibition against chondrosarcomas and suggest that targeted epigenetic therapies could represent a new therapeutic approach in the treatment of chondrosarcomas, and this is being tested in an ongoing clinical trial (NCT04340843).
Repurposing Vandetanib plus Everolimus for the Treatment ofACVR1-Mutant Diffuse Intrinsic Pontine Glioma
Authors: Carvalho Diana M. , Richardson Peter J. , Olaciregui Nagore , Stankunaite Reda , Lavarino Cinzia , Molinari Valeria , Corley Elizabeth A. , Smith Daniel P. , Ruddle Ruth , Donovan Adam , Pal Akos , Raynaud Florence I. , Temelso Sara , Mackay Alan , Overington John P. , Phelan Anne , Sheppard David , Mackinnon Andrew , Zebian Bassel , Al-Sarraj Safa , Merve Ashirwad , Pryce Jeremy , Grill Jacques , Hubank Michael , Cruz Ofelia , Morales La Madrid Andres , Mueller Sabine , Carcaboso Angel M. , Carceller Fernando , Jones Chris 
Published: September 2021

AbstractSomatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.Significance:Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275
Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI–Mediated High-Density Lipoprotein Uptake
Authors: Xu Hao , Thomas Michael J. , Kaul Sushma , Kallinger Rachel , Ouweneel Amber B. , Maruko Elisa , Oussaada Sabrina M. , Jongejan Aldo , Cense Huib A. , Nieuwdorp Max , Serlie Mireille J. , Goldberg Ira J. , Civelek Mete , Parks Brian W. , Lusis Aldons J. , Knaack Darcy , Schill Rebecca L. , May Sarah C. , Reho John J. , Grobe Justin L. , Gantner Benjamin , Sahoo Daisy , Sorci-Thomas Mary G. 
Published: September 2021

Objective:
To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)–mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage.

Approach and Results:

Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI– mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI–mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI–mediated HDL-C uptake is unknown. Differentiated cells from
Ldlr
−/−
/
Pcpe2
−/−
(Pcpe2
−/−
) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to
Ldlr
−/−
(control) adipose tissue. SR-BI–mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans.

Conclusions:
Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

Graphic Abstract:
A graphic abstract is available for this article.