bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grain-size variability in debris flows of different runout lengths, Wenchuan, China
Authors: Harvey Erin L. , Hales Tristram C. , Liu Jie , Hobley Daniel E.J. , Yang Fan , Xia Bing , Fan Xuanmei 
Published: November 2023

Abstract
Debris-flow grain-size distributions (GSDs) control runout length and mobility. Wide, bimodal GSDs and those containing a higher proportion of silt and clay have been shown experimentally to increase runout length. However, the relationship between grain size and mobility has not been well established in field conditions. Here, we compared the grain-size characteristics of two debris flows with considerably different runout lengths (1.5 km vs. 8 km) to understand the role of grain size in governing runout. The two debris flows were triggered in the same rainfall event from coseismic landslide debris generated in the 2008 Wenchuan earthquake in catchments with similar lithology and topography. We compared the deposited GSDs and their spatial patterns using our rare, three-dimensional GSD datasets. Surprisingly, the proportions of each size fraction deposited by the two flows were statistically indistinguishable. The spatial pattern of grain size differed between the two flows, with evidence of inverse grading only preserved in the smaller deposit. From these observations, we can infer that the GSDs of both flows were determined by the coseismic landslide source material, and that there was little difference in the GSDs of material entrained as the flows bulked. The contrasting spatial distributions of grains indicated that different internal processes were dominant within the two flows. These findings demonstrate that where GSDs are dominated by coarse grains and are governed by similar source conditions, grain size plays a lesser role relative to sediment supply and hydrology in controlling the runout length of large catastrophic post-earthquake debris flows.
Enhanced recovery support for people with eating disorders during the COVID-19 pandemic: quality improvement using a web-based, stepped-care programme in Canada
Authors: Wood Michael D , Smith Jeannine L , Healey Hannah , Görges Matthias , Lokker Cynthia 
Published: November 2023

BackgroundThroughout the COVID-19 pandemic, the number of individuals struggling with eating disorders (EDs) increased substantially. Body Brave (a not-for-profit) created and implemented a web-based stepped-care Recovery Support Programme (RSP) to improve access to community-based ED services. This quality improvement study describes the RSP and assesses its ability to deliver timely access to treatment and platform engagement.MethodsWe conducted a retrospective cohort study comparing access to, and use of Body Brave services 6 months before and 12 months after implementation of the RSP platform (using 6-month increments for two postimplementation periods). Primary programme quality measures included registration requests, number of participants onboarded and time to access services; secondary measures included use of RSP action plans, attendance for recovery sessions and workshops, number of participants accessing treatment and text-based patient experience data.ResultsA substantial increase in registration requests was observed during the first postimplementation period compared with the preimplementation period (176.5 vs 85.5; p=0.028). When compared with the preimplementation period, the second postimplementation observed a significantly larger percentage of successfully onboarded participants (76.6 vs 37.9; p<0.01) and a reduction in the number of days to access services (2 days vs 31 days; p<0.01). Although participant feedback rates were low, many users found the RSP helpful, easy to access, user-friendly and were satisfied overall. Users provided suggestions for improvement (eg, a platform instructional video, offer multiple times of day for live sessions and drop-in hours).ConclusionsAlthough clinical benefit needs to be assessed, our findings demonstrate that the RSP enabled participants to quickly onboard and access initial services and have informed subsequent improvements. Understanding initial programme effects and usage will help assess the feasibility of adapting and expanding the RSP across Canada to address the urgent need for low-barrier, patient-centred ED care.
Loss of ADAR1 in macrophages in combination with interferon gamma suppresses tumor growth by remodeling the tumor microenvironment
Authors: Lin Weiwei , Luo Yikai , Wu Jie , Zhang Haowan , Jin Ge , Guo Chahua , Zhou Hang , Liang Han , Xu Xiaoyan 
Published: November 2023

BackgroundADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.MethodsWe first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain the mechanistic insights, we performed human cytokine arrays to identify differentially secreted cytokines in response to ADAR1 perturbations in THP-1 cells. Furthermore, we examined the effects of ADAR1 loss and IFN-γ treatment on vessel formation through immunohistochemical staining of mouse tumor sections and tube-forming experiments using HUVEC and SVEC4-10 cells. We also assessed the effects on CD8+T cells using immunofluorescent and immunohistochemical staining and flow cytometry. To explore the translational potential, we examined the consequences of injecting ADAR1-deficient macrophages alongside IFN-γ treatment on tumor growth in LLC-tumor-bearing mice.ResultsOur analysis on public data suggests that ADAR1 loss in macrophages promotes antitumor immunity as in cancer cells. Indeed, ADAR1 loss in macrophages combined with IFN-γ treatment results in tumor regression in diverse disease mouse models. Mechanistically, the loss of ADAR1 in macrophages leads to the differential secretion of key cytokines: it inhibits the translation of CCL20, GDF15, IL-18BP, and TIM-3 by activating PKR/EIF2α signaling but increases the secretion of IFN-γ through transcriptional upregulation and interleukin (IL)-18 due to the 5'UTR uORF. Consequently, decreased CCL20 and GDF15 and increased IFN-γ suppress angiogenesis, while decreased IL-18BP and TIM-3 and increased IL-18 induce antitumor immunity by enhancing cytotoxicity of CD8+T cells. We further demonstrate that combination therapy of injecting ADAR1-deficient macrophages and IFN-γ effectively suppresses tumors in vivo.ConclusionThis study provides a comprehensive elucidation of how ADAR1 loss within macrophages contributes to the establishment of an antitumor microenvironment, suggesting the therapeutic potential of targeting ADAR1 beyond the scope of cancer cells.
Cytoplasmic-delivery of polyinosine-polycytidylic acid inhibits pancreatic cancer progression increasing survival by activating Stat1-CCL2-mediated immunity
Authors: Bhoopathi Praveen , Kumar Amit , Pradhan Anjan K , Maji Santanu , Mannangatti Padmanabhan , Windle Jolene J , Subler Mark A , Zhang Dongyu , Vudatha Vignesh , Trevino Jose G , Madan Esha , Atfi Azeddine , Sarkar Devanand , Gogna Rajan , Das Swadesh K , Emdad Luni , Fisher Paul B 
Published: November 2023

BackgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine–polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth. When pIC is delivered into the cytoplasm using polyethyleneimine (PEI), pIC-PEI, programmed-cell death is induced in PDAC. Transfection of [pIC]PEIinto PDAC cells inhibits growth, promotes toxic autophagy and also induces apoptosis in vitro and in vivo in animal models.MethodsThe KPC transgenic mouse model that recapitulates PDAC development in patients was used to interrogate the role of an intact immune system in vivo in PDAC in response to [pIC]PEI. Antitumor efficacy and survival were monitored endpoints. Comprehensive analysis of the tumor microenvironment (TME) and immune cells, cytokines and chemokines in the spleen, and macrophage polarization were analyzed.ResultsCytosolic delivery of [pIC]PEIinduces apoptosis and provokes strong antitumor immunityin vivoin immune competent mice with PDAC. The mechanism underlying the immune stimulatory properties of [pIC]PEIinvolves Stat1 activation resulting in CCL2 and MMP13 stimulation thereby provoking macrophage polarization. [pIC]PEIinduces apoptosis via the AKT-XIAP pathway, as well as macrophage differentiation and T-cell activation via the IFNγ-Stat1-CCL2 signaling pathways in PDAC. In transgenic tumor mouse models, [pIC]PEIpromotes robust and profound antitumor activity implying that stimulating the immune system contributes to biological activity. The [pIC]PEIanti-PDAC effects are enhanced when used in combination with a standard of care (SOC) treatment, that is, gemcitabine.ConclusionsIn summary, [pIC]PEItreatment is non-toxic toward normal pancreatic cells while displaying strong cytotoxic and potent immune activating activities in PDAC, making it an attractive therapeutic when used alone or in conjunction with SOC therapeutic agents, potentially providing a safe and effective treatment protocol with translational potential for the effective therapy of PDAC.
Titin copy number variations associated with dominant inherited phenotypes
Authors: Perrin Aurélien , Métay Corinne , Savarese Marco , Ben Yaou Rabah , Demidov German , Nelson Isabelle , Solé Guilhem , Péréon Yann , Bertini Enrico Silvio , Fattori Fabiana , D'Amico Adele , Ricci Federica , Ginsberg Mira , Seferian Andreea , Boespflug-Tanguy Odile , Servais Laurent , Chapon Françoise , Lagrange Emmeline , Gaudon Karen , Bloch Adrien , Ghanem Robin , Guyant-Maréchal Lucie , Johari Mridul , Van Goethem Charles , Fardeau Michel , Morales Raul Juntas , Genetti Casie A , Marttila Minttu , Koenig Michel , Beggs Alan H , Udd Bjarne , Bonne Gisèle , Cossée Mireille 
Published: November 2023

BackgroundTitinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs inTTNhave been reported without clear genotype–phenotype associations.MethodsOur study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in theTTNgene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients’ muscles and performed genotype–phenotype inheritance association study by combining the clinical and biological data of these eight families.ResultsSeven deletion-type CNVs in theTTNgene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype–phenotype associations of titinopathies.ConclusionIdentifyingTTNCNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in theTTNgene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype–phenotype associations of titinopathies, mainly distal myopathy in most of the patients.
Vall d’Hebron Risk Score II for myocardial infarction and cardiac death
Authors: Romero-Farina Guillermo , Aguadé-Bruix Santiago , Ferreira González Ignacio 
Published: November 2023

ObjectivesThe aim of this study was to create a new Vall d’Hebron Risk Score-II (VH-RS-II) for non-fatal myocardial infarction (MI) and/or cardiac death (CD), excluding patients with coronary revascularisation (CR) during the follow-up.MethodsWe analysed 5215 consecutive patients underwent gated single photon emission CT (SPECT); 2960 patients (age 64.2±11, male 58.1%) had no previous MI and/or CR, and 2255 patients (age 63.3±11, male 81.9%) had previous MI and/or CR. During a follow-up of 4.3±2.6 years, the cardiac event (MI and CD) was evaluated. This study was reviewed and approved by the ethics committee of our institution (number form trial register, PR(AG)168.2012). To obtain the predictor model, multivariate Cox regression analysis and multivariate logistic regression analysis were used. RS-VH-II was validated with 679 patients.ResultsIn patients without previous MI and/or CR, age (HR: 1.01; p<0.001), diabetes (HR: 2.1, p=0.001), metabolic equivalent (METs) (HR: 0.89, p=0.038), ST segment depression (HR: 1.4, p=0.011), ejection fraction (EF) (HR: 0.97, p<0.001) and summed stress score (HR: 1.2, p<0.001) were the independent predictors of CE (C-statistic: 0.8). In patients with previous MI and/or CR, age (HR: 1.06, p<0.001), male (HR: 1.9, p=0.047), smoker (HR: 1.5, p=0.047), METs (HR: 0.8, p<0.001), ST segment depression (HR: 1.4, p=0.002), EF (HR: 0.96; p<0.001) and summed difference score (HR: 1.03, p=0.06) were the independent predictors of CE (C-statistic:0.8).ConclusionThe VH-RS-II obtained from different clinical exercise and gated SPECT variables allow the risk stratification for MI and CD in patients with or without previous MI and/or CR in due form.
E-commerce licensing loopholes: a case study of online shopping for tobacco products following a statewide sales restriction on flavoured tobacco in California
Authors: Leas Eric C , Mejorado Tomas , Harati Raquel , Ellis Shannon , Satybaldiyeva Nora , Morales Nicolas , Poliak Adam 
Published: November 2023

IntroductionRetailer licensing programmes can be an effective method of enforcing tobacco control laws, but most programmes do not require e-commerce retailers to obtain licenses. California’s implementation of a statewide flavour restriction (Senate Bill 793 (SB-793)) in December 2022 enforced through its tobacco retailer licensing programme presented an opportunity to assess whether the exclusion of e-commerce in the definition of ‘tobacco retailer’ might have resulted in a shift in consumer behaviour towards e-commerce.MethodsTo examine the association between SB-793 implementation and online shopping for tobacco, we collected weekly Google search rates related to online shopping for cigarettes and vaping products in California from January 2018 to May 2023. We compared observed rates of shopping queries after SB-793 implementation to counterfactual expected rates and prediction intervals (PI) calculated from autoregressive iterative moving average models fit to historical trends. Content analysis was performed on the search results to identify websites marketing flavoured vaping products and menthol cigarettes.ResultsThe week SB-793 was implemented, shopping queries were 194.4% (95% PI 100.8% to 451.5%) and 161.7% (95% PI 81.7% to 367.5%) higher than expected for cigarettes and vapes, respectively. Cigarette shopping queries remained elevated significantly for 11 weeks and vape shopping queries for 6 weeks. All search results contained links to websites that offered flavoured vaping products or menthol cigarettes to Californian consumers.DiscussionThese findings raise concerns about potential loopholes in policy enforcement created by the absence of explicit regulations on e-commerce sales in retailer licensing programmes. Strengthening regulations to include e-commerce and monitoring e-commerce compliance are recommended to enhance the impact of laws enforced through retailer licensing programmes.
Prioritizing rapid COVID-19 testing in emergency general surgery patients decreases burden of inpatient hospital admission
Authors: Thomas Madeline B , Carmichael Heather , Harrison Madison , Abbitt Danielle , Moore Allison , Myers Quintin W O , Velopulos Catherine G 
Published: November 2023

ObjectivesThe COVID-19 pandemic has changed delivery of emergency general surgery (EGS) and contributed to widespread bed shortages. At our institution, rapid testing is not routinely approved for EGS patients. We examined common EGS conditions (appendicitis and acute cholecystitis), hypothesizing that necessity of testing for COVID-19 significantly delayed operative intervention.MethodsWe performed a prepost study to examine a 2-month timeframe, or historical control, prior to COVID-19 testing (January 1, 2020–March 1, 2020) as well as a 2-month timeframe during the COVID-19 era (January 1, 2021–March 1, 2021). We chose conditions that are frequently treated surgically as outpatient or observation status. We examined time for COVID-19 test to result, and associated time to operative intervention (operating room (OR)) and need for admission.ResultsMedian time to COVID-19 test results was 7.4 hours (IQR 5.8–13.1). For appendectomy, time to surgical consultation or case request did not differ between cohorts. Time to OR after case request was significantly longer (12.5 vs 1.9 hours, p<0.001) and patients more frequently required admission prior to operative intervention if receiving treatment in the COVID-19 timeframe. Similarly, for cholecystectomy there were no differences in time to surgical consultation or case request, but time to OR after case request was longer in the COVID-19 era (21.1 vs 9.0 hours, p<0.001).ConclusionWhile COVID-19 positivity rates have declined, the purpose of this study was to reflect on one element of our hospital system’s response to the COVID-19 pandemic. Based on our institutional experience, waiting for COVID-19 test results directly impacts time to surgery, as well as the need for admission for a historically outpatient procedure. In the future, if the healthcare system is asked to respond to another pandemic or similar situation, expediting time to OR to eliminate unnecessary time in the hospital and non-critical admissions should be paramount.Level of evidenceLevel III, prognostic/epidemiological.
Extraction of the strong coupling with HERA and EIC inclusive data
Authors: Cerci Salim , Demiroglu Zuhal Seyma , Deshpande Abhay , Newman Paul R. , Schmookler Barak , Sunar Cerci Deniz , Wichmann Katarzyna 
Published: November 2023

AbstractSensitivity to the strong coupling $$\alpha _S(M^2_Z)$$

α
S

(

M
Z
2

)

is investigated using existing Deep Inelastic Scattering data from HERA in combination with projected future measurements from the Electron Ion Collider (EIC) in a next-to-next-to-leading order QCD analysis. A potentially world-leading level of precision is achievable when combining simulated inclusive neutral current EIC data with inclusive charged and neutral current measurements from HERA, with or without the addition of HERA inclusive jet and dijet data. The result can be obtained with substantially less than one year of projected EIC data at the lower end of the EIC centre-of-mass energy range. Some questions remain over the magnitude of uncertainties due to missing higher orders in the theoretical framework.
A new low gain avalanche diode concept: the double-LGAD
Authors: Carnesecchi F. , Strazzi S. , Alici A. , Arcidiacono R. , Cartiglia N. , Cavazza D. , Durando S. , Ferrero M. , Margotti A. , Menzio L. , Nania R. , Sabiu B. , Scioli G. , Siviero F. , Sola V. , Vignola G. 
Published: November 2023

AbstractThis paper describes the new concept of the double LGAD (low-gain avalanche diodes). The goal was to increase the charge at the input of the electronics, keeping a time resolution equal to or better than a standard (single) LGAD; this has been realized by adding the charges of two coupled LGADs while still using a single front-end electronics. The study here reported has been done starting from single LGAD with a thickness of 25 µm, 35 µm and 50 µm.
QuCloud+: A Holistic Qubit Mapping Scheme for Single/Multi-programming on 2D/3D NISQ Quantum Computers
Authors: Liu Lei , Dou Xinglei 
Published: November 2023

Qubit mapping for NISQ superconducting quantum computers is essential to fidelity and resource utilization. The existing qubit mapping schemes meet challenges, e.g., crosstalk, SWAP overheads, diverse device topologies, etc., leading to qubit resource underutilization and low fidelity in computing results. This article introduces QuCloud+, a new qubit mapping scheme that tackles these challenges. QuCloud+ has several new designs. (1) QuCloud+ supports single/multi-programming quantum computing on quantum chips with 2D/3D topology. (2) QuCloud+ partitions physical qubits for concurrent quantum programs with the crosstalk-aware community detection technique and further allocates qubits according to qubit degree, improving fidelity, and resource utilization. (3) QuCloud+ includes an X-SWAP mechanism that avoids SWAPs with high crosstalk errors and enables inter-program SWAPs to reduce the SWAP overheads. (4) QuCloud+ schedules concurrent quantum programs to be mapped and executed based on estimated fidelity for the best practice. Experimental results show that, compared with the existing typical multi-programming study [
12
], QuCloud+ achieves up to 9.03% higher fidelity and saves on the required SWAPs during mapping, reducing the number of CNOT gates inserted by 40.92%. Compared with a recent study [
30
] that enables post-mapping gate optimizations to further reduce gates, QuCloud+ reduces the post-mapping circuit depth by 21.91% while using a similar number of gates.
Disruption of SUV39H1-Mediated H3K9 Methylation Sustains CAR T-cell Function
Authors: Jain Nayan , Zhao Zeguo , Koche Richard P. , Antelope Chenling , Gozlan Yosi , Montalbano Antonino , Brocks David , Lopez Michael , Dobrin Anton , Shi Yuzhe , Gunset Gertrude , Giavridis Theodoros , Sadelain Michel 
Published: November 2023

Abstract

Suboptimal functional persistence limits the efficacy of adoptive T-cell therapies. CD28-based chimeric antigen receptors (CAR) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall antitumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges. Transcriptional and genome accessibility profiling of repeatedly challenged CAR T cells shows improved expression and accessibility of memory transcription factors in SUV39H1-edited CAR T cells. SUV39H1 editing also reduces expression of inhibitory receptors and limits exhaustion in CAR T cells that have undergone multiple rechallenges. Our findings thus demonstrate the potential of epigenetic programming of CAR T cells to balance their function and persistence for improved adoptive cell therapies.

Significance:
T cells engineered with CD28-based CARs possess robust effector function and antigen sensitivity but are hampered by limited persistence, which may result in tumor relapse. We report an epigenetic strategy involving disruption of the SUV39H1-mediated histone-silencing program that promotes the functional persistence of CD28-based CAR T cells.
See related article by López-Cobo et al., p. 120.
This article is featured in Selected Articles from This Issue, p. 5