bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural insights into engineering a T-cell receptor targeting MAGE-A10 with higher affinity and specificity for cancer immunotherapy
Authors: Simister Philip C , Border Ellen C , Vieira João F , Pumphrey Nicholas J 
Published: July 2022

BackgroundT-cell receptor (TCR) immunotherapy is becoming a viable modality in cancer treatment with efficacy in clinical trials. The safety of patients is paramount, so innovative cell engineering methods are being employed to exploit adaptive immunity while controlling the factors governing antigen receptor (ie, TCR) specificity and cross-reactivity. We recently reported a TCR engineering campaign and selectivity profiling assay (X-scan) targeting a melanoma antigen gene (MAGE)-A10 peptide. This helped to distinguish between two well-performing TCRs based on cross-reactivity potential during preclinical drug evaluation, allowing one to be advanced to T-cell immunotherapeutic clinical trials. Here, we present three-dimensional structural information on those TCRs, highlighting engineering improvements and molecular mechanisms likely underpinning differential selectivity.MethodsParental and engineered TCRs were purified and crystallized either alone or complexed to human leucocyte antigen (HLA)-A*02:01 presenting the MAGE-A10 9-mer peptide, GLYDGMEHL (pHLA/MAGE-A10-9). Using X-ray diffraction, we solved four high-resolution crystal structures and evaluated them relative to previously reported functional results.ResultsThe unligated parental TCR displayed similar complementarity-determining region (CDR) loop conformations when bound to pHLA/MAGE-A10-9; a rigid-body movement of TCR beta chain variable domain (TRBV) relative to TCR alpha chain variable domain helped optimal pHLA engagement. This first view of an HLA-bound MAGE-A10 peptide revealed an intrachain non-covalent ‘staple’ between peptide Tyr3 and Glu7. A subtle Glu31-Asp mutation in βCDR1 of the parental TCR generated a high-affinity derivative. Its pHLA-complexed structure shows that the shorter Asp leans toward the pHLA with resulting rigid-body TRBV shift, creating localized changes around the peptide’s C-terminus. Structural comparison with a less selective TCR indicated that differential cross-reactivity to MAGE-A10 peptide variants is most readily explained by alterations in surface electrostatics, and the size and geometry of TCR-peptide interfacial cavities.ConclusionsModest changes in engineered TCRs targeting MAGE-A10 produced significantly different properties. Conformational invariance of TCR and antigen peptide plus more space-filling CDR loop sequences may be desirable properties for clinically relevant TCR–pHLA systems to reduce the likelihood of structurally similar peptide mimics being tolerated by a TCR. Such properties may partially explain why the affinity-enhanced, in vitro-selected TCR has been generally well tolerated in patients.
Dark matter in a charged variant of the Scotogenic model
Authors: De Romeri Valentina , Puerta Miguel , Vicente Avelino 
Published: July 2022

AbstractScotogenic models are among the most popular possibilities to link dark matter and neutrino masses. In this work we discuss a variant of the Scotogenic model that includes charged fermions and a doublet with hypercharge 3/2. Neutrino masses are induced at the one-loop level thanks to the states belonging to the dark sector. However, in contrast to the standard Scotogenic model, only the scalar dark matter candidate is viable in this version. After presenting the model and explaining some particularities about neutrino mass generation, we concentrate on its dark matter phenomenology. We show that the observed dark matter relic density can be correctly reproduced in the usual parameter space regions found for the standard Scotogenic model or the Inert Doublet model. In addition, the presence of the charged fermions opens up new viable regions, not present in the original scenarios, provided some tuning of the parameters is allowed.
Unfolded Protein Response Differentially Modulates the Platelet Phenotype
Authors: Jain Kanika , Tyagi Tarun , Du Jing , Hu Xiaoyue , Patell Kanchi , Martin Kathleen A. , Hwa John 
Published: July 2022

Background:
Unfolded protein response (UPR) is a multifaceted signaling cascade that alleviates protein misfolding. Although well studied in nucleated cells, UPR in absence of transcriptional regulation has not been described. Intricately associated with cardiovascular diseases, platelets, despite being anucleate, respond rapidly to stressors in blood. We investigate the UPR in anucleate platelets and explore its role, if any, on platelet physiology and function.

Methods:
Human and mouse platelets were studied using a combination of ex vivo and in vivo experiments. Platelet lineage-specific knockout mice were generated independently for each of the 3 UPR pathways, PERK (protein kinase RNA [PKR]-like endoplasmic reticulum kinase), XBP1 (X-binding protein), and ATF6 (activating transcription factor 6). Diabetes patients were prospectively recruited, and platelets were evaluated for activation of UPR under chronic pathophysiological disease conditions.

Results:
Tunicamycin induced the IRE1α (inositol-requiring enzyme-1alpha)-XBP1 pathway in human and mouse platelets, while oxidative stress predominantly activated the PERK pathway. PERK deletion significantly increased platelet aggregation and apoptosis and phosphorylation of PLCγ2, PLCβ3, and p38 MAPK. Deficiency of XBP1 increased platelet aggregation, with higher PLCβ3 and PKCδ activation. ATF6 deletion mediated a relatively modest effect on platelet phenotype with increased PKA (protein kinase A). Platelets from diabetes patients exhibited a positive correlation between disease severity, platelet activation, and protein aggregation, with only IRE1α-XBP1 activation. Moreover, IRE1α inhibition increased platelet aggregation, while clinically approved chemical chaperone, sodium 4-phenylbutyrate reduced the platelet hyperactivation.

Conclusions:
We show for the first time, that UPR activation occurs in platelets and can be independent of genomic regulation, with selective induction being specific to the source and severity of stress. Each UPR pathway plays a key role and can differentially modulate the platelet activation pathways and phenotype. Targeting the specific arms of UPR may provide a new antiplatelet strategy to mitigate thrombotic risk in diabetes and other cardiovascular diseases.
Community-Based, Cluster-Randomized Pilot Trial of a Cardiovascular Mobile Health Intervention: Preliminary Findings of the FAITH! Trial
Authors: Brewer LaPrincess C. , Jenkins Sarah , Hayes Sharonne N. , Kumbamu Ashok , Jones Clarence , Burke Lora E. , Cooper Lisa A. , Patten Christi A. 
Published: July 2022

Background:
African Americans continue to have suboptimal cardiovascular health (CVH) based on the American Heart Association Life’s Simple 7 (LS7), 7 health-promoting behaviors and biological risk factors (eg, physical activity, blood pressure). Innovative, community-level interventions in partnership with trusted institutions such as African American churches are potential means to improve CVH in this population.

Methods:
Using a community-based participatory research approach, the FAITH! Trial (Fostering African American Improvement in Total Health) rigorously assessed the feasibility and preliminary efficacy of a refined, community-informed, mobile health intervention (FAITH! App) for promoting CVH among African Americans in faith communities using a cluster randomized controlled trial. Participants from 16 churches in Rochester and Minneapolis-St Paul, MN, were randomized to receive the FAITH! App (immediate intervention) or were assigned to a delayed intervention comparator group. The 10-week intervention core features included culturally relevant and LS7-focused education modules, diet/physical activity self-monitoring, and a group sharing board. Data were collected via electronic surveys and health assessments. Primary outcomes were average change in mean LS7 score (continuous measure of CVH ranging from poor to ideal [0–14 points]) from baseline to 6 months post-intervention (using generalized estimating equations) and app engagement/usability (by the Health Information Technology Usability Evaluation Scale; range, 0–5).

Results:

Of 85 enrolled participants (randomized to immediate [N=41] and delayed [control] intervention [N=44] groups), 76 and 68 completed surveys/health assessments at baseline and 6 months post-intervention, respectively (80% retention rate with assessments at both baseline and 6-month time points); immediate intervention [N=30] and control [N=38] groups). At baseline, the majority of participants (mean age [SD], 54.2 [12.3] years, 71% female) had <4-year college education level (39/66, 59%) and poor CVH (44% in poor category; mean LS7 score [SD], 6.8 [1.9]). The mean LS7 score of the intervention group increased by 1.9 (SD 1.9) points compared with 0.7 (SD 1.7) point in the control group (both
P
<0.0001) at 6 months. The estimated difference of this increase between the groups was 1.1 (95% CI, 0.6–1.7;
P
<0.0001). App engagement/usability was overall high (100% connection to app; >75% completed weekly diet/physical activity tracking; Health Information Technology Usability Evaluation Scale, mean [SD], 4.2 [0.7]).

Conclusions:
On the basis of preliminary findings, the refined FAITH! App appears to be an efficacious mobile health tool to promote ideal CVH among African Americans.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03777709.
Racial and Ethnic Differences in All-Cause and Cardiovascular Disease Mortality: The MESA Study
Authors: Post Wendy S. , Watson Karol E. , Hansen Spencer , Folsom Aaron R. , Szklo Moyses , Shea Steven , Barr R. Graham , Burke Gregory , Bertoni Alain G. , Allen Norrina , Pankow James S. , Lima Joao A.C. , Rotter Jerome I. , Kaufman Joel D. , Johnson W. Craig , Kronmal Richard A. , Diez-Roux Ana V. , McClelland Robyn L. 
Published: July 2022

Background:
Despite improvements in population health, marked racial and ethnic disparities in longevity and cardiovascular disease (CVD) mortality persist. This study aimed to describe risks for all-cause and CVD mortality by race and ethnicity, before and after accounting for socioeconomic status (SES) and other factors, in the MESA study (Multi-Ethnic Study of Atherosclerosis).

Methods:
MESA recruited 6814 US adults, 45 to 84 years of age, free of clinical CVD at baseline, including Black, White, Hispanic, and Chinese individuals (2000–2002). Using Cox proportional hazards modeling with time-updated covariates, we evaluated the association of self-reported race and ethnicity with all-cause and adjudicated CVD mortality, with progressive adjustments for age and sex, SES (neighborhood SES, income, education, and health insurance), lifestyle and psychosocial risk factors, clinical risk factors, and immigration history.

Results:
During a median of 15.8 years of follow-up, 22.8% of participants (n=1552) died, of which 5.3% (n=364) died of CVD. After adjusting for age and sex, Black participants had a 34% higher mortality hazard (hazard ratio [HR], 1.34 [95% CI, 1.19–1.51]), Chinese participants had a 21% lower mortality hazard (HR, 0.79 [95% CI, 0.66–0.95]), and there was no mortality difference in Hispanic participants (HR, 0.99 [95% CI, 0.86–1.14]) compared with White participants. After adjusting for SES, the mortality HR for Black participants compared with White participants was reduced (HR, 1.16 [95% CI, 1.01–1.34]) but still statistically significant. With adjustment for SES, the mortality hazards for Chinese and Hispanic participants also decreased in comparison with White participants. After further adjustment for additional risk factors and immigration history, Hispanic participants (HR, 0.77 [95% CI, 0.63–0.94]) had a lower mortality risk than White participants, and hazard ratios for Black participants (HR, 1.08 [95% CI, 0.92–1.26]) and Chinese participants (HR, 0.81 [95% CI, 0.60–1.08]) were not significantly different from those of White participants. Similar trends were seen for CVD mortality, although the age- and sex-adjusted HR for CVD mortality for Black participants compared with White participants was greater than all-cause mortality (HR, 1.72 [95% CI, 1.34–2.21] compared with HR, 1.34 [95% CI, 1.19–1.51]).

Conclusions:
These results highlight persistent racial and ethnic differences in overall and CVD mortality, largely attributable to social determinants of health, and support the need to identify and act on systemic factors that shape differences in health across racial and ethnic groups.
US Surveillance of Acute Ischemic Stroke Patient Characteristics, Care Quality, and Outcomes for 2019
Authors: Ziaeian Boback , Xu Haolin , Matsouaka Roland A. , Xian Ying , Khan Yosef , Schwamm Lee S. , Smith Eric E. , Fonarow Gregg C. 
Published: July 2022

Background:
The United States lacks a timely and accurate nationwide surveillance system for acute ischemic stroke (AIS). We use the Get With The Guidelines-Stroke registry to apply poststratification survey weights to generate national assessment of AIS epidemiology, hospital care quality, and in-hospital outcomes.

Methods:
Clinical data from the Get With The Guidelines-Stroke registry were weighted using a Bayesian interpolation method anchored to observations from the national inpatient sample. To generate a US stroke forecast for 2019, we linearized time trend estimates from the national inpatient sample to project anticipated AIS hospital volume, distribution, and race/ethnicity characteristics for the year 2019. Primary measures of AIS epidemiology and clinical care included patient and hospital characteristics, stroke severity, vital and laboratory measures, treatment interventions, performance measures, disposition, and clinical outcomes at discharge.

Results:
We estimate 552 476 patients with AIS were admitted in 2019 to US hospitals. Median age was 71 (interquartile range, 60–81), 48.8% female. Atrial fibrillation was diagnosed in 22.6%, 30.2% had prior stroke/transient ischemic attack, and 36.4% had diabetes. At baseline, 46.4% of patients with AIS were taking antiplatelet agents, 19.2% anticoagulants, and 46.3% cholesterol-reducers. Mortality was 4.4%, and only 52.3% were able to ambulate independently at discharge. Performance nationally on AIS achievement measures were generally higher than 95% for all measures but the use of thrombolytics within 3 hours of early stroke presentations (81.9%). Additional quality measures had lower rates of receipt: dysphagia screening (84.9%), early thrombolytics by 4.5 hours (79.7%), and statin therapy (80.6%).

Conclusions:
We provide timely, reliable, and actionable US national AIS surveillance using Bayesian interpolation poststratification weights. These data may facilitate more targeted quality improvement efforts, resource allocation, and national policies to improve AIS care and outcomes.
Application of Microwave Space-Based Environmental Monitoring (SBEM) Data for Operational Tropical Cyclone Intensity Estimation at the Joint Typhoon Warning Center
Authors: Howell Brian , Egan Sean , Fine Caitlin 
Published: July 2022

Abstract
The Joint Typhoon Warning Center (JTWC) utilized new space-based environmental monitoring (SBEM) data alongside traditional data to adjust JTWC tropical cyclone (TC) intensity and structure estimates during production of the official 2019 Best Track dataset. Intensity estimates from multiple platforms such as Advanced Microwave Scanning Radiometer-2 (AMSR2), the Soil Moisture Active Passive (SMAP) and Soil Moisture and Ocean Salinity (SMOS) radiometers, and synthetic aperture radar (SAR), along with objective Dvorak and satellite consensus algorithms, not only aided the poststorm best track (BT) process, but also provided robust data that supported real-time analysis and forecasting. This summary attempts to communicate with the TC community the extent to which these new data affected the 2019 official BT data, how JTWC utilized these new data in the poststorm BT process, and provide examples of how these data influenced forecaster decision-making in real time. This paper makes no attempt to validate the accuracy of the wind speed estimates from these methods (SAR, SMAP/SMOS, or AMSR2) and does not outline the entirety of the JTWC process for determining TC intensity, but it does outline, briefly, the impact of these new datasets on the final JTWC BT intensity estimates and on real-time analysis. These methodologies are valuable sources of cyclone intensity estimates in an otherwise data-sparse area of responsibility, and in many cases provide critical data not captured by traditional methods alone, which are detailed further in this summary.
An Ensemble Forecasting Method for Dealing with the Combined Effects of the Initial and Model Errors and a Potential Deep Learning Implementation
Authors: Duan Wansuo , Ma Junjie , Vannitsem Stéphane 
Published: July 2022

Abstract
In this paper, a new nonlinear forcing singular vector (NFSV) approach is proposed to provide mutually independent optimally combined modes of initial perturbations and model perturbations (C-NFSVs) in ensemble forecasts. The C-NFSVs are a group of optimally growing structures that take into account the impact of the interaction between the initial errors and the model errors effectively, generalizing the original NFSV for simulations of the impact of the model errors. The C-NFSVs method is tested in the context of the Lorenz-96 model to demonstrate its potential to improve ensemble forecast skills. This method is compared with the orthogonal conditional nonlinear optimal perturbations (O-CNOPs) method for estimating only the initial uncertainties and the orthogonal NFSVs (O-NFSVs) for estimating only the model uncertainties. The results demonstrate that when both the initial perturbations and model perturbations are introduced in the forecasting system, the C-NFSVs are much more capable of achieving higher ensemble forecasting skills. The use of a deep learning approach as a remedy for the expensive computational costs of the C-NFSVs is evaluated. The results show that learning the impact of the C-NFSVs on the ensemble provides a useful and efficient alternative for the operational implementation of C-NFSVs in forecasting suites dealing with the combined effects of the initial errors and the model errors.

Significance Statement
A new ensemble forecasting method for dealing with combined effects of initial errors and model errors, i.e., the C-NFSVs, is proposed, which is an extension of the NFSV approach for simulating the model error effects in ensemble forecasts. The C-NFSVs provide mutually independent optimally combined modes of initial perturbations and model perturbations. This new method is tested for generating ensemble forecasts in the context of the Lorenz-96 model, and there are indications that the optimally growing structures may provide reliable ensemble forecasts. Furthermore, it is found that a hybrid dynamical–deep learning approach could be a potential avenue for real-time ensemble forecasting systems when perturbations combine the impact of the initial and the model errors.
Kinematic Differences Between the Dominant and Nondominant Legs During a Single-Leg Drop Vertical Jump in Female Soccer Players
Authors: Nakahira Yu , Taketomi Shuji , Kawaguchi Kohei , Mizutani Yuri , Hasegawa Masato , Ito Chie , Uchiyama Emiko , Ikegami Yosuke , Fujiwara Sayaka , Yamamoto Ko , Nakamura Yoshihiko , Tanaka Sakae , Ogata Toru 
Published: July 2022

Background: In soccer, the roles of the dominant (kicking) and nondominant (supporting) legs are different. The kinematic differences between the actions of the dominant and nondominant legs in female soccer players are not clear. Purpose: To clarify the kinematic differences between dominant and nondominant legs during a single-leg drop vertical jump (DVJ) in female soccer players. Study Design: Controlled laboratory study. Methods: A total of 64 female high school and college soccer players were included in this study. Participants performed a single-leg DVJ test utilizing video motion capture with artificial intelligence during the preseason period. This study assessed the knee flexion angles, knee valgus angles, hip flexion angles, and lower leg anterior inclination angle at 3 time points (initial contact, maximum flexion of the knee, and toe-off) and compared them between the dominant and nondominant legs. These angles were calculated from motion capture data and analyzed in 3 dimensions. A paired t test was used to analyze the differences between legs, and the significance level was set at P < .05. Results: The knee valgus angle at initial contact was greater in the nondominant leg (mean ± SD, 0.8°± 5.2°) than the dominant leg (−0.9°± 4.9°) ( P < .01). There were no differences between legs for any other angles at any of the time points. Conclusion: The kinematics of the dominant and nondominant legs of female soccer players in a single-leg DVJ differ in knee valgus angle. Clinical Relevance: Leg dominance is associated with the risk of sports injuries. Kinematic differences between the dominant and nondominant legs may be a noteworthy factor in elucidating the mechanisms and risk of sports injury associated with leg dominance.
Creativity Development With Problem-Based Digital Making and Block-Based Programming for Science, Technology, Engineering, Arts, and Mathematics Learning in Middle School Contexts
Authors: Weng Xiaojing , Ng Oi-Lam , Cui Zhihao , Leung Suzannie 
Published: July 2022

Creativity, one of the cornerstones of students’ 21st-century skills, is regarded as an important learning outcome of science, technology, engineering, arts, and mathematics (STEAM) education. Meanwhile, problem-based digital making (DM), which combines the child-friendly programming activities of DM with problem-solving elements, is an emerging instructional design to facilitate STEAM learning. This qualitative case study examines the implementation of a problem-based DM instructional program that used the block-based programming tool Scratch to cultivate the participants’ creativity. Fifty-four middle school students (aged 10–14 years) in Hong Kong participated in the program, which totaled 10 contact hours over five consecutive weeks. Through triangulating students’ DM artifacts, video recordings, field notes, and interviews, the researchers characterized the students’ creative expression, examined the role of problem-based DM in encouraging creative work, and investigated the use of Scratch for mediating student creativity. The results showed that problem-based DM activities fostered students’ creative expressions in the dimensions of novelty, utility, aesthetics, and authenticity. While Scratch mediated the way the students presented their solutions, it had limitations that hindered the students’ digital artifact construction. The findings provide theoretical insights for framing creativity and offer practical implications for the implementation of problem-based DM in K–12 contexts.