bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a compact bidirectional promoter-driven dual chimeric antigen receptor (CAR) construct targeting CD19 and CD20 in the Sleeping Beauty (SB) transposon system
Authors: Khaniya Asmita , Rad S M Ali Hossieni , Halpin Josh , Tawinwung Supannikar , McLellan Alexander , Suppipat Koramit , Hirankarn Nattiya 
Published: April 2024

BackgroundA bidirectional promoter-driven chimeric antigen receptor (CAR) cassette provides the simultaneous expression of two CARs, which significantly enhances dual antigen-targeted CAR T-cell therapy.MethodsWe developed a second-generation CAR directing CD19 and CD20 antigens, incorporating them in a head-to-head orientation from a bidirectional promoter using a single Sleeping Beauty transposon system. The efficacy of bidirectional promoter-driven dual CD19 and CD20 CAR T cells was determined in vitro against cell lines expressing either, or both, CD19 and CD20 antigens. In vivo antitumor activity was tested in Raji lymphoma-bearing immunodeficient NOD-scid IL2Rgammanull(NSG) mice.ResultsOf all tested promoters, the bidirectional EF-1αpromoter optimally expressed transcripts from both sense (CD19-CAR) and antisense (GFP.CD20-CAR) directions. Superior cytotoxicity, cytokine production and antigen-specific activation were observed in vitro in the bidirectional EF-1αpromoter-driven CD19/CD20 CAR T cells. In contrast, a unidirectional construct driven by the EF-1αpromoter, but using self-cleaving peptide-linked CD19 and CD20 CARs, showed inferior expression and in vitro function. Treatment of mice bearing advanced Raji lymphomas with bidirectional EF-1αpromoter-driven CD19/CD20 CAR T cells effectively controlled tumor growth and extended the survival of mice compared with group treated with single antigen targeted CAR T cells.ConclusionThe use of bidirectional promoters in a single vector offers advantages of size and robust CAR expression with the potential to expand use in other forms of gene therapies like CAR T cells.
Machine learning classification of sphalerons and black holes at the LHC
Authors: Grefsrud Aurora Singstad , Buanes Trygve , Koutroulis Fotis , Lipniacka Anna , Masełek Rafał , Papaefstathiou Andreas , Sakurai Kazuki , Sjursen Therese B. , Slazyk Igor 
Published: April 2024

AbstractIn models with large extra dimensions, “miniature” black holes (BHs) might be produced in high-energy proton–proton collisions at the Large Hadron Collider (LHC). In the semi-classical regime, those BHs thermally decay, giving rise to large-multiplicity final states with jets and leptons. On the other hand, similar final states are also expected in the production of electroweak sphaleron/instanton-induced processes. We investigate whether one can discriminate these scenarios when BH or sphaleron-like events are observed in the LHC using machine learning (ML) methods. Classification among several BH scenarios with different numbers of extra dimensions and the minimal BH masses is also examined. In this study we consider three ML models: XGBoost algorithms with (1) high- and (2) low-level inputs, and (3) a Residual Convolutional Neural Network. In the latter case, the low-level detector information is converted into an input format of three-layer binned event images, where the value of each bin corresponds to the energy deposited in various detector subsystems. We demonstrate that only a small number of detected events are sufficient to effectively discriminate between the sphaleron and BH processes. Separation between BH scenarios with different minimal masses is possible with an order of 10 events passing the preselection. A sufficient number of events could be observed in combined Run-2 and -3 data, if the production cross section is not much smaller than the present limit $$\sim 0.1$$

∼
0.1

fb. We find, however, that a large number of events is needed to discriminate between BH hypotheses with the same minimal BH mass, but different numbers of extra dimensions.
Unimodular proca theory: breaking the U(1) gauge symmetry of unimodular gravity via a mass term
Authors: Isichei Raymond , Magueijo João 
Published: April 2024

AbstractWe study the Hamiltonian structure of unimodular-like theories, where the cosmological constant (or other supposed constants of nature) are demoted from fixed parameters to classical constants of motion. No new local degrees of freedom are present as a result of a U(1) gauge invariance of the theory. Hamiltonian analysis of the action reveals that the only possible gauge fixing that can be enforced is setting the spatial components of the four-volume time vector $$\mathcal{T}^{i}\approx 0$$

T

i

≈
0

. As a consequence of this, the gauge-fixed unimodular path integral is equivalent to the minisuperspace unimodular path integral. However, should we break the U(1) gauge invariance, two things happen: a massless propagating degree of freedom appears, and the (gauge-invariant) zero-mode receives modified dynamics. The implications are investigated, with the phenomenology depending crucially on the target “constant”.
Evaluating Gesture Generation in a Large-scale Open Challenge: The GENEA Challenge 2022
Authors: Kucherenko Taras , Wolfert Pieter , Yoon Youngwoo , Viegas Carla , Nikolov Teodor , Tsakov Mihail , Henter Gustav Eje 
Published: April 2024

This article reports on the second GENEA Challenge to benchmark data-driven automatic co-speech gesture generation. Participating teams used the same speech and motion dataset to build gesture-generation systems. Motion generated by all these systems was rendered to video using a standardised visualisation pipeline and evaluated in several large, crowdsourced user studies. Unlike when comparing different research articles, differences in results are here only due to differences between methods, enabling direct comparison between systems. The dataset was based on 18 hours of full-body motion capture, including fingers, of different persons engaging in a dyadic conversation. Ten teams participated in the challenge across two tiers: full-body and upper-body gesticulation. For each tier, we evaluated both the human-likeness of the gesture motion and its appropriateness for the specific speech signal. Our evaluations decouple human-likeness from gesture appropriateness, which has been a difficult problem in the field.
The evaluation results show some synthetic gesture conditions being rated as significantly more human-like than 3D human motion capture. To the best of our knowledge, this has not been demonstrated before. On the other hand, all synthetic motion is found to be vastly less appropriate for the speech than the original motion-capture recordings. We also find that conventional objective metrics do not correlate well with subjective human-likeness ratings in this large evaluation. The one exception is the Fréchet gesture distance (FGD), which achieves a Kendall’s tau rank correlation of around -0.5. Based on the challenge results we formulate numerous recommendations for system building and evaluation.
Cervicovaginal Metabolome and Tumor Characteristics for Endometrial Cancer Detection and Risk Stratification
Authors: Lorentzen Georgia M. , Łaniewski Paweł , Cui Haiyan , Mahnert Nichole D. , Mourad Jamal , Borst Matthew P. , Willmott Lyndsay , Chase Dana M. , Roe Denise J. , Herbst-Kralovetz Melissa M. 
Published: April 2024

Abstract

Purpose:
Endometrial cancer is highly prevalent and lacking noninvasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve the understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for noninvasive diagnostic and prognostic tests.

Experimental Design:
Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n = 66) and non-malignant conditions (n = 108), and global untargeted metabolomics was performed. Using the metabolite data (n = 920), we completed a multivariate biomarker discovery analysis.

Results:
We analyzed grade 1/2 endometrioid carcinoma (n = 53) and other endometrial cancer subtypes (n = 13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (P &lt; 0.0001), tryptophan (P &lt; 0.0001), and glutamate (P &lt; 0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q &lt; 0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion.

Conclusions:
Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement in diagnosis. The metabolic dysregulation described in this article linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighboring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of noninvasive diagnostics can improve both the acceptability and accessibility of diagnosis.
Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study
Authors: Weber Brittany , Weisenfeld Dana , Massarotti Elena , Seyok Thany , Cremone Gabrielle , Lam Ethan , Golnik Charlotte , Brownmiller Seth , Liu Feng , Huang Sicong , Todd Derrick J. , Coblyn Jonathan S. , Weinblatt Michael E. , Cai Tianrun , Dahal Kumar , Kohler Minna , Yinh Janeth , Barrett Leanne , Solomon Daniel H. , Plutzky Jorge , Schelbert Heinrich R. , Campisi Roxana , Bolster Marcy B. , Di Carli Marcelo , Liao Katherine P. 
Published: April 2024

Background
Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk.

Methods and Results

Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high‐sensitivity C‐reactive protein [hsCRP], interleukin‐1b, and high‐sensitivity cardiac troponin T [hs‐cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs‐cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs‐cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs‐cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64,
P
=0.6) or hs‐cTnT. A correlation was observed between a reduction in hsCRP and interleukin‐1b with a reduction in hs‐cTnT.

Conclusions
In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin‐1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02714881.
Invasive Cardiac Hemodynamics in Apical Hypertrophic Cardiomyopathy
Authors: Malik Awais A. , Saraswati Ushasi , Miranda William R. , Covington Megan , Scott Christopher G. , Lee Alex T. , Arruda‐Olson Adelaide , Geske Jeffrey B. , Klarich Kyle W. , Anand Vidhu 
Published: April 2024

Background
Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy.

Methods and Results
Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right‐sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right‐sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise‐induced elevation in left ventricular filling pressures.

Conclusions
In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right‐sided heart failure.
Perioperative Risk of Noncardiac Surgery in Patients With Asymptomatic Significant Aortic Stenosis: A 10‐Year Retrospective Study
Authors: Bak Minjung , Lee Seung‐Hwa , Park Sung‐Ji , Park Jungchan , Kim Jihoon , Kim Darae , Kim Eun Kyoung , Chang Sung‐A , Lee Sang‐Chol , Park Seung Woo 
Published: April 2024

Background
Aortic stenosis (AS) is a representative geriatric disease, and there is an anticipated rise in the number of patients requiring noncardiac surgeries in patients with AS. However, there is still a lack of research on the primary predictors of noncardiac perioperative complications in patients with asymptomatic significant AS.

Methods and Results

Among the cohort of noncardiac surgeries under general anesthesia, with an intermediate to high risk of surgery from 2011 to 2019, at Samsung Medical Center, 221 patients were identified to have asymptomatic significant AS. First, to examine the impact of significant AS on perioperative adverse events, the occurrences of major adverse cardiovascular events and perioperative adverse cardiovascular events were compared between patients with asymptomatic significant AS and the control group. Second, to identify the factors influencing the perioperative adverse events in patients with asymptomatic significant AS, a least absolute shrinkage and selection operator regression model was used. There was no significant difference between the control group and the asymptomatic significant AS group in the event rate of major adverse cardiovascular events (4.6% at control group versus 5.5% at asymptomatic significant AS group;
P
=0.608) and perioperative adverse cardiovascular events (13.8% at control group versus 18.3% at asymptomatic significant AS group;
P
=0.130). Cardiac damage stage was a significant risk factor of major adverse cardiovascular events and perioperative adverse cardiovascular events.

Conclusions
There was no significant difference in major postoperative cardiovascular events between patients with asymptomatic significant AS and the control group. Advanced cardiac damage stage in significant AS is an important factor in perioperative risk of noncardiac surgery.
Screening of probiotic strains to improve visceral hypersensitivity in irritable bowel syndrome by using in vitro and in vivo approaches
Authors: Torres-Maravilla E. , Carvalho F.A. , Holowacz S. , Delannoy J. , Lenoir L. , Jacouton E. , Barbut F. , Langella P. , Bermúdez-Humarán L.G. , Waligora-Dupriet A.-J. 
Published: April 2024

Abstract
Oral administration of probiotics has been proposed as a promising biotherapy to prevent and treat different diseases related to gastrointestinal disorders, such as irritable bowel syndrome (IBS). Due to the increasing research area on the characterisation of new probiotic bacterial strains, it is necessary to perform suitable in vitro experiments, using pertinent cellular models, in order to establish appropriate readout profiles based on IBS symptoms and subtypes. In this work, a collection of 30 candidate strains, belonging mainly to the Lactobacillus and Bifidobacterium genera, were screened using three different sets of in vitro experiments with different readouts to identify promising probiotic strains with: (1) the ability to inhibit the synthesis of IL-8 production by TNF-α stimulated HT-29 cells, (2) immunomodulatory properties quantified as increased IL-10 levels in peripheral blood mononuclear cell (PBMCs), and (3) the ability to maintain epithelial barrier integrity by increasing the trans-epithelial/endothelial electrical resistance (TEER) values in Caco-2 cells. Based on these criteria, three strains were selected: Lactobacillus gasseri PI41, Lacticaseibacillus rhamnosus PI48 and Bifidobacterium animalis subsp. lactis PI50, and tested in a murine model of low-grade inflammation induced by dinitrobenzene sulfonic acid (DNBS), which mimics some of the symptoms of IBS. Among the three strains, L. gasseri PI41 improved overall host well-being by preventing body weight loss in DNBS-treated mice and restored gut homeostasis by normalising the intestinal permeability and reducing pro-inflammatory markers. Therefore, the potential of this strain was confirmed in a second murine model known to reproduce IBS symptoms: the neonatal maternal separation (NMS) model. The PI41 strain was effective in preventing intestinal permeability and reducing colonic hypersensitivity. In conclusion, the set of in vitro experiments combined with in vivo assessments allowed us to identify a promising probiotic candidate strain, L. gasseri PI41, in the context of IBS.
The Legal Definition of Artificial Intelligence
Authors: Chiappini Daniele 
Published: April 2024

Abstract
In the last five years, several issues related to the development of artificial intelligence have been tackled by various countries and international organisations and the legal definition is one of them. Fundamentally to understand what Artificial Intelligence is, and when to apply the related rules, the definition issue is addressed in this essay considering various documents adopted by several countries and international organizations, such as the European Union, United Kingdom, United States of America, China and the Organization for Economic Co-operation and Development (oecd). Moreover, the paper also considers the intended meaning of “trustworthy ai” in considered countries and supranational organizations and eventually, aims to give a comprehensive definition of Artificial Intelligence starting from what is exposed and trying to merge the considered solutions.
Defatted black soldier fly larvae meal in lactating sow and pre-weaning piglet diets: impacts on growth performance, fecal microbiota, and metabolic pathways
Authors: Zhao J. , Sato M. , Takao N. , Ban T. , Tamamaki K. , Kagami M. , Yano K. , Kawasaki K. 
Published: April 2024

Abstract
To address the underexplored use of black soldier fly larval (BSFL) meal in pig farming for sustainable development, this study examined the effects of substituting conventional protein with defatted BSFL meal in the pre-weaning diet of piglets farrowed from sows fed defatted BSFL diets (0%, 2.3%, and 4.6%). Fifty-four piglets (18 piglets in each treatment) were housed with sows until 28 days of age and fed a pre-weaning diet containing 0%, 12.5%, or 25% defatted BSFL meal based on their respective sows’ dietary treatments (0%, 2.3%, and 4.6% defatted BSFL diets) from 21 to 35 days of age. The growth performances and fecal microbiota of piglets were investigated. The results showed that sow diets and defatted BSFL meal-incorporated pre-weaning diets did not have a significant effect on the growth performance of piglets (). However, piglet growth tended to decrease with increasing defatted BSFL meals in the pre-weaning diets. Additionally, piglets nursed by sows fed defatted BSFL diets showed higher fecal short-chain fatty acid and lower ammonia levels at 21 days of age than those nursed by sows fed a control diet (). Furthermore, defatted BSFL meal-incorporated pre-starter diets decreased fecal amino acids and modified the gut microbial metabolic pathways associated with stress response. These findings suggest that the appropriate inclusion of defatted BSFL meal in the diets of lactating sows and piglets did not adversely affect the growth performance of piglets and may potentially improve the health of piglets at weaning; however, attention should be paid to the chitin content in BSFL diets, which may affect nutrient digestibility. Incorporating 2.3% defatted BSFL to sow and 12.5% to pre-weaning piglet diets may serve as a feeding strategy in pig farming. The results obtained will aid the application of BSFL meal in the swine industry and the study of its dietary effect on weaning stress in piglets.
Risk Factors for Skin Flap and Nipple-Areolar Necrosis in Patients Undergoing Nipple-Sparing Mastectomy With Deep Inferior Epigastric Perforator Flap Reconstruction
Authors: Ray Hannah R. , Doren Erin L. , Adamson Karri , Kong Amanda L. , Cortina Chandler S. 
Published: April 2024

Introduction Nipple-sparing mastectomy (NSM) with deep inferior epigastric perforator (DIEP) flap reconstruction is a surgical option for select patients with or at risk of breast cancer. However, post-operative skin flap and nipple-areolar complex (NAC) necrosis remain common complications. This study aimed to identify factors associated with necrosis in patients undergoing NSM with DIEP reconstruction. Methods A retrospective cohort study was performed from 2015 to 2023. 74 variables were analyzed in patients undergoing NSM with DIEP. Patients were stratified into 3 groups based on post-operative skin/NAC necrosis: none, partial thickness, and full thickness. Comparative and descriptive statistics were performed via t-tests, ANOVA, and chi-squared tests. Results 34 women with 31 breast cancers met inclusion. 44% experienced necrosis: 15% partial thickness and 29% full thickness. The majority were white (85.3%) with mean age of 50 years (SD = 9.11). In patients with immediate DIEP reconstruction, hypoperfused areas identified by SPY angiography increased risk of necrosis ( P = .012). Approximately 50% of both partial thickness and full thickness necrosis patients had concerns on SPY angiography. Former smokers in the full thickness necrosis group had more pack years than those without necrosis (9 vs .65 pack years, P = .035). Conclusion In patients receiving NSM with DIEP flap reconstruction, those with hypoperfusion on SPY angiography and longer smoking history had higher necrosis rates. This supports the continued used of SPY angiography and the role of pre-operative counseling in former smokers with increased pack years on their risk of necrosis and the role of preventative measures in the perioperative setting.