bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifurcations of a discrete-time SIR epidemic model with logistic growth of the susceptible individuals
Authors: Eskandari Z. , Khoshsiar Ghaziani R. , Avazzadeh Z.
Published: October 2022

This study focuses on the stability and local bifurcations of a discrete-time SIR epidemic model with logistic growth of the susceptible individuals analytically, and numerically. The analytical results are obtained using thenormal form technique and numerical results are obtained using the numerical continuation method. For this model, a number of bifurcations are studied, including the transcritical (pitchfork) and flip bifurcations, the Neimark–Sacker (NS) bifurcations, and the strong resonance bifurcations. We especially determine the dynamical behaviors of the model for higher iterations up to fourth-order. Numerical simulation is employed to present a closed invariant curve emerging about an NS point, and its breaking down to several closed invariant curves and eventuality giving rise to a chaotic strange attractor by increasing the bifurcation parameter.
Modules whose z-closed submodules are essentially embedded in summands
Authors: Mutlu Figen Takil , Tercan Adnan
Published: October 2022

In this paper, we work out modules with the property that every [Formula: see text]-closed submodules are essentially embedded in direct summands. This class of modules properly contains the class of CS-modules as well as some of their generalizations. It is shown that the class of modules with former property is closed under direct sums under a certain condition. Taking into account this case, we obtain several results on the inheritance of the latter closure property. Moreover, we consider the behavior of this new property for extensions of modules.
The new wizard of Menlo Park
Authors: Clegg Brian
Published: October 2022

From the intersection of computational science and technological speculation, with boundaries limited only by our ability to imagine what could be.

An ambitious reporter's quest to interview a reclusive tech CEO leads her to find out who really pulls the strings.
Rethinking Silicon Valley
Authors: Markoff John
Published: October 2022

Discovering a hidden chapter in computing history.
Up with data science, and the first programmer
Authors: Hazzan Orit , Mike Koby , Bruderer Herbert
Published: October 2022

The
Communications
website, https://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

twitter

Follow us on Twitter at http://twitter.com/blogCACM

https://cacm.acm.org/blogs/blog-cacm

Orit Hazzan and Koby Mike suggest a more focused approach to teaching machine learning, while Herbert Bruderer considers the identity of the first programmer.
A Framework for Online Hate Speech Detection on Code-mixed Hindi-English Text and Hindi Text in Devanagari
Authors: Chopra Abhishek , Sharma Deepak Kumar , Jha Aashna , Ghosh Uttam
Published: October 2022

Social Media has been growing and has provided the world with a platform to opine, debate, display, and discuss like never before. It has a major influence in research areas that analyze human behavior and social groups, and the phenomenon of social interactions is even being used in areas such as Internet of Things. This constant stream of data connecting individuals and organizations across the globe has had a tremendous impact on the functioning of society and even has the power to sway elections. Despite having numerous benefits, social media has certain issues such as the prevalence of fake news, which has also led to the rise of the hate speech phenomenon. Due to lax security throughout these social media platforms, these issues continue to exist without any repercussions. This leads to cyberbullying, defamation, and presents grave security concerns. Even though some work has been done independently on native scripts, hate speech detection, and code-mixed data, there exists a lack of academic work and research in the area of detecting hate speech in transliterated code-mixed data and in-text containing native language scripts. Research in this field is inhibited greatly due to the multiple variations in grammar and spelling and in general a lack of availability of annotated datasets, especially when it comes to native languages. This article comes up with a method to automate hate speech detection in code-mixed and native language text. The article presents an architecture containing a Tabnet classifier-based model trained on features extracted using MuRIL from transliterated code-mixed textual data. The article also shows that the same model works well on features extracted from text in Devanagari despite being trained on transliterated data.
On the User Behavior Leakage from Recommender System Exposure
Authors: Xin Xin , Yang Jiyuan , Wang Hanbing , Ma Jun , Ren Pengjie , Luo Hengliang , Shi Xinlei , Chen Zhumin , Ren Zhaochun
Published: October 2022

Modern recommender systems are trained to predict users’ potential future interactions from users’ historical behavior data. During the interaction process, despite the data coming from the user side, recommender systems also generate exposure data to provide users with personalized recommendation slates. Compared with the sparse user behavior data, the system exposure data are much larger in volume since only very few exposed items would be clicked by the user. In addition, user historical behavior data are privacy sensitive and commonly protected with careful access authorization. However, the large volume of recommender exposure data generated by the service provider itself usually receives less attention and could be accessed within a relatively larger scope of various information seekers or even potential adversaries.

In this article, we investigate the problem of user behavior data leakage in the field of recommender systems. We show that the privacy-sensitive user past behavior data can be inferred through the modeling of system exposure. In other words,
one can infer which items the
user
has clicked just from the observation of current
system
exposure for this user
. Given the fact that system exposure data could be widely accessed from a relatively larger scope, we believe that user past behavior privacy has a high risk of leakage in recommender systems. More precisely, we conduct an attack model whose input is the current recommended item slate (i.e., system exposure) for the user while the output is the user’s historical behavior. Specifically, we exploit an encoder-decoder structure to construct the attack model and apply different encoding and decoding strategies to verify attack performance. Experimental results on two real-world datasets indicate a great danger of user behavior data leakage. To address the risk, we propose a two-stage privacy-protection mechanism that first selects a subset of items from the exposure slate and then replaces the selected items with uniform or popularity-based exposure. Experimental evaluation reveals a trade-off effect between the recommendation accuracy and the privacy disclosure risk, which is an interesting and important topic for privacy concerns in recommender systems.
The Role of Zoos and Aquariums in a Changing World
Authors: Miranda Rafael , Escribano Nora , Casas María , Pino-del-Carpio Andrea , Villarroya Ana
Published: October 2022

Zoos and aquariums have evolved significantly. From their origins as enclosures for the mere entertainment of the public, these institutions have undertaken new functions responding to the biodiversity crisis and social demands. Modern zoos and aquariums have the opportunity to educate people, contribute to species conservation, and produce animal-related research. However, there is increasing criticism toward the outcomes of their actions and the holding of species in their facilities. This review offers an integrated analysis of the state of knowledge about the role that zoos and aquariums play today. It describes their performance regarding their conservation, education, and research functions, highlighting general patterns and offering future perspectives. It identifies some challenges common to all these institutions, concluding that the way they keep up with the ever-growing social and environmental expectations will be decisive hereafter.
Non-Hermitian Topological Phenomena: A Review
Authors: Okuma Nobuyuki , Sato Masatoshi
Published: October 2022

The past decades have witnessed an explosion of interest in topological materials, and a lot of mathematical concepts have been introduced in condensed matter physics. Among them, the bulk-boundary correspondence is the central topic in topological physics, which has inspired researchers to focus on boundary physics. Recently, the concepts of topological phases have been extended to non-Hermitian Hamiltonians, whose eigenvalues can be complex. Besides the topology, non-Hermiticity can also cause a boundary phenomenon called the non-Hermitian skin effect, which is an extreme sensitivity of the spectrum to the boundary condition. In this article, we review developments in non-Hermitian topological physics by focusing mainly on the boundary problem. As well as the competition between non-Hermitian and topological boundary phenomena, we discuss the topological nature inherent in non-Hermiticity itself.
Six Statistical Senses
Authors: Craiu Radu V. , Gong Ruobin , Meng Xiao-Li
Published: October 2022

This article proposes a set of categories, each one representing a particular distillation of important statistical ideas. Each category is labeled a “sense” because we think of these as essential in helping every statistical mind connect in constructive and insightful ways with statistical theory, methodologies, and computation, toward the ultimate goal of building statistical phronesis. The illustration of each sense with statistical principles and methods provides a sensical tour of the conceptual landscape of statistics, as a leading discipline in the data science ecosystem.
Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals
Authors: Ripplinger Crystal M. , Glukhov Alexey V. , Kay Matthew W. , Boukens Bastiaan J. , Chiamvimonvat Nipavan , Delisle Brian P. , Fabritz Larissa , Hund Thomas J. , Knollmann Bjorn C. , Li Na , Murray Katherine T. , Poelzing Steven , Quinn T. Alexander , Remme Carol Ann , Rentschler Stacey L. , Rose Robert A. , Posnack Nikki G.
Published: October 2022

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, preclinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, and drug effects and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for the assessment of cardiac electrophysiology and a plethora of parameters may be assessed with each approach. This guidelines article will provide an overview of the strengths and limitations of several common techniques used to assess electrophysiology and arrhythmia mechanisms at the whole animal, whole heart, and tissue level with a focus on small animal models. We also define key electrophysiological parameters that should be assessed, along with their physiological underpinnings, and the best methods with which to assess these parameters.

Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-cardiac-electrophysiology/ .
Brain insulin resistance and cognitive function: influence of exercise
Authors: Malin Steven K. , Stewart Nathan R. , Ude Andrew A. , Alderman Brandon L.
Published: October 2022

Exercise has systemic health benefits in people, in part, through improving whole body insulin sensitivity. The brain is an insulin-sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. Although brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer’s disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer’s dementia.
miR-31 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviates Intervertebral Disc Degeneration by Inhibiting NFAT5 and Upregulating the Wnt/β-Catenin Pathway
Authors: Wang Baodong , Xu Na , Cao Li , Yu Xiaojun , Wang Shanxi , Liu Qikun , Wang Yinguang , Xu Haoran , Cao Yang
Published: October 2022

In this study, we explored the regulatory mechanism of intervertebral disc degeneration (IDD) that involves miR-31 shuttled by bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) and its downstream signaling molecules. Nucleus pulposus cells (NPCs) were isolated and treated with TNF-α to simulate IDD in vitro. The TNF-α-exposed NPCs were then cocultured with hBMSCs or hBMSC-EVs in vitro to detect the effects of hBMSC-EVs on NPC viability, apoptosis, and ECM degradation. Binding between miR-31 and NFAT5 was determined. A mouse model of IDD was prepared by vertebral disc puncture and injected with EVs from hBMSCs with miR-31 knockdown to discern the function of miR-31 in vivo. The results demonstrated that hBMSC-EVs delivered miR-31 into NPCs. hBMSC-EVs enhanced NPC proliferation and suppressed cell apoptosis and ECM degradation, which was associated with the transfer of miR-31 into NPCs. In NPCs, miR-31 bound to the 3

′

UTR of NFAT5 and inhibited NFAT5 expression, leading to activation of the Wnt/β-catenin pathway and thus promoting NPC proliferation and reducing cell apoptosis and ECM degradation. In addition, miR-31 in hBMSC-EVs alleviated the IDD in mouse models. Taken together, miR-31 in hBMSC-EVs can alleviate IDD by targeting NFAT5 and activating the Wnt/β-catenin pathway.
LQR Active Control of Fractional-Order Pantograph-Catenary System Based on Feedback Linearization
Authors: Wang Beining , Wen Shaofang , Shen Yongjun
Published: October 2022

Fractional-order calculus has exclusive advantages in modeling the viscoelastic components with obvious fractional-order characteristics such as air springs and metal rubbers in the pantograph structure. In this paper, the air spring is tested, and fractional-order calculus is applied to the modeling of pantograph-catenary system of the high-speed train. The parameter identification method of fractional-order derivative is analytically derived. The traditional lumped mass model is improved and a coupling two-degree-of-freedom model of the fractional-order pantograph-catenary system is established. The fractional-order derivative term in the pantograph-catenary model is approximately calculated by the Oustaloup filter algorithm. Taking the time-varying nature into consideration, the catenary is treated as an extended variable to obtain an augmented model. On this basis, the system is linearized based on differential geometry theory, and an LQR controller is designed to control the pantograph-catenary system. The feedback linearized LQR control and PID control are used to control the same type of traditional pantograph, and the results are compared. Meanwhile, the control effects of feedback linearized LQR control under different pantograph parameters and at different train speeds are analyzed. The results show that the feedback linearized LQR control can present a much better control performance than PID control, and the pantograph-catenary contact force and pantograph head vibration amplitude are both reduced obviously. Even at different train speeds or under different pantograph parameters, it can also effectively reduce these control indexes and provide more robust control performance. These results help to put forward new control ideas and theoretical basis for the vibration control of the pantograph-catenary or similar dynamical system.
Variations of Nutrient and Antinutrient Components of Bambara Groundnut (Vigna subterranea (L.) Verdc.) Seeds
Authors: Olanrewaju Oluwaseyi Samuel , Oyatomi Olaniyi , Abberton Michael , Babalola Olubukola Oluranti
Published: October 2022

Bambara groundnut (BGN) fits the bill when it comes to an acceptable level of nutrient and mineral composition. BGN is a balanced food that can help eradicate food and nutritional insecurity if it is incorporated into the major food system. However, there is a large degree of variation in nutrient composition and antinutritional factors among BGN accessions. Here, we show the degree of variability of nutrient and antinutrient components such as percentage ash, moisture, protein, fat, tryptophan, tannin, and phytate contents in seeds of 95 accessions of BGN. Data were subjected to analysis of variance (ANOVA), followed by correlation and principal component analysis. Clustering was done to show the relatedness between the accessions in response to the various traits. A high level of heterogeneity was observed among the accessions for the various traits studied. PC1 and PC2 show 41.2% of the total observed variations. Cluster analysis grouped accessions into four main clusters. This study was able to confirm the high level of diversity in the components of nutrients and antinutrients previously reported in BGN. The results of this study are expected to aid in identifying parent lines for improved breeding programs.
Fluorescence Radiation and Thermal Effect at the Edge of the Disk-Shaped Laser Crystal
Authors: Chen Yongqian , Chen Si , Huang Yuzhi , Jia Xianshi , Chen Hantian , Wu Xiwang
Published: October 2022

The fluorescence radiation property at the edge of the thin disk crystal is very important to the design of thin disk lasers. In order to study this effect, in this paper, we established a theoretical model to describe the edge fluorescence radiation process in thin disk lasers. Subsequently, we used a thin disk crystal with indium absorption cladding to quantitatively test the edge fluorescence intensity. The significant difference between measured and simulated data can be described as P (probability value) < 0.1 at the edge when the measured temperature is lower than the melting point of the metal cladding, and

P
<
0.05

at the pump area. Finally, we analyze the influence of the edge fluorescence radiation on the thin disk laser operation, and the results show that the edge thermal effect will reduce the conversion efficiency of the disk laser by 20%. To the best of our knowledge, this is the first quantitative study on the edge radiation intensity of disk lasers. The research can provide theoretical guidance for the designing and packaging process of crystal elements in thin disk lasers.
Vascular Protective Effects of Malus toringoides (Rehd.) Hughes Extracts and their Mechanism in Diabetic Rats and HUVECs
Authors: Wang Xiangyu , Wang Tong , Gao Liying , Dikye Tsering , Dong Linsha , Yuan Ruiying , Meng Ning , Yang Jing , Woo Eun-Rhan , Lee Dong-Sung , Wang Yuefei , Li Bin , Huang Shan
Published: October 2022

Malus toringoides (Rehd.) Hughes (Rosaceae) is used as a traditional folk medicine in the Tibet autonomous region of China to treat hypertension, hyperglycemia, and hyperlipidemia. However, few modern pharmacological data on the use of this plant against diabetic syndrome are available. In this study, we examined the vascular protection provided by a 70% ethanol extract of M. toringoides (EMT) in human umbilical vein endothelial cells (HUVECs) grown in high-glucose medium and in a high-fat diet/streptozotocin-induced rat diabetes model. EMT significantly suppressed the expression of cell adhesion molecules in both HUVECs and diabetic rats. EMT also inhibited activation of the CX3CL1/CX3CR1 axis and the nuclear factor kappa B (NF-κB) signaling pathway in vivo and in vitro. The results provide a significant information on the vasoprotective properties of M. toringoides that may contribute to the development and application of related herbal medicines.
Trajectory Privacy Protection Based on Sensitive Stay Area Replacement in Publishing
Authors: Yali Ji , Xiaolin Gui , Huijun Dai , Jian An , Hongyi Zhu , Zhenlong Peng , Xinyang Lin
Published: October 2022

In data opening and sharing, a trajectory privacy protection based on sensitive stay area replacement (SSAR) is proposed in order to improve the availability of protected trajectory while maintaining the same security. Firstly, the stay areas are extracted by analyzing the movement characteristics. Secondly, the sensitive stay areas are obtained according to the user-defined sensitive semantic positions. Then, the sensitive areas are constructed according to the user's privacy requirement needs to randomly select the substitution. Finally, part of the sampling positions in the sensitive area are reset. The parameter selection experiment and the comparison experiment with other schemes show that the trajectory similarity is improved by more than 35% in SSAR. That is to say, SSAR can greatly improve the availability of protected trajectory on the basis of ensuring the safety degree.
The Correlation between the Triglyceride-Glucose Index and Coagulation Markers in Patients with Recent Acute Myocardial Infarction
Authors: Košuta Daniel , Novaković Marko , Božič Mijovski Mojca , Jug Borut
Published: October 2022

Background. Metabolic abnormalities and hypercoagulability seem to have an important predictive role in patients with coronary artery disease (CAD). The triglyceride-glucose (TyG) index has emerged as a good marker for metabolic syndrome with predictive value for cardiovascular events. Overall haemostatic potential (OHP) is a reliable global haemostatic essay to identify hypercoagulability in CAD patients. The aim of our study was therefore to evaluate a possible correlation between the TyG index and haemostatic derangements in patients with CAD. Methods. Consecutive patients referred for the first follow-up visit after acute myocardial infarction between December 1, 2018, and March 31, 2020, and did not meet exclusion criteria were included. We determined OHP, overall coagulation potential (OCP), overall fibrinolytic potential (OFP), fibrinogen, D-dimer, and von Willebrand factor from peripheral blood samples. The TyG index was calculated with the previously described and validated formula. Linear regression models were constructed for the multivariate analysis. Results. A total of 117 patients (mean age

56
±
10

years, 20% women) were included. A correlation was found between TyG index and OCP (

r
=
0.229
,
p
=
0.026

), TyG index and OHP (

r
=
0.202
,
p
=
0.050

), and TyG index and fibrinogen (

r
=
0.271
,
p
=
0.005

). In the multivariate model which accounted for sex, age, and BMI, the correlation between TyG index and OCP (

R

2

0.108; ANOVA for regression

p
=
0.035

; beta 2.08 [0.79-4.01],

p
=
0.042

) and between TyG index and fibrinogen (

R

2

0.11; ANOVA for regression

p
=
0.015

; beta 0.35 [0.08-0.62],

p
=
0.012

) emerged as statistically significant. Conclusion. The TyG index, a marker of metabolic syndrome, has a strong correlation with a hypercoagulability state in CAD, as determined by the OCP and higher fibrinogen levels. Our findings suggest that metabolic syndrome may be an important driver of atherothrombotic risk in patients with CAD.
A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition
Authors: Soto-Feliciano Yadira M. , Sánchez-Rivera Francisco J. , Perner Florian , Barrows Douglas W. , Kastenhuber Edward R. , Ho Yu-Jui , Carroll Thomas , Xiong Yijun , Anand Disha , Soshnev Alexey A. , Gates Leah , Beytagh Mary Clare , Cheon David , Gu Shengqing , Liu X. Shirley , Krivtsov Andrei V. , Meneses Maximiliano , de Stanchina Elisa , Stone Richard M. , Armstrong Scott A. , Lowe Scott W. , Allis C. David
Published: October 2022

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1–Menin and MLL3/4–UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials.

Significance:

Menin–MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin–MLL inhibitor–resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses.

This article is highlighted in the In This Issue feature, p. 1
Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON
Authors: Hartmaier Ryan J. , Markovets Aleksandra A. , Ahn Myung Ju , Sequist Lecia V. , Han Ji-Youn , Cho Byoung Chul , Yu Helena A. , Kim Sang-We , Yang James Chih-Hsin , Lee Jong-Seok , Su Wu-Chou , Kowalski Dariusz M. , Orlov Sergey , Ren Song , Frewer Paul , Ou Xiaoling , Cross Darren A.E. , Kurian Nisha , Cantarini Mireille , Jänne Pasi A.
Published: October 2022

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non–small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations.

Significance:

The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making.

This article is highlighted in the In This Issue feature, p. 1
Enhancing the Antitumor Immunity of T Cells by Engineering the Lipid-Regulatory Site of the TCR/CD3 Complex
Authors: Liang Wenhua , Yi Ruirong , Wang Weifang , Shi Yiwei , Zhang Jiqin , Xu Xiang , Wang Qingcan , Liu Mingyao , Wang Feng
Published: October 2022

The engagement of the T-cell receptor (TCR) by a specific peptide–MHC ligand initiates transmembrane signaling to induce T-cell activation, a key step in most adaptive immune responses. Previous studies have indicated that TCR signaling is tightly regulated by cholesterol and its sulfate metabolite, cholesterol sulfate (CS), on the membrane. Here, we report a novel mechanism by which CS modulates TCR signaling through a conformational change of CD3 subunits. We found that the negatively charged CS interacted with the positively charged cytoplasmic domain of CD3ε (CD3εCD) to enhance its binding to the cell membrane and induce a stable secondary structure. This secondary structure suppressed the release of CD3εCD from the membrane in the presence of Ca2+, which in turn inhibited TCR phosphorylation and signaling. When a point mutation (I/A) was introduced to the intracellular immunoreceptor tyrosine-based activation motifs (YxxI-x6–8-YxxL) of CD3ε subunit, it reduced the stability of the secondary structure and regained sensitivity to Ca2+, which abolished CS-mediated inhibition and enhanced the signaling of the TCR complex. Notably, the I/A mutation could be applied to both murine and human TCR-T cell therapy to improve the antitumor efficacy. Our study reveals insights into the regulatory mechanism of TCR signaling and provides a strategy to functionally engineer the TCR/CD3 complex for T cell–based cancer immunotherapy.
Magnifying Narrow-Band Imaging with Acetic Acid Spray for Superficial Non-Ampullary Duodenal Epithelial Tumors Based on the Mucin Phenotype
Authors: Tanaka Yasuyuki , Fujii Shigehiko , Okada Keijiro , Aoki Kentaro , Shibuya Shinsuke , Kusaka Toshihiro
Published: October 2022

Introduction: This study aimed to identify the characteristics of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on the mucin phenotype using magnifying narrow-band imaging with acetic acid spray (MA-NBI) and evaluate the efficacy of MA-NBI in differentiating gastric-type (G-type) from intestinal-type (I-type) lesions. Methods: We retrospectively identified 59 resected SNADETs in 59 patients who underwent MA-NBI. We evaluated surface patterns using MA-NBI to differentiate G-type from I-type lesions. Surface structures were classified into three patterns: tubular, villous, or oval structures. Lesions displaying a single pattern among the three patterns were classified as monotype, whereas those displaying multiple surface patterns were classified as mixed type. In addition, lesions with disorganized and unclear structures with irregular margins were classified as irregular surface structures. Results: In total, 32 (54%), 26 (44%), and 1 (2%) lesions were classified as Vienna category 3, 4, and 5 tumors, respectively, whereas 49 (83%) and 10 (17%) were classified as I- and G-type lesions, respectively. Oval structures were more frequently observed in G-type lesions (70%), whereas tubular structures were more frequently observed in I-type lesions (78%) (p < 0.001). Category 4 and 5 lesions had significantly higher mixed and irregular surface structure rates than category 3 lesions (41 vs. 6%, p = 0.003 and 81 vs. 3%, p < 0.001, respectively). Conclusion: MA-NBI can distinguish the mucin phenotypes of SNADETs and may facilitate histological grade diagnosis.
Allergy Workup in the Diagnosis of COVID-19 Vaccines-Induced Hypersensitivity Reactions and Its Impact on Vaccination
Authors: Petrelli Fiorella , Giannini Daiana , Pucci Celestino , Del Corso Isabella , Rocchi Valeria , Dolcher Maria Pia , Pieve Giulio , Pratesi Federico , Migliorini Paola , Puxeddu Ilaria
Published: October 2022

Introduction: Immediate and delayed hypersensitivity reactions (HSR) to COVID-19 vaccines are rare adverse events that need to be prevented, diagnosed, and managed in order to guarantee adherence to the vaccination campaign. The aims of our study were to stratify the risk of HSR to COVID-19 vaccines and propose alternative strategies to complete the vaccination. Methods: 1,640 subjects were screened for vaccinal eligibility, according to national and international recommendations. Among them, we enrolled for allergy workup 152 subjects, 43 with HSR to COVID-19 vaccines and 109 at high risk of HSR to the first dose. In vivo skin tests with drugs and/or vaccines containing PEG/polysorbates were performed in all of them, using skin prick test and, when negative, intradermal tests. In a subgroup of patients resulted negative to the in vivo skin tests, the programmed dose of COVID-19 vaccine (Pfizer/BioNTech) was administered in graded doses regimen, and detection of neutralizing anti-spike antibodies was performed in these patients after 4 weeks from the vaccination, using the SPIA method. Results: Skin tests for PEG/polysorbates resulted positive in only 3% (5/152) of patients, including 2 with previous HSR to COVID-19 vaccines and 3 at high risk of HSR to the first dose. Among the 147 patients with negative skin tests, 97% (143/147) were eligible for vaccination and 87% (124/143) of them received safely the programmed COVID-19 vaccine dose. Administration of graded doses of Pfizer/BioNTech vaccine were well tolerated in 17 out of 18 patients evaluated; only 1 developed an HSR during the vaccination, less severe than the previous one, and all developed neutralizing anti-spike antibodies after 4 weeks with values comparable to those subjects who received the vaccine in unfractionated dose. Conclusion: On the whole, the usefulness of the skin tests for PEG/polysorbates seems limited in the diagnosis of HSR to COVID-19 vaccines. Graded doses regimen (Pfizer/BioNTech) is a safe and effective alternative strategy to complete the vaccinal course.
Isolation and in vitro Expansion of Regulatory T Cells from β-Thalassemia Major Kids and in vitro Evaluation of Their Plasticity and Inhibitory Effects in the Presence of Pro-Inflammatory Cytokines
Authors: Mansourabadi Amir Hossein , Mohamed Khosroshahi Leila , Noorbakhsh Farshid , Hamidieh Amir Ali , Amirzargar Aliakbar
Published: October 2022

Introduction: Graft-versus-host disease (GvHD) is a life-threatening syndrome commonly associated with hematopoietic stem cell transplantation (HSCT). Preventing the incidence of GVHD after HSCT along with minimizing long-term immunosuppression is currently under investigation with regulatory T cells (Tregs). As Tregs are a low-frequency population and the yield of all memory Tregs is not sufficient for clinical application, an initial Treg expansion is essential. Methods: Thirty milliliters of peripheral blood from the β-thalassemia major (beta-TM) patients and healthy controls were obtained and Tregs were isolated using MACS. Isolated cells were cultured in the presence of rapamycin and rIL-2 followed by activated with anti-CD3/CD28-coated beads. To evaluate Treg plasticity, expanded Tregs were cultured in a medium containing IL1β, IL6, TGFβ, and IL2, with or without 500 nM rapamycin for 72 h. To assess the functional properties of Tregs, CFSE dilution assays were performed to evaluate the ability of in vivo expanded Tregs from beta-TM patients. Statistical analysis was performed using paired t-test and independent t-test, with the aid of SPSS version 12.0. p-value ≤0.05 was considered significant. Results: The percentage of Tregs isolated from the control group was significantly higher than the Tregs isolated from patients (p-value = 0.01), which is probably due to the iron overload in beta-TM patients as a result of continuous blood transfusion. Also, the percentage of Tregs after 5 days of expansion had a significant increase in both groups compared to before expansion (p-value = 0.03). Our results also showed that the expansion of Tregs after 72 h in the presence of inflammatory cytokines and in the absence of rapamycin led to the increase in the intracellular expression of IL-17 (p-value = 0.01), while intracellular expression of IL-17 remained low following the addition of 100 nM rapamycin to the culture medium (pvalue = 0.073). The results of the functional evaluation of expanded Tregs showed relatively differences in both patient and control groups. Thus, expanded Tregs inhibited the proliferation of responder T cells in a dose-dependent manner in the control group (p-value = 0.028), while in the patient group this inhibitory effect was not significant (p-value = 0.055). Conclusion: Tregs isolated from beta-TM patients have poorer inhibitory performance than Tregs isolated from healthy individuals. Also, we concluded that rapamycin stabilizes the Treg population by inhibiting the production of IL-17, all necessitating the administration of appropriate immunosuppressive drugs in patients receiving Treg therapy.
Modeling Low Muscle Mass Screening in Hemodialysis Patients
Authors: Senzaki Daiki , Yoshioka Nobuo , Nagakawa Osamu , Inayama Emi , Nakagawa Takafumi , Takayama Hidehito , Endo Toko , Nakajima Fumitaka , Fukui Masayoshi , Kijima Yasuaki , Oyama Yasuo , Kudo Risshi , Toyama Tadashi , Yamada Yosuke , Tsurusaki Kiyoshi , Aoyama Naoki , Matsumura Takayasu , Yamahara Hideki , Miyasato Kenro , Kitamura Tetsuya , Ikenoue Tatsuyoshi
Published: October 2022

Introduction: Computed tomography (CT) can accurately measure muscle mass, which is necessary for diagnosing sarcopenia, even in dialysis patients. However, CT-based screening for such patients is challenging, especially considering the availability of equipment within dialysis facilities. We therefore aimed to develop a bedside prediction model for low muscle mass, defined by the psoas muscle mass index (PMI) from CT measurement. Methods: Hemodialysis patients (n = 619) who had undergone abdominal CT screening were divided into the development (n = 441) and validation (n = 178) groups. PMI was manually measured using abdominal CT images to diagnose low muscle mass by two independent investigators. The development group’s data were used to create a logistic regression model using 42 items extracted from clinical information as predictive variables; variables were selected using the stepwise method. External validity was examined using the validation group’s data, and the area under the curve (AUC), sensitivity, and specificity were calculated. Results: Of all subjects, 226 (37%) were diagnosed with low muscle mass using PMI. A predictive model for low muscle mass was calculated using ten variables: each grip strength, sex, height, dry weight, primary cause of end-stage renal disease, diastolic blood pressure at start of session, pre-dialysis potassium and albumin level, and dialysis water removal in a session. The development group’s adjusted AUC, sensitivity, and specificity were 0.81, 60%, and 87%, respectively. The validation group’s adjusted AUC, sensitivity, and specificity were 0.73, 64%, and 82%, respectively. Discussion/Conclusion: Our results facilitate skeletal muscle screening in hemodialysis patients, assisting in sarcopenia prophylaxis and intervention decisions.
Localized Elevation of Wall Shear Stress Is Linked to Recent Symptoms in Patients with Carotid Stenosis
Authors: Zhang Xun , Jiao Zhouyang , Hua Zhaohui , Cao Hui , Liu Shirui , Zhang Linfeng , Lian Chong , Li Chong , Li Zhen
Published: October 2022

Background: Estimation of symptomatic and asymptomatic carotid atherosclerosis differences can be the basis for prevention and management of carotid artery stenosis disease. In clinical practice, carotid plaque vulnerability is assessed only on the basis of luminal stenosis. However, the evolution of carotid plaque from an asymptomatic state to a symptomatic one is a complex process and the underlying hemodynamic mechanisms are unknown. We aimed to investigate the differences in hemodynamic parameters between patients with recently symptomatic carotid stenosis and asymptomatic ones. Methods: Hemodynamic simulations were performed on 26 carotid plaques from 25 patients with carotid artery stenosis ≥50%, 16 of whom had recent cerebrovascular ischemic events. Using human-specific flow parameters and 3D reconstruction of carotid computed tomography angiography images, we assessed hemodynamic characteristics such as wall shear stress (WSS), time-averaged WSS (TAWSS), oscillatory shear index, and relative residence time (RRT) during the cardiac cycle in patients with and without symptoms. Results: We found that symptomatic carotid stenosis patients had greater local TAWSS (99.59 ± 26.29 vs. 60.40 ± 20.46 dyn/cm2, p = 0.0007) and maximal WSS (116.65 ± 39.11 vs. 68.28 ± 23.67 dyn/cm2, p = 0.003), but lower RRT (0.019 ± 0.006 vs. 0.013 ± 0.069 s, p = 0.049), than asymptomatic patients, but this hemodynamic difference was not associated with carotid stenosis severity (p = 0.70). Patients with transient ischemic attack (TIA) or stroke had higher local TAWSS and WSSmax than patients with asymptomatic stenosis (p < 0.05). Subgroup analysis showed that there was no statistical difference in local hemodynamic variables between TIA and stroke patients with carotid artery stenosis. Conclusions: Patients with carotid artery stenosis are more likely to experience acute ischemic cerebrovascular accidents if they have higher WSS. Simultaneous assessment with hemodynamic parameters like WSS along with stenosis severity may aid risk stratification in patients with asymptomatic carotid artery stenosis.
Cerebral Small Vessel Disease Burden and Futile Reperfusion after Endovascular Treatment for Patients with Acute Ischemic Stroke
Authors: Lee Minwoo , Kim Yerim , Oh Mi Sun , Yu Kyung-Ho , Lee Byung-Chul , Kim Chul-Ho , Mo Hee Jung ,   Lee
Published: October 2022

Introduction: Cerebral small vessel disease (SVD) burden includes increased risk of poor functional outcomes after acute ischemic stroke (AIS). We aimed to investigate the impact of cerebral SVD on 3-month functional outcomes in patients with AIS who received endovascular treatment (EVT) and to determine whether SVD is associated with futile reperfusion (FR). Methods: Using a multicenter stroke registry, we analyzed consecutive patients with AIS with either intracranial and/or extracranial anterior circulation large artery occlusion, who were treated with EVT and achieved successful reperfusion (thrombolysis in cerebral infarction grade 2b–3). The cerebral SVD burden was evaluated using baseline brain magnetic resonance imaging using a modified Fazekas score (mFS). The main outcome variable was FR, defined as poor functional outcomes (modified Rankin scale 3–6) at 3 months after stroke, despite successful recanalization. Secondary outcomes included stroke progression/recurrence and any hemorrhagic transformation. Results: Among 10,890 patients with AIS, 577 (5.3%) received EVT within 12  h of onset, including 354 who met study eligibility criteria. FR was observed in 191 patients (53.5%) and was positively associated with SVD burden. After adjustment for covariates including age, sex, stroke etiology, initial stroke severity, collateral status, Alberta stroke program early CT score, initial serum glucose, systemic blood pressure, and vascular risk factors, mFS grade 3 was significantly associated with FR (odds ratio: 3.93, 95% confidence interval: 1.602–9.619; p = 0.003). Conclusions: We demonstrated that cerebral SVD assessed with baseline brain MRI is associated with the futility of successful recanalization after EVT and any hemorrhagic transformation but not with early stroke progression or recurrence. Nevertheless, our findings do not justify withholding EVT in otherwise eligible patients with AIS based on the presence of severe SVD.
Effectiveness of Progressive Resistance Training in Parkinson’s Disease: A Systematic Review and Meta-Analysis
Authors: Yang Xiaoxia , Wang Zhiyun
Published: October 2022

Introduction: The aim of this study was to systematically explore progressive resistance training (PRT) effects in Parkinson’s disease (PD). Methods: Eligible literature was systematically searched from five electronic databases (PubMed, Web of Science, Ovid, Wanfang, and China National Knowledge Infrastructure) from their inception to February 2022. Included studies were selected based on strict eligibility criteria. RevMan 5.3 software was used for statistical analysis. Results: A total of 14 studies with 761 PD patients were selected for eligibility in this systematic review and meta-analysis. A total of 383 performed trunk or upper or lower extremity PRT and 378 underwent balance training, modified fitness counts, or did not change their lifestyle. The results demonstrated positive PRT effect on freezing of gait (standardized mean difference [SMD] = −0.55, 95% CI = −0.95 to −0.16, p = 0.006), muscular strength (SMD = 1.9, 95% CI = 0.55–3.24, p = 0.006), and quality of life (SMD = −0.86, 95% CI = −1.66 to −0.06, p = 0.04) in adults with PD compared with other training programmes but not for gait velocity, stride length, timed up and go test, and Berg Balance Scale. Conclusions: This meta-analysis revealed that PRT had positive effects on freezing of gait, muscle strength, and improved quality of life during rehabilitation in PD patients.
Curing the SICK and Other NLI Maladies
Authors: Kalouli Aikaterini-Lida , Hu Hai , Webb Alexander F. , Moss Lawrence S. , de Paiva Valeria
Published: October 2022

Against the backdrop of the ever-improving Natural Language Inference (NLI) models, recent efforts have focused on the suitability of the current NLI datasets and on the feasibility of the NLI task as it is currently approached. Many of the recent studies have exposed the inherent human disagreements of the inference task and have proposed a shift from categorical labels to human subjective probability assessments, capturing human uncertainty. In this work, we show how neither the current task formulation nor the proposed uncertainty gradient are entirely suitable for solving the NLI challenges. Instead, we propose an ordered sense space annotation, which distinguishes between logical and common-sense inference. One end of the space captures non-sensical inferences, while the other end represents strictly logical scenarios. In the middle of the space, we find a continuum of common-sense, namely, the subjective and graded opinion of a “person on the street.” To arrive at the proposed annotation scheme, we perform a careful investigation of the SICK corpus and we create a taxonomy of annotation issues and guidelines. We re-annotate the corpus with the proposed annotation scheme, utilizing four symbolic inference systems, and then perform a thorough evaluation of the scheme by fine-tuning and testing commonly used pre-trained language models on the re-annotated SICK within various settings. We also pioneer a crowd annotation of a small portion of the MultiNLI corpus, showcasing that it is possible to adapt our scheme for annotation by non-experts on another NLI corpus. Our work shows the efficiency and benefits of the proposed mechanism and opens the way for a careful NLI task refinement.
Hacking Hearts: Establishing a Dialogue in Art/Science Education
Authors: Nohara Kayoko , Marenko Betti , Salani Giorgio
Published: October 2022

This paper discusses Hacking Hearts, a transdisciplinary educational collaboration between the art school Central Saint Martins (U.K.) and a science and engineering university, the Tokyo Institute of Technology (Japan). The concept of performativity—which was brought into the construction of the workshop setting—is used to explain the mechanisms of interaction across disciplinary boundaries commonly accepted in these institutions and academic areas. The collaboration transformed performative elements into a resource by creating an educational environment that enabled communication through encounters “on stage” between research scientists and art/design students. The discussion is situated within a growing literature on art/science education and offers lessons for establishing collaborative workshops between diverse participants.