bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalized “Riesel” numbers and nice numbers
Authors: Kowitz Krzysztof
Published: October 2024

We introduce generalized “Riesel” numbers. We show closed formulae for calculating the [Formula: see text]th generalized “Riesel” number [Formula: see text] and we give the formula for the sum of the reciprocals generalized “Riesel” numbers. In the later part of the paper, we look at prime number tests and their relationship to “Riesel” numbers. We answer negatively to Question 2.15 from the paper [8]. In the end, we prove that there exists [Formula: see text] such that [Formula: see text] is a complete residue system modulo [Formula: see text] for some permutation [Formula: see text] of [Formula: see text], but [Formula: see text] and [Formula: see text] are not safe primes (i.e., [Formula: see text] and [Formula: see text] are not primes associated with a Sophie Germain prime). Such a number is 62, because 62 is a nice number, but neither 62 nor 31 are safe primes. This is a counterexample to the hypothesis posed in one of Paolo Leonetti’s papers.
SecoInfer: Secure DNN End-Edge Collaborative Inference Framework Optimizing Privacy and Latency
Authors: Yao Yunhao , Hou Jiahui , Wu Guangyu , Cheng Yihang , Yuan Mu , Luo Puhan , Wang Zhiqiang , Li Xiang-Yang
Published: October 2024

End-edge collaborative inference enhances computational efficiency by segmenting a deep neural network (DNN) model into two parts, executed across the end device and the edge node. However, existing collaborative inference strategies often involve transmitting original inputs from the end device to the edge node, resulting in significant risks of user detail leakage without requiring input reconstruction. Therefore, in this work, we present SecoInfer, a secure layer-level DNN end-edge collaborative inference framework. SecoInfer achieves joint optimization of data privacy and inference latency for DNN partition solutions that meet latency constraints, supported by three key designs. First, the privacy-aware DNN layer projection measurement quantifies the difficulty adversaries encounter in reconstructing the original input from the intermediate output of each layer. Then, the latency-privacy integrated structure modeling enables the direct calculation of the privacy measurement and inference latency for each partition solution from a list element or a directed acyclic graph (DAG) cut. Finally, the two-stage latency constraint adjustment scheme narrows down the search space of feasible partition solutions at the block level and fine-tunes the final one to meet the latency constraint based on layer depth. We prototype SecoInfer, utilizing a Raspberry Pi 4B as the end device and a server with an NVIDIA GeForce RTX 3060 GPU as the edge node. Experimental results demonstrate that under latency constraints of 20 ms, 33 ms, and 40 ms, SecoInfer reduces adversarial data reconstruction by 9.84%, 19.26%, and 25.18%, respectively, without any loss of task model accuracy. SecoInfer also enhances efficiency, reducing the time needed to determine optimal end-edge partition solutions on a Raspberry Pi 4B by 18.04%.
How Biologics Have Changed the Drug Discovery Landscape
Authors: McGonigle Paul
Published: October 2024

Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA–based therapeutics and the application of artificial intelligence.
Menstrual cycle and the protective effects of remote ischemic preconditioning against endothelial ischemia/reperfusion injury: comparison with postmenopausal women
Authors: Durchslag Janinka (Nina) , Tanner Shelby M. , Mason Alexandra R. , Roth Nasya R. , Thiros Alexia S. , Van Guilder Gary P.
Published: October 2024

The capacity of remote ischemic preconditioning to protect against vascular endothelial ischemia/reperfusion injury varies widely across the phases of the menstrual cycle in healthy premenopausal women. Robust protection was afforded during the late follicular and mid-luteal phases. In contrast, weakened protection was demonstrated during the early follicular phase, with a level of impairment similar to estrogen-deficient postmenopausal women.
Fractional‐Order Epidemic Model for Measles Infection
Authors: Akuka Philip N. A. , Seidu Baba , Okyere Eric , Abagna Stephen
Published: October 2024

In this study, a nonlinear dynamic SEVIQR measles epidemic model is constructed and analyzed using the novel Caputo fractional‐order derivative operator. The model’s existence and uniqueness are established. In addition, the model equilibria are determined, and the novel Jacobian determinant method recently constructed in the literature of epidemiological modeling of infectious diseases is applied to determine the threshold quantity, . Furthermore, we construct appropriate Lyapunov functions to establish the global asymptotic stability of the disease‐free and endemic equilibrium points. Finally, the numerical solution of the model is executed employing the efficient and widely known Adams‐type predictor‐corrector iterative scheme, and simulation is conducted to investigate the impact of memory index and diverse preventive measures on the occurrence of the disease. Numerical simulation of the model indicates that quarantine, vaccination, and treatment can reduce the numbers of infectious and exposed populations, thereby controlling the disease. Therefore, it is recommended that the government provide financial assistance for vaccine distribution.
Predictive Modeling of Tool Life in Turning Using ANN‐Taguchi Hybridization
Authors: B. Shrishail Sollapur , Suryawanshi Shubham R. , S. Mitali Mhatre , Dond Dipak K. , Chate Ganesh , Bhowmik Abhijit
Published: October 2024

A tool that will last is crucial for refining machining processes, influencing the quality of products, and reducing the expenses of making them. Previous research has demonstrated that several factors influence tool longevity, including the cutting depth, speed, the feed rate, the properties of the tool’s material, and those of the workpiece being machined. Understanding precisely how each of these factors impacts tool life is essential for refining processes and choosing the right tool. There are established mathematical models for estimating the tool’s lifespan, particularly for CBN tools when performing turning operations. Nonetheless, understanding the link between tool lifespan and cutting speed is challenging, given that it does not follow a linear pattern. Traditional methods for determining the equation for a tool lifespan using cutting speed often necessitate conducting tests at various speeds, which may not provide the statistical foundation required by the design of experiment (DoE) techniques. In this research, we delve into the complex relationship between tool lifespan and cutting speed through experiments guided by the Taguchi method and artificial neural network (ANN) models. Several case studies have been conducted to test the practicality and effectiveness of this method in representing complex tool lifespan‐cutting speed relationships.
Supplementary Fig S5 from Memory-like Differentiation Enhances NK Cell Responses to Melanoma
Authors: Marin Nancy D. , Krasnick Bradley A. , Becker-Hapak Michelle , Conant Leah , Goedegebuure Simon P. , Berrien-Elliott Melissa M. , Robbins Keenan J. , Foltz Jennifer A. , Foster Mark , Wong Pamela , Cubitt Celia C. , Tran Jennifer , Wetzel Christopher B. , Jacobs Miriam , Zhou Alice Y. , Russler-Germain David , Marsala Lynne , Schappe Timothy , Fields Ryan C. , Fehniger Todd A.
Published: October 2024

Immunohistochemistry staining of S100, Melan A and SOX10 in patient derived cell lines
Supplementary Data from Memory-like Differentiation Enhances NK Cell Responses to Melanoma
Authors: Marin Nancy D. , Krasnick Bradley A. , Becker-Hapak Michelle , Conant Leah , Goedegebuure Simon P. , Berrien-Elliott Melissa M. , Robbins Keenan J. , Foltz Jennifer A. , Foster Mark , Wong Pamela , Cubitt Celia C. , Tran Jennifer , Wetzel Christopher B. , Jacobs Miriam , Zhou Alice Y. , Russler-Germain David , Marsala Lynne , Schappe Timothy , Fields Ryan C. , Fehniger Todd A.
Published: October 2024

Supplementary methods and tables
Figure S4 from ATR Inhibition Induces CDK1–SPOP Signaling and Enhances Anti–PD-L1 Cytotoxicity in Prostate Cancer
Authors: Tang Zhe , Pilié Patrick G. , Geng Chuandong , Manyam Ganiraju C. , Yang Guang , Park Sanghee , Wang Daoqi , Peng Shan , Wu Cheng , Peng Guang , Yap Timothy A. , Corn Paul G. , Broom Bradley M. , Thompson Timothy C.
Published: October 2024

Supplementary Figure S4 shows ATRi or ATR siRNA knockdown downregulates PD-L1 protein expression in RM-1-BM prostate cancer cells (immunoblot analysis), and SPOP siRNA transfection does not alter PD-L1 mRNA levels in RM-1-BM and C4-2b prostate cancer cells (suggesting SPOP post-transcriptional regulation of PD-L1 expression).
Figure S4 from Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for gBRCA Advanced Breast Cancer (BROCADE3 Crossover)
Authors: Puhalla Shannon L. , Diéras Véronique , Arun Banu K. , Kaufman Bella , Wildiers Hans , Han Hyo S. , Ayoub Jean-Pierre , Stearns Vered , Yuan Yuan , Helsten Teresa , Riley-Gillis Bridget , Murphy Erin , Kundu Madan G. , Wu Meijing , Maag David , Ratajczak Christine K. , Ramathal Cyril Y. , Friedlander Michael
Published: October 2024

Molecular characteristics of BRCA reversion mutations
Figure S3 from Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for gBRCA Advanced Breast Cancer (BROCADE3 Crossover)
Authors: Puhalla Shannon L. , Diéras Véronique , Arun Banu K. , Kaufman Bella , Wildiers Hans , Han Hyo S. , Ayoub Jean-Pierre , Stearns Vered , Yuan Yuan , Helsten Teresa , Riley-Gillis Bridget , Murphy Erin , Kundu Madan G. , Wu Meijing , Maag David , Ratajczak Christine K. , Ramathal Cyril Y. , Friedlander Michael
Published: October 2024

PFS KM curves
Supplementary Information from 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study
Authors: Ascierto Paolo A. , Dréno Brigitte , Larkin James , Ribas Antoni , Liszkay Gabriella , Maio Michele , Mandalà Mario , Demidov Lev , Stroyakovskiy Daniil , Thomas Luc , de la Cruz-Merino Luis , Atkinson Victoria , Dutriaux Caroline , Garbe Claus , Hsu Jessie , Jones Surai , Li Haocheng , McKenna Edward , Voulgari Athina , McArthur Grant A.
Published: October 2024

Tables S1-S3
Supplementary Data from Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study
Authors: Yap Timothy A. , Krebs Matthew G. , Postel-Vinay Sophie , El-Khouiery Anthony , Soria Jean-Charles , Lopez Juanita , Berges Alienor , Cheung S.Y. Amy , Irurzun-Arana Itziar , Goldwin Andrew , Felicetti Brunella , Jones Gemma N. , Lau Alan , Frewer Paul , Pierce Andrew J. , Clack Glen , Stephens Christine , Smith Simon A. , Dean Emma , Hollingsworth Simon J.
Published: October 2024

Supplementary material
Supplementary Table 6 from Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia
Authors: Ding Yang-Yang , Kim Hannah , Madden Kellyn , Loftus Joseph P. , Chen Gregory M. , Allen David Hottman , Zhang Ruitao , Xu Jason , Chen Chia-Hui , Hu Yuxuan , Tasian Sarah K. , Tan Kai
Published: October 2024

OCN pairs nominated to be synergistic, along with small molecule inhibitors identified from querying Therapeutic Target Database (TTD), DrugBank, DGIdb, and PubChem. BH, Benjamini-Hochberg method for multiple testing correction.
Supplementary Figure 4 from Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia
Authors: Ding Yang-Yang , Kim Hannah , Madden Kellyn , Loftus Joseph P. , Chen Gregory M. , Allen David Hottman , Zhang Ruitao , Xu Jason , Chen Chia-Hui , Hu Yuxuan , Tasian Sarah K. , Tan Kai
Published: October 2024

Gene expression changes in Ph-like ALL cells treated with combination therapy. (A) PCA plot showing replicate samples for each treatment condition for the three Ph-like cell lines. Inter-cell line differences predominate. DMSO- (vehicle control) and venetoclax-treated samples of each cell line cluster closely, whereas single-agent TKI and dual TKI/venetoclax-treated samples cluster together. (B) Gene expression changes during monotherapy and combination therapy in select apoptosis pathway and cytokine/kinase signaling pathway genes including those in SRC-family and MAPK-family pathways, as well as in 11 of the 14 OCNs. Expression changes in 3 of the 14 OCNs (STAT5B, BAG1, DUSP3) are shown in Figure 3E.
Data from Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia
Authors: Ding Yang-Yang , Kim Hannah , Madden Kellyn , Loftus Joseph P. , Chen Gregory M. , Allen David Hottman , Zhang Ruitao , Xu Jason , Chen Chia-Hui , Hu Yuxuan , Tasian Sarah K. , Tan Kai
Published: October 2024

AbstractPurpose:
Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance.
Experimental Design:
We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome–like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance.
Results:
We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair STAT5B and BCL2-associated athanogene 1 (BAG1) significantly reduced leukemia cell viability in vitro. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1–rearranged (Ph+) B-ALL and more similar to prognostically favorable childhood B-ALL subtypes.
Conclusions:
Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.
A Small-Molecule BCL6 Inhibitor as an Anti-Proliferative Agent for Diffuse Large B-Cell Lymphoma
Authors: Xing Yajing , Guo Weikai , Wu Min , Xie Jiuqing , Huang Dongxia , Hu Pan , Zhou Miaoran , Zhang Lin , Zhong Yadong , Liu Mingyao , Chen Yihua , Yi Zhengfang
Published: October 2024

The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in the establishment of germinal center (GC) formation. Diffuse large B-cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors’ interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare, and there are no clinically approved BCL6 inhibitors. In this study, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The lead compound WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased the proportion of follicular helper T cells, and impaired Ig affinity maturation. Further studies showed that WK692 inhibits DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.
Clinical Variability of Shashi-Pena Syndrome: A Novel ASXL2 Variant Associated with Overgrowth and Minor Neurodevelopmental Features
Authors: Minotti Chiara , Graziani Ludovico , Micalizzi Alessia , Dentici Maria Lisa , Capolino Rossella , Sinibaldi Lorenzo , Lanari Valentina , Dallapiccola Bruno , Novelli Giuseppe , Novelli Antonio , Digilio Maria Cristina
Published: October 2024

Introduction: Shashi-Pena syndrome (SHAPNS) is a rare congenital disorder characterized by macrocephaly, delayed psychomotor development with intellectual disability, hypotonia, seizures, episodic hypoglycemia, distinct facial features, and glabellar nevus flammeus, caused by heterozygous variants of the ASXL2 gene. Case Presentation: We report on a 15-year-old patient in care at our hospital since the age of 4 years presenting with minor neurodevelopmental problems, marked postnatal overgrowth without advanced bone age, and dental anomalies. Conclusion: Patients described in the literature with SHAPNS are reported indicating a broad spectrum of clinical manifestations. The present patient manifests an atypical presentation of SHAPNS due to a novel heterozygous ASXL2 variant. This study supports the inclusion of SHAPNS in overgrowth disorders with macrocephaly, suggesting the analysis of the ASXL2 gene even in suspected subjects with normal bone age and confirms dental anomalies as a clinical feature of this syndrome. SHAPNS could be inferred even in the absence of developmental delay or epilepsy.
Neurodevelopmental Changes and Postnatal Growth in the First 3 Years of Extremely Preterm Infants
Authors: Matsunaga Yuka , Inoue Hirosuke , Miyauchi Yuta , Watabe Takahide , Yasuoka Kazuaki , Sawano Toru , Ochiai Masayuki , Sakai Yasunari , Ohga Shouichi
Published: October 2024

Introduction: Infants born extremely preterm are at high risk for neurodevelopmental problems. However, their neurodevelopment exhibits a variety of trajectories. This study aimed to investigate the association between changes in neurodevelopmental outcomes and clinical characteristics among extremely preterm infants. Methods: This is a retrospective study of surviving children born at gestational age 22–28 weeks in Kyushu University Hospital between 2010 and 2020. We collected perinatal and post-discharge data and investigated the association between clinical characteristics and changes in developmental quotient (DQ) scores between 1.5 and 3 years of corrected age. Results: Out of the 179 eligible extremely preterm infants, 115 (64%) underwent neurological evaluations at 1.5 and 3 years of corrected age. Among them, 33 (29%) showed improvement in their DQ scores (+10 or more), 62 (54%) showed no change (−9 to +9), and 20 (17%) showed a decline (−10 or less). Gestational age, birth weight, and perinatal complications during the NICU stay did not affect individual changes in DQ scores. Multivariable analysis revealed that greater growth in height until age 3 years was a significant predictor of increasing DQ scores, while male sex and having siblings had a negative effect on changes in the DQ scores. Conclusion: We first demonstrate clinical data conceptualizing that growth in height, sex, and sibling status, rather than perinatal complications, are biologically linked with favorable or unfavorable neurodevelopmental changes of extremely preterm infants during the first 3 years of life.
Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases
Authors: Potere Nicola , Bonaventura Aldo , Abbate Antonio
Published: October 2024

Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays key pathogenic roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutic strategies across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs, and discusses major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.
ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet–Fed

ApoE
−/−

Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux
Authors: Zhang Yuyan , Jiang Xinhai , Wang Weizhi , Lei Lijuan , Sheng Ren , Li Shunwang , Luo Jinque , Liu Huan , Zhang Jing , Han Xiaowan , Li Yining , Zhang Yuhao , Wang Chenyin , Si Shuyi , Jin Zheng-Gen , Xu Yanni
Published: October 2024

BACKGROUND:

Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice.

METHODS:

We engineered
Asgr1
knockout mice (
Asgr1

−/−

),
Asgr1
and
ApoE
double-knockout mice (
Asgr1

−/−

ApoE

−/−

), and ASGR1-overexpressing mice on an
ApoE

−/−

background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury.

RESULTS:

After being fed a Western diet for 12 weeks,
Asgr1

−/−

ApoE

−/−

mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in
ApoE

−/−

mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing
ApoE

−/−

mice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet–induced
Asgr1

−/−

ApoE

−/−

mice and high-fat diet–induced but not normal laboratory diet–induced and high-fat and high-cholesterol diet–induced
Asgr1

−/−

mice, while its overexpression mitigates liver injury in Western diet–induced ASGR1-overexpressing
ApoE

−/−

mice.

CONCLUSIONS:

Inhibition of ASGR1 inhibits atherosclerosis in Western diet–fed
ApoE

−/−

mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.
Immunoregulatory Macrophages Modify Local Pulmonary Immunity and Ameliorate Hypoxic Pulmonary Hypertension
Authors: Fernandez-Gonzalez Angeles , Mukhia Amit , Nadkarni Janhavi , Willis Gareth R. , Reis Monica , Zhumka Kristjan , Vitali Sally , Liu Xianlan , Galls Alexandra , Mitsialis S. Alex , Kourembanas Stella
Published: October 2024

BACKGROUND:

Macrophages play a significant role in the onset and progression of vascular disease in pulmonary hypertension, and cell-based immunotherapies aimed at treating vascular remodeling are lacking. We aimed to evaluate the effect of pulmonary administration of macrophages modified to have an anti-inflammatory/proresolving phenotype in attenuating early pulmonary inflammation and progression of experimentally induced pulmonary hypertension.

METHODS:

Mouse bone marrow–derived macrophages were polarized in vitro to a regulatory (M2
reg
) phenotype. M2
reg
profile and anti-inflammatory capacity were assessed in vitro upon lipopolysaccharide/IFNγ (interferon-γ) restimulation, before their administration to 8- to 12-week-old mice. M2
reg
protective effect was evaluated at early (2–4 days) and late (4 weeks) time points during hypoxia (8.5% O
2
) exposure. Levels of inflammatory markers were quantified in alveolar macrophages and whole lung, while pulmonary hypertension development was ascertained by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy measurements. Bronchoalveolar lavage from M2
reg
-transplanted hypoxic mice was collected and its inflammatory potential evaluated on naive bone marrow–derived macrophages.

RESULTS:

M2
reg
macrophages expressing
Tgf
β,
Il10
, and
Cd206
demonstrated a stable anti-inflammatory phenotype in vitro, by downregulating the induction of proinflammatory cytokines and surface molecules (
Cd86
,
Il6
, and
Tnf
α) upon a subsequent proinflammatory stimulus. A single dose of M2
regs
attenuated hypoxic monocytic recruitment and perivascular inflammation. Early hypoxic lung and alveolar macrophage inflammation leading to pulmonary hypertension development was significantly reduced, and, importantly, M2
regs
attenuated right ventricular hypertrophy, right ventricular systolic pressure, and vascular remodeling at 4 weeks post-treatment.

CONCLUSIONS:

Adoptive transfer of M2
regs
halts the recruitment of monocytes and modifies the hypoxic lung microenvironment, potentially changing the immunoreactivity of recruited macrophages and restoring normal immune functionality of the lung. These findings provide new mechanistic insights into the diverse role of macrophage phenotype on lung vascular homeostasis that can be explored as novel therapeutic targets.
Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial
Authors: Cui Yu , He Chao , Li Zi-Ang , Wang Yue , Chen Hui-Sheng
Published: October 2024

BACKGROUND:

Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO).

METHODS:

This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments.

RESULTS:

Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, −4.8% [95% CI, −6.9% to −2.6%];
P
<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, −17.6% to 22.3%];
P
=0.82). The interaction was marginally significant between groups (
P
=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, −6.4% [95% CI, −8.9% to −3.9%];
P
<0.001). Other safety outcomes were similar between the 2 treatments.

CONCLUSIONS:

Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03661411.
Not Eliminate but Aggregate: Post-Hoc Control over Mixture-of-Experts to Address Shortcut Shifts in Natural Language Understanding
Authors: Honda Ukyo , Oka Tatsushi , Zhang Peinan , Mita Masato
Published: October 2024

Recent models for natural language understanding are inclined to exploit simple patterns in datasets, commonly known as shortcuts. These shortcuts hinge on spurious correlations between labels and latent features existing in the training data. At inference time, shortcut-dependent models are likely to generate erroneous predictions under distribution shifts, particularly when some latent features are no longer correlated with the labels. To avoid this, previous studies have trained models to eliminate the reliance on shortcuts. In this study, we explore a different direction: pessimistically aggregating the predictions of a mixture-of-experts, assuming each expert captures relatively different latent features. The experimental results demonstrate that our post-hoc control over the experts significantly enhances the model’s robustness to the distribution shift in shortcuts. Additionally, we show that our approach has some practical advantages. We also analyze our model and provide results to support the assumption.1
Southernmost record and diet of Leptobrachella eos (Ohler, Woollen, Grosjean, Hendrix, Vences, Ziegler & Dubois, 2011) in Vietnam
Authors: Pham Anh Van , Le Minh Duc , Ho Anh Ngoc Thi , Nguyen Truong Quang , Nguyen Tham Thi , Ziegler Thomas , Tran Cuong Thien , Pham Cuong The
Published: October 2024

The Rosy Litter Frog (Leptobrachella eos) is known from Thailand, Laos, and Vietnam. Knowledge about the natural history of this species is virtually lacking. As a result of our field work in Son La, Nghe An, and Ha Tinh provinces of Vietnam, we provide data on the food composition of L. eos for the first time. Using the stomach-flushing method, we analyzed stomach contents of 34 individuals (23 males and 11 females) from a total of 42 frogs, with stomachs of five males and three females (19%) being empty. A total of 13 prey categories were observed in the stomachs of L. eos, with 232 items, comprising 230 items of invertebrates and two unidentified items. The most important (IRI) groups among the prey of L. eos were Blattodea (26.31%), Araneae (17.26%), Orthoptera (13.21%), Coleoptera (12.39%), and Opiliones (10.09%). There was an overlap of 51.11 % in the diet between males and females, The trophic spectrum of males comprising 11 prey categories revealed to be wider than that of females comprising nine prey categories. Despite differences in diets between the sexes, Blattodea, Orthoptera, Araneae, Coleoptera, and Opiliones represented the most important prey category for all of them. In addition, we also report a new find of Leptobrachella eos, with a new subpopulation from Ha Tinh Province, Vietnam.
Challenges of Private International Law in Asia
Authors: Nishitani Yuko
Published: October 2024

The presence of Asia in the global arena has become notable due to its thriving economy. Arguably, it is time to consider how private international law (or conflict of laws) should develop in Asia and what kind of opportunity it can engender, considering that private international law has the potential to promote economic and legal cooperation without unifying substantive law. First, this paper considers the role of the Hague Conference on Private International Law (HCCH) and the varying significance of its conventions on judicial assistance, litigation, and child protection in the pursuit of private international law unification in Asia. Second, this study elaborates and supports the use of non-binding instruments (or soft law) – model laws, principles, legislative guides, etc. – as a fallback method of harmonizing private international law. Third, this paper examines the increasing extraterritoriality of regulatory norms of the US, the EU, China, and other countries in the global market. This will clarify the problems of conflicting, overlapping regulations and allow scrutiny of potential pathways to restrict the exercise of the states’ prescriptive jurisdiction. Some future perspectives will conclude this study.
Admissibility of ILA Principles on Intellectual Property and Private International Law in Vietnam
Authors: Trang Bui Thi Quynh , Nguyen Phan Dinh , Trinh Nguyen Thi Hong
Published: October 2024

Private law on intellectual property (IP) has achieved significant international harmonization, but international jurisdiction is subject to national regulations. As a result, enforcement of IP rights is carried out on a country-by-country basis. This approach leads to multiple concurrent legal proceedings, increasing the risk of conflicting judgments and escalating litigation costs. These costs create a disparity between multinational corporations and small and medium-sized enterprises. As a potential model for future international agreements on intellectual property and private international law, the International Law Association (ILA) Committee on ‘Intellectual Property and Private International Law’ seeks to address cross-border IP disputes. This paper will explore whether the ILA principles can be utilized as models for legislators, judges, arbitrators and other competent authorities in Vietnam, a legal system characterized by a lack of case law on the topic.
Korean Judicial Decisions
Authors: Baek Buhm-Suk , Ahn Hosung
Published: October 2024

This article reviews four selected major decisions by domestic courts in 2023 by taking a closer look at the changing legal practices and attitudes of the Korean judiciary in applying international law in domestic cases.
Fruit and seed of Eriotheca dolichopoda (Malvaceae) revealed after 45 years: Emended description, typification, new records, and conservation status of a poorly known Atlantic Forest species
Authors: CARVALHO-SOBRINHO JEFFERSON , MOTA ALINE C. , ALVERSON WILLIAM S. , DORR LAURENCE J.
Published: October 2024

Eriotheca dolichopoda (Malvaceae) is a tree species endemic to Atlantic Forest in the state of Bahia, northeastern Brazil. Its fruit and seed were unknown and had not been illustrated. Herein we describe and illustrate for the first time the fruit and seed of E. dolichopoda, provide an emended morphological description, designate a lectotype, and designate an epitype to permit a precise application of the name. We also discuss morphological variation in E. dolichopoda and its affinities with similar species. Finally, we use fieldwork and herbarium data to provide a distribution map and an updated conservation assessment of E. dolichopoda based on IUCN criteria.
Spatial Transcriptomics Unravel the Tissue Complexity of Oral Pathogenesis
Authors: Haller J. , Abedi N. , Hafedi A. , Shehab O. , Wietecha M.S.
Published: October 2024

Spatial transcriptomics (ST) is a cutting-edge methodology that enables the simultaneous profiling of global gene expression and spatial information within histological tissue sections. Traditional transcriptomic methods lack the spatial resolution required to sufficiently examine the complex interrelationships between cellular regions in diseased and healthy tissue states. We review the general workflows for ST, from specimen processing to ST data analysis and interpretations of the ST dataset using visualizations and cell deconvolution approaches. We show how recent studies used ST to explore the development or pathogenesis of specific craniofacial regions, including the cranium, palate, salivary glands, tongue, floor of mouth, oropharynx, and periodontium. Analyses of cranial suture patency and palatal fusion during development using ST identified spatial patterns of bone morphogenetic protein in sutures and osteogenic differentiation pathways in the palate, in addition to the discovery of several genes expressed at critical locations during craniofacial development. ST of salivary glands from patients with Sjögren’s disease revealed co-localization of autoimmune antigens with ductal cells and a subpopulation of acinar cells that was specifically depleted by the dysregulated autoimmune response. ST of head and neck lesions, such as premalignant leukoplakia progressing to established oral squamous cell carcinomas, oral cancers with perineural invasions, and oropharyngeal lesions associated with HPV infection spatially profiled the complex tumor microenvironment, showing functionally important gene signatures of tumor cell differentiation, invasion, and nontumor cell dysregulation within patient biopsies. ST also enabled the localization of periodontal disease–associated gene expression signatures within gingival tissues, including genes involved in inflammation, and the discovery of a fibroblast subtype mediating the transition between innate and adaptive immune responses in periodontitis. The increased use of ST, especially in conjunction with single-cell analyses, promises to improve our understandings of craniofacial development and pathogenesis at unprecedented tissue-level resolution in both space and time.
Designing Effective Hybrid Course Curriculum: A Design Science Approach to Gamification and Student Outcomes Validation
Authors: Thi Binh An Duong , Hoang Thu-Hang , Quang Huy Truong
Published: October 2024

In the modern educational landscape, the integration of gamification into hybrid learning environments has emerged as a promising approach to enhance student outcomes. However, there remains a lack of comprehensive frameworks for designing gamified hybrid courses and validating their impact on student outcomes. This paper proposes a design science-based approach to gamified course design in hybrid learning contexts. Drawing on the principles of design science research, we developed a framework for designing a gamified hybrid course curriculum that incorporates course content, activities, and assessments based on four elements of gamification (achievement elements, utilitarian value, hedonic benefits, and competition). To validate the effectiveness of our approach, we conducted a study with 294 students enrolled in a hybrid business course that implemented the proposed gamification framework. Our findings indicate that all gamification elements of our proposed gamified hybrid courses positively enhance student engagement, achievement, and satisfaction. Ultimately, this paper not only contributes to the ‘gamification in education’ literature by providing a comprehensive framework for designing engaging and effective hybrid courses but also proposes a roadmap for the application of design science to embed gamification in business course curriculum design within the context of modern hybrid learning environments.
Protocol for a Cluster Randomized Controlled Trial to Reduce Susceptibility to Tobacco Use Among School Going Adolescents in a South-Indian District—(Project TEACH)
Authors: Bantwal Priyanka , Kamath Veena G , Britton John , Bogdanovica Ilze , Kunder Manjula A , Praharaj Samir K , Kulkarni Muralidhar M
Published: October 2024

Background:

Adolescents are susceptible to using tobacco because of early exposure to tobacco through family members, easy access, or peer pressure. School-based educational programs are crucial for raising awareness of the harms of tobacco, thus preventing its uptake among adolescents. Studies conducted recently have recognized the need to bring change and reinforce ongoing school-based anti-tobacco education programs. Our study protocol aims to evaluate the effectiveness of a revised school-based anti-tobacco education on susceptibility to tobacco use among school-going adolescents.

Method:

Project TEACH (Tobacco Education and Awareness for Creating Healthier Adolescents) is an educational intervention that will comprise an animated video on the effects of tobacco on physical and mental health, along with dispelling myths about tobacco, which will be delivered along with a standard education program. The control group will only receive the standard school-based anti-tobacco education program. It will be conducted among students between 6th to 10th grade, with a sample size of 3,310 students.

Results:

Bivariate relations between the main socio-demographic characteristics and susceptibility to tobacco use will be tested using Pearson or Spearman’s correlation coefficients. For multivariable analyses, the binary logistic regression analysis is used to establish a risk model to correlate the socio-demographic factors with susceptibility to tobacco use and awareness of the harms of tobacco.

Conclusion:

Project TEACH aims to provide a sustainable school-based anti-tobacco education intervention. It will help test the effectiveness of the revised intervention, which could be incorporated into the current school education program being conducted in the district.
Effects of wearable device training on upper limb motor function in patients with stroke: a systematic review and meta-analysis
Authors: Song Qianqian , Qin Qin , Suen Lorna Kwai Ping , Liang Guangmei , Qin Haixia , Zhang Lingling
Published: October 2024

Objective

To evaluate the effect of wearable device training on improving upper limb motor function in patients who experienced strokes.

Methods

The PubMed, Embase, Cochrane Library, Web of Science, MEDLINE, SCOPUS, China National Knowledge Infrastructure, WanFang, and VIP databases were searched for randomized controlled trials (RCTs) that assessed the effectiveness of wearable device training in improving upper limb motor function in patients with stroke. Two investigators independently screened studies by their titles and abstracts and cross-checked, downloaded, and evaluated the results. Disagreements were resolved by a third highly experienced researcher. Risk of bias was evaluated using the Cochrane risk-of-bias tool. This meta-analysis was registered in PROSPERO (registration No. CRD42023421633).

Results

This study comprised 508 patients from 14 RCTs. The experimental group assessed various wearable devices, including 3D-printed dynamic orthoses, inertial measurement unit (IMU) sensors, electrical stimulation devices, and virtual reality (VR) devices for virtual interactive training. The control group received traditional rehabilitation therapies, including physical and conventional rehabilitation. The experimental group scored better on the Fugl–Meyer Assessment (FMA-UE) scale (standardized mean difference [SMD] 0.26, 95% confidence interval [CI] 0.07, 0.45) and Box and Block Test (BBT) (SMD 0.43, 95% CI 0.17, 0.69) versus controls. No significant intergroup differences were observed in the Action Research Arm Test (SMD 0.20, 95% CI −0.15, 0.55), motor activity log (mean difference [MD] 0.32, 95% CI −0.54, 0.33), and modified Ashworth scale (MD −0.08, 95% CI −0.81, 0.64). The probability rankings of wearable devices that improved FMA-UE scores in patients with stroke were: orthotic devices, with the highest probability ranking of 0.45, followed by sensor devices at 0.23, electrical stimulation devices at 0.21, and VR devices at 0.11.

Conclusions

Wearable device training was found to significantly improve upper limb motor function in patients with stroke, particularly for large-range movements. Improvements in FMA-UE and BBT scores reflected reduced impairment and enhanced manual dexterity, respectively. However, the training had no significant effect on hand movement frequency, fine motor skills, or spasticity. Among the different wearable devices tested, orthoses produced the most effective results.
The Effect of Abnormal Marketing and Capital Expenditure on Firm Value
Authors: Teja Adrian , Safriyana Safriyana , Darmawan Steven , Chanry Kevin
Published: October 2024

The study analyzed the effect of abnormal marketing and capital expenditure on firm value. Public firms in consumer staples sectors within the Association of Southeast Asian Nations (ASEAN)-5 countries, such as Indonesia, Malaysia, Thailand, the Philippines, and Vietnam, were chosen as the sample. Data collection yielded 432 data points from 144 firms during the period 2018–2020. The effect of abnormal marketing and capital expenditure on firm value was analyzed using cross-sectional regression analysis. The dependent variable was firm value, proxied by Tobin’s Q. The independent variables were abnormal marketing and capital expenditure. Abnormal marketing expenditure was measured using the difference between the marketing expenditure to total assets ratio for the year of interest, that is, 2018–2020, and the 5-year average of the marketing expenditure to total assets ratio for the years 2013–2017. The same methods applied to abnormal capital expenditure. The control variables were internal financial constraints, that is, Kaplan–Zingales (KZ) index; external financial constraints, that is, financial development index; and COVID-19, which is a dummy variable with a value of 1 for the pandemic period and zero otherwise. The study revealed that positive abnormal marketing and capital expenditure exhibit an adverse impact on firm value and financial constraints increase the negative effect of abnormal marketing and capital expenditure on firm value.