bluuebunny/crossref_metadata_2025 huggingface dataset:
OMP38 of Carbapenem‐Resistant Acinetobacter Baumannii‐Mediated mtDNA Release Activates the cGAS‐STING Signaling to Induce Inflammatory Response
Authors: Yang Yang , Zeng Yuanyuan , Zhu Jianjie , Li Jianjun , Gu Lei , Wei Lin , Liu Zeyi , Huang Jian‐an
Published: December 2024

Carbapenem‐resistant Acinetobacter baumannii (CRAB) has become a major threat in the treatment of bacterial infection, and immunotherapy in a non‐antibiotic‐dependent manner is an effective way to overcome CRAB infection. However, the role of the innate immune response in CRAB infection is poorly understood. Here, it is reported that CRAB infection induced a cytosolic DNA‐sensing signaling pathway and significant IFN‐β production in mice post‐CRAB infection. The knockout of STING reduced bacterial burden, the production of inflammatory cytokines, and lung injury in mice post CRAB infection. The cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS) and the adaptor protein stimulator of interferon genes (STING) are required for CRAB‐induced IFN‐β expression in macrophages. Intriguingly, CRAB utilized outer membrane vesicles (OMVs) to transport outer membrane protein 38 (OMP38) into mitochondria, triggering mitochondrial DNA (mtDNA) release into the cytosol through the mitochondrial permeability transition pore (mPTP) and activating the cGAS‐STING signaling. Finally, epigallocatechin gallate (EGCG) is demonstrated to block the activation of the cGAS‐STING pathway and ameliorate CRAB‐induced excessive inflammatory response. These results demonstrated that the early innate immune response to CRAB infection is activated in a cGAS‐STING‐dependent manner, which could be a potential therapeutic target for CRAB infection.
Targeting Caveolin‐1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell‐Mediated Immunotherapy
Authors: Zhan Dewen , Du Zhimin , Zhang Shang , Huang Juanru , Zhang Jian , Zhang Hui , Liu Zhongrui , Menu Eline , Wang Jinheng
Published: December 2024

The cell membrane transport capacity and surface targets of multiple myeloma (MM) cells heavily influence chemotherapy and immunotherapy. Here, it is found that caveolin‐1 (CAV1), a primary component of membrane lipid rafts and caveolae, is highly expressed in MM cells and is associated with MM progression and drug resistance. CAV1 knockdown decreases MM cell adhesion to stromal cells and attenuates cell adhesion‐mediated drug resistance to bortezomib. CAV1 inhibition in MM cells enhances natural killer cell‐mediated cytotoxicity through increasing CXCL10, SLAMF7, and CD112. CAV1 suppression reduces mitochondrial membrane potential, increases reactive oxygen species, and inhibits autophagosome‐lysosome fusion, resulting in the disruption of redox homeostasis. Additionally, CAV1 knockdown enhances glutamine addiction by increasing ASCT2 and LAT1 and dysregulates glutathione metabolism. As a result of CAV1 inhibition, MM cells are more sensitive to starvation, glutamine depletion, and glutamine transporter inhibition, and grow more slowly in vivo in a mouse model treated with bortezomib. The observation that CAV1 inhibition modulated by 6‐mercaptopurine, daidzin, and statins enhances the efficacy of bortezomib in vitro and in vivo highlights the translational significance of these FDA‐approved drugs in improving MM outcomes. These data demonstrate that CAV1 serves as a potent therapeutic target for enhancing chemotherapy and immunotherapy for MM.
Thermal Management Approach to Stabilization of Disordered Active Sites for Sabatier Reaction
Authors: Duan Delong , Wu Di , Shou Hongwei , Hu Chuansheng , Hu Canyu , Zhou Min , Long Ran , Bi Yingpu , Xiong Yujie
Published: December 2024

The transition metal nanocatalysts containing disordered active sites can potentially achieve efficient Sabatier reactions with high selectivity. However, it remains a challenge to maintain the stability of these active sites in such an exothermic reaction. Here, a thermal management approach is reported to address this challenge. Specifically, an efficient and stable catalytic system is developed by integrating urchin‐like Ru nanoparticles with disordered active sites (d‐RuNUs) and multi‐walled carbon nanotubes (MWCNTs) as heat transfer framework, which achieves a CH4 yield of 3.3 mol g−1 h−1 with nearly 100% selectivity in 12 h. The characterizations reveal that the thermal‐induced crystallization seriously weakens the adsorption of CO2, leading to significant degradation of catalytic performance. The heat transfer simulation confirms that the MWCNTs with high thermal conductivity play a key role in rapidly redistributing the reaction heat, thereby preventing the crystallization of disordered structures. This work elucidates the deactivation mechanism of disordered active sites in exothermic reactions and opens the avenue for local thermal management of non‐thermal equilibrium reactions.
Sustainable Immunomodulatory via Macrophage P2Y12 Inhibition Mediated Bioactive Patche for Peritendinous Antiadhesion
Authors: Tao Zaijin , Wang Shuo , Liu Jingwen , Zhu Tonghe , Jiang Jia , Liu Shen , Ma Xin
Published: December 2024

Persistent anti‐inflammatory responses are critical for the prevention of peritendinous adhesion. Although modified anti‐adhesion barriers have been studied extensively, the immune response induced by the implants and the unclear mechanism limits their application. In this research, the advantage of the multi‐functionalities of CA (caffeic acid) is taken to synthesize biodegradable poly (ester urethane) urea elastomers with ester‐ and carbamate‐bonded CA (PEUU‐CA). PEUU‐CA is electrospun into bioactive patches that can uniquely present a sustained CA niche, referred to as BPSN. In the early stage of degradation, the breakage of the ester bond from BPSN is the dominant factor contributing to the early release of CA. In the later stage of BPSN degradation, the breakage of the ester and carbamate bonds contributes to the sustained release of CA. In vitro experiments showed that CA, when specifically bound to the P2Y12 receptor, down‐regulated the expression and function of active P2Y12, effectively inhibiting the aberrant activation of macrophages and the secretion of inflammatory chemokines. BPSN addresses the foreign body reaction induced by macrophage‐dominated biomaterial implantation and the issue of the short‐term release of drugs at later stages of adhesion, providing a feasible strategy for the prevention and treatment of tissue adhesion, and more broadly, the well‐known implant‐derived inflammatory responses.
Non‐Reciprocity, Metastability, and Dynamic Reconfiguration in Co‐Assembly of Active and Passive Particles
Authors: Al Harraq Ahmed , Patel Ruchi , Lee Jin Gyun , Owoyele Ope , Chun Jaehun , Bharti Bhuvnesh
Published: December 2024

Living organisms often exhibit non‐reciprocal interactions where the forces acting on the objects are not equal in magnitude or opposite in direction. The combination of reciprocal and non‐reciprocal interactions between synthetic building blocks remains largely unexplored. Here, out‐of‐equilibrium assemblies of non‐motile isotropic passive and metal‐patched motile active particles are formed by overlapping bulk interactions with directed self‐propulsion. An external alternating current (AC) electric field generates concurrent dipolar and induced‐charge electrophoretic forces between the particles which are evaluated using microscopy. The interaction force measurements allow to determine the degree of reciprocity in interactions, which is tunable by designing the active particle and its trajectory. While linearly‐propelled active particles evade assembly with passive particles, helically propelled active particles form active‐passive clusters with dynamic reconfiguration and long‐lived metastability. Large clusters display programmable fluctuations and reconfigurability by controlling the fraction of active particles. The study establishes principles of integrating reciprocal and non‐reciprocal interactions in guided colloidal assembly of reconfigurable metastable structures.
High‐Throughput Single‐Nucleus RNA Profiling of Minimal Puncture FFPE Samples Reveals Spatiotemporal Heterogeneity of Cancer
Authors: Jiang Weiqin , Zhang Xiang , Xu Ziye , Cheng Qing , Li Xiaohan , Zhu Yuyi , Lu Fangru , Dong Ling , Zeng Linghui , Zhong Weixiang , Wang Yongcheng , Fan Longjiang , Chen Hongyu
Published: December 2024

Puncture biopsy, especially those preserved by formalin fixed paraffin embedding (FFPE) samples, play an important role in various research purposes. Diverse single‐nucleus RNA sequencing (snRNA‐seq) techniques have been developed for FFPE samples, however, how to perform high‐throughput snRNA‐seq on small FFPE puncture samples is still a challenge. Here, the previously developed snRNA‐seq technique (snRandom‐seq) is optimized by implementing a pre‐indexing procedure for the minimal puncture FFPE samples. In analyzing 20 samples from various solid tumors, optimized snRandom‐seq still detected ≈17 000 genes and 12 000 long non‐coding RNAs (lncRNAs), achieving precise clustering based on tissue origin. A head‐to‐head comparison with 10× Genomics on fresh biopsy samples showed a similar gene detection rate, with significantly enhanced lncRNA detection, indicating that the optimized snRandom‐seq technique maintains its established gene detection advantages even when applied to small samples. Utilizing 7 puncture FFPE samples of liver metastases from 3 colorectal cancer patients pre‐ and post‐immunotherapy, the cellular developmental trajectories are reconstructed and revealed dynamic spatiotemporal heterogeneity during treatment, including insights into pseudoprogression of immunotherapy. Therefore, the optimized snRandom‐seq offers a solution for high‐throughput single‐cell RNA and non‐coding RNA analysis in minimal puncture FFPE sample.
Programmable Multiplexed Nucleic Acid Detection by Harnessing Specificity Defect of CRISPR‐Cas12a
Authors: Guan Xin , Yang Rui , Zhang Jiongyu , Moon Jeong , Hou Chengyu , Guo Chong , Avery Lori , Scarola Danielle , Roberts Daniel S. , LaSala Rocco , Liu Changchun
Published: December 2024

CRISPR‐Cas12a works like a sophisticated algorithm in nucleic acid detection, yet its challenge lies in sometimes failing to distinguish targets with mismatches due to its specificity limitations. Here, the mismatch profiles, including the quantity, location, and type of mismatches in the CRISPR‐Cas12a reaction, are investigated and its various tolerances to mismatches are discovered. By harnessing the specificity defect of the CRISPR‐Cas12a enzyme, a dual‐mode detection strategy is designed, which includes approximate matching and precise querying of target sequences and develop a programmable multiplexed nucleic acid assay. With the assay, 14 high‐risk human papillomavirus (HPV) subtypes are simultaneously detected, collectively responsible for 99% of cervical cancer cases, with attomolar sensitivity. Specifically, the assay not only distinguishes HPV16 and HPV18, the two most common subtypes but also detects 12 other high‐risk pooled HPV subtypes. To enable low‐cost point‐of‐care testing, the assay is incorporated into a paper‐based microfluidic chip. Furthermore, the clinical performance of the paper‐based microfluidic chip is validated by testing 75 clinical swab samples, achieving performance comparable to that of PCR. This programmable multiplexed nucleic acid assay has the potential to be widely applied for sensitive, specific, and simultaneous detection of different pathogens.
Novel Ru‐O3Se4 Single Atoms Regulate the Charge Redistribution at Ni3Se2/FeSe2 Interface for Improved Overall Water Splitting in Alkaline Media
Authors: Guo Linke , Liu Tianpeng , Zhang Le , Ma Mengyao , Gao Peng , Cao Dong , Cheng Daojian
Published: December 2024

Developing low‐cost, highly active, and stable bifunctional catalysts is of great significance for electrochemical water splitting. Herein, novel Ru‐O3Se4 single atoms doped Ni3Se2/FeSe2 interface catalyst is fabricated by a two‐step method for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Notably, Ru‐Ni3Se2/FeSe2 nanosheets exhibit excellent HER (43 mV@10 mA cm−2) and OER (283 mV@100 mA cm−2) activities in alkaline solution. In particular, the mass activity of Ru‐Ni3Se2/FeSe2 catalyst is 3593.61 mA mg Ru−1 at 200 mV for HER and 7073.80 mA mgRu−1 at 400 mV for OER, which is 25.91 and 367.28 times of commercial Pt/C and RuO2, respectively. In situ spectroscopy techniques confirm Ru‐O3Se4 single atoms facilitate the adsorption of intermediates H* and OOH* during HER and OER processes, respectively. Further density functional theory calculations reveal introducing Ru‐O3Se4 single atoms causes the transfer of electrons from Ru to Ni and Fe atoms, leading to a redistribution of charge at the Ni3Se2/FeSe2 interface, thus reducing the energy barriers of rate‐determining step to −0.37 and 1.92 eV for HER and OER, respectively. This work emphasizes the significant role of single atoms at the interface for overall water splitting.
Combined In Situ X‐Ray Spectroscopic and Theoretical Study on Trimetal Synergistic Enhancement of Water Oxidation
Authors: Fan Yalei , Ye Xubin , Zhou Jing , Lu Dabiao , Kuo Chang‐Yang , Huang Yu‐Cheng , Chan Ting‐Shan , Chen Chien‐Te , Long Youwen , Wang Jian‐Qiang , Hu Zhiwei , Zhang Linjuan
Published: December 2024

Electrochemical water‐splitting is vital in energy storage and conversion applications. However, the sluggish kinetics of the oxygen evolution reaction (OER) hinders the electrochemical water‐splitting. Therefore, developing efficient catalysts and understanding the OER mechanism are highly desirable. This study successfully synthesized a new quadruple perovskite oxide CaCu3Co2Ru2O12 (CCCRO) catalyst exhibiting high OER activity with overpotential 198 mV at 10 mA cm−2, a Tafel slope of 37 mV dec−1, and long‐term operational stability with a current density of 500 mA cm−2 for >500 h. The in situ X‐ray absorption near‐edge structure (XANES) indicated that a part of high‐spin (HS) Co3+ ions and low‐spin (LS) Ru5+ ions transitioned to the tetravalent Co (IV) and hexavalent Ru (VI) valence states under OER. However, the Cu2+ valence state remained unchanged. Furthermore, the density functional theory (DFT) calculations reveal that the lattice‐oxygen oxidation mechanism (LOM) rather than conventional adsorbate evolution mechanism (AEM) is responsible for high OER activity in Ru (VI)‐O‐Co (IV) network, and that the Cu(A’)/Co(B)/Ru(B’) three sites synergistically facilitate the OER activity for CCCRO.
Identifying and Prioritizing Hazardous Chemicals in Construction Metal Structure Coating Systems: A Roadmap for Data‐Driven Disease Prevention
Authors: Patel Paridhi , Bello Dhimiter , Bello Anila
Published: December 2024

Introduction

Occupational exposure as a painter was classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen (carcinogenic to humans) in 1989. Chemical agents responsible for cancers and other illnesses among industrial painters are not well‐documented. The goal of this systematic review and synthesis was to document the chemistries of metal structure coating systems, summarize data gaps on occupational exposures and health effects among painters, and identify and prioritize hazardous chemicals to guide future exposure and occupational health studies, and ultimately disease prevention efforts.

Methods

We reviewed coating products approved by the Northeast Protective Coating Committee (NEPCOAT) for use in steel bridges in New England, with a special focus on Part B of these reactive chemical systems, and related literature on exposures and health effects.

Results

From the review of safety datasheets (SDS), we identified 61 unique CAS numbers belonging to different Part B chemical groups of isocyanate‐ and epoxy‐based formulations, including amine hardeners, solvents, nanomaterials, and other additives. The list of identified ingredients contained 14 potent sensitizers, two IARC Group 1 known carcinogens, and 7 IARC Group 2B possible carcinogens. Cancers of the lungs, urinary bladder, liver, kidneys, and gastrointestinal system, allergic contact dermatitis, lung fibrosis, and asthma were some possible disease endpoints. Existing occupational exposure studies focused on solvent exposures, while exposure and biomonitoring studies of amine hardeners and other ingredients of concern in these formulations are lacking.

Conclusions

The list of chemicals of concern identified here, including sensitizers and carcinogens, can serve as a basis for analytical method development and field exposure assessment studies. A national multi‐pronged strategy to reduce chemical exposures and health risks among construction painters is warranted, including research on exposure monitoring and reduction efforts, longitudinal epidemiological studies, and product reformulation.
Rat models of frozen shoulder: Classification and evaluation
Authors: Gu Hezirui , Xie Wenqing , Li Hengzhen , Liu Shuguang , Li Yusheng
Published: December 2024

Frozen shoulder (FS), also known as adhesive capsulitis, is a condition that causes contraction and stiffness of the shoulder joint capsule. The main symptoms are persistent shoulder pain and a limited range of motion in all directions. These symptoms and poor prognosis affect people's physical health and quality of life. Currently, the specific mechanisms of FS remain unclear, and there is variability in treatment methods and their efficacy. Additionally, the early symptoms of FS are difficult to distinguish from those of other shoulder diseases, complicating early diagnosis and treatment. Therefore, it is necessary to develop and utilize animal models to understand the pathogenesis of FS and to explore treatment strategies, providing insights into the prevention and treatment of human FS. This paper reviews the rat models available for FS research, including external immobilization models, surgical internal immobilization models, injection modeling models, and endocrine modeling models. It introduces the basic procedures for these models and compares and analyzes the advantages, disadvantages, and applicability of each modeling method. Finally, our paper summarizes the common methods for evaluating FS rat models.
Influence on the lipase concentration and substrate on the lipid profile and sensory characteristics of enzyme‐modified cheese
Authors: Vieitez Ignacio , Miraballes Marcelo , Irigaray Bruno , Ellis Ana Claudia , Callejas Nicolás , Hodos Natalia , Cano Andrea , Romero Melissa , da Rosa Gonzalo , Gámbaro Adriana
Published: December 2024

Enzymatically modified cheeses (EMC) aim to achieve, in a shorter time frame, a composition and sensory characteristics akin to those of aged cheese. This study analyzed the lipid profile, composition, free fatty acid (FFA) content, and sensory attributes of EMC pastes with the objective of emulating the flavor profile of a red smear‐ripened cheese (SR). Two different smear ripened cheeses were utilized as references: SR1, aged for 2–3 months, and SR2 aged for 10 months. Twelve formulations of EMC were prepared using a fatty medium moisture cheese corresponding to Mercosur's Danbo type cheese (MD) as sole base, with the addition of the two types of SR cheeses and enzymes including exopeptidase, endopeptidase, and lipase, with varying concentrations of the latter. The EMC formulations exhibited a different physicochemical composition compared to the SR cheeses, with higher moisture, ash content, lower fat, and protein content. The highest total FFA contents were found in formulations with SR2, followed by formulations with SR1. As the concentration of lipase increased in the formulations, a greater degree of lipolysis was observed. Sensory profile was not influenced by the concentration of lipase, but rather depended on the type of cheese used as the base. All EMC samples prepared with SR1 besides those prepared with SR2 as the base cheese and the highest concentration of lipase, exhibited sensory profiles more closely resembling that of lightly aged SR1. The enzymatic modification of cheeses proved to be a useful tool for generating sensory profiles similar to slightly aged SR cheese.
Glutathione S‐Transferase Contributes to the Resistance of Megalurothrips usitatus Against Lambda‐Cyhalothrin by Strengthening Its Antioxidant Defense Mechanisms
Authors: Dong Wenbo , Wang Chaozheng , Li Xia , Huang Tianbao , Li Fen , Wu Shaoying
Published: December 2024

The damage caused by Megalurothrips usitatus, a common pest, has significantly affected the Chinese vegetable industry. The inappropriate application of chemical pesticides has caused M. usitatus to become highly resistant to conventional insecticides. Glutathione S‐transferase (GST), known for its multifunctional properties, contributes to detoxification and antioxidation. It enhances insects' adaptability to pesticides by facilitating the elimination of lipid peroxidation products resulting from pyrethroid insecticides. This research employed RT‐qPCR to identify GST genes that exhibited significant expression in response to lambda‐cyhalothrin stress. It also quantified changes in antioxidant and apoptosis markers within the M. usitatus under lambda‐cyhalothrin exposure. The functional significance of GST was validated by assessing alterations in the antioxidant defense system and resistance to lambda‐cyhalothrin following the inhibition of GST activity. The study's outcomes indicated that MuGSTs1 was markedly upregulated in response to lambda‐cyhalothrin stress (p < 0.0001). The GST activity was effectively suppressed by the specific inhibitor, diethyl maleate, achieving an inhibition rate of 64.05%. Following the inhibition of GST, the overall antioxidant capacity was reduced by 3.1‐fold compared with the control, and the M. usitatus exhibited a 7.91‐fold increase in sensitivity to lambda‐cyhalothrin. These findings confirm the pivotal role of GST in the oxidative stress response of the M. usitatus and their contribution to the development of resistance to lambda‐cyhalothrin through enhanced antioxidant defenses. This research offers valuable perspectives on the adaptive reactions of insects to chemical stressors, facilitating the management of resistance and the formulation of effective pest control strategies.
NiFe‐NO3 Layered Double Hydroxide as a Novel Anode for Sodium Ion Batteries
Authors: Fortunato Marco , Sarapulova Angelina , Schwarz Björn , Cardinale Anna Maria , Dsoke Sonia
Published: December 2024

2D materials are emerging materials for energy storage and among these layered double hydroxides (LDHs) seem particularly promising due to their structure, easily adjustable composition, and cheapness. This study marks the first reported application of an LDH, specifically NiFe‐NO3 LDH, as conversion anode material in a sodium half‐cell, to the best of our knowledge. Despite an initial loss in capacity, the material demonstrates notable stability, retains a high specific capacity even after 50 discharge/charge cycles (~500 mAh/g). The intricate reaction mechanism was explored using various ex‐situ techniques such as DC magnetometry and FTIR, as well as in‐operando X‐ray Absorption Spectroscopy (XAS). The proposed Na‐storage mechanism in NiFe‐NO3 LDH involves an initial irreversible “activation” during the first sodiation, characterized by a phase change reaction that leads to the formation of NiOx and Fe3O4, followed by a reversible mechanism involving both intercalation and conversion in subsequent cycles.
Design Principles of an Engineered Metastatic Niche for Monitoring of Cancer Progression
Authors: Escalona Guillermo , Ocadiz‐Ruiz Ramon , Ma Jeffrey A. , Schrack Ian A. , Ross Brian C. , Morrison Alexis K. , Jeruss Jacqueline S. , Shea Lonnie D.
Published: December 2024

Across many types of cancer, metastatic disease is associated with a substantial decrease in 5‐year survival rates relative to only a localized primary tumor. Many patients self‐report metastatic disease due to disruption of normal organ or tissue function, and earlier detection could enable treatment with a lower burden of disease. We have previously reported a subcutaneous biomaterial implant for early detection by serving as an engineered metastatic niche, which has been reported to recruit tumor cells before colonization of solid organs. In this report, we investigated the design principles of the scaffold and defined the conditions for use in disease detection. Using the metastatic 4T1 triple‐negative breast cancer model, we identified that a porous structure was essential to capture tumor and immune cells. Scaffolds of multiple diameters were investigated for their ability to serve as a metastatic niche, with a porous scaffold with a diameter as small as 2 mm identifying disease accurately. Additionally, scaffolds that had been in vivo for 1–5 weeks were able to identify disease accurately. Finally, the sensitivity of the scaffold relative to liquid biopsies was analyzed, with scaffolds accurately detecting disease at earlier time points than liquid biopsy. Collectively, these studies inform the design principles and use conditions for porous scaffolds to detect metastatic disease.
Comparison of Back Tuina and Oral Astragalus Methods to Enhance Immunosuppression in Rabbits and Prediction of Astragalus Targets for Immune Function Improvement
Authors: Dai Mengyao , Fan Enshuo , Pan Ting , Li Xuefeng , Li Mengqi , Lu Qi , Wang Weizheng , Guo Xiaole , Shang Kun , Zhang Xin
Published: December 2024

Back tuina massage and oral administration of astragalus are two methods used in traditional Chinese medicine (TCM) to improve immune function. The aim of this study is to analyze the effects of tuina and orally administered astragalus on immunosuppressed rabbits using proteomics technology. Additionally, we investigate the potential mechanism of action of astragalus components on immunosuppression using an integration of network pharmacology and molecular docking technology. The findings suggested that cyclophosphamide‐induced immunosuppression is primarily mediated through signaling pathways that include complement and coagulation cascades and chemical carcinogenesis. Immunosuppression is modulated by tuina and the oral administration of astragalus through various proteins and signaling pathways. A network pharmacology analysis indicated that quercetin, trichothecene isoflavones, and kaempferol in astragalus exhibited immunomodulatory effects. Molecular docking validation demonstrated that 15 major targets showed strong binding affinities to their respective interacting active ingredients. This trial provides references for future studies on the immune‐boosting properties of tuina and oral astragalus.
Effects of CYP3A4 Variants on Methadone Metabolism In Vitro
Authors: Wang Chen‐chen , Zhang Ming‐lei , Xu Yan‐dan , Hu Guo‐xin , Cai Jian‐ping , Lan Tian , Bai Yong‐feng
Published: December 2024

In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the in vitro oxidative metabolism of methadone. We utilized a baculovirus‐insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N‐demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.
Investigating the Mediating Role of Mental Disorders in the Relationship Between Early Sexual Intercourse and Intentional Self‐Harm: A Two‐Step and Multivariable Mendelian Randomization Study
Authors: Dong Dameng , Saeed Saboor , Chen Rucheng , Chen An , Zheng Weijun
Published: December 2024

Background

Epidemiological studies have established an association between early sexual intercourse and intentional self‐harm. However, the causal mechanisms, particularly the role of mental health disorders, remain elusive.

Methods

In this Mendelian randomization (MR) study, we leveraged genome‐wide association study data from multiple sources. Age at first sexual intercourse (AFSI) statistics were derived from the UK Biobank, encompassing up to 406,457 participants of European ancestry. Intentional self‐harm (ISH) genome‐wide association study (GWAS) data were obtained from the FinnGen Biobank, comprising 218,792 European‐descent individuals. We investigated the causal relationship between AFSI and ISH and quantified the mediating effects of major depressive disorder (MDD; n = 173,005), schizophrenia (SCZ; n = 127,906), and attention deficit hyperactivity disorder (ADHD; n = 55,374). Both two‐step and multivariable MR approaches were employed to estimate the mediation effects of these psychiatric disorders.

Results

The F‐statistics of all retained SNPs are over 10, indicating our study has no weak instrument bias. The odds ratio (OR) indicated that early sexual intercourse substantially increases the risk of ISH (IVW: OR = 0.60, 95% CI = 0.54–0.66, p < 0.05). Specifically, MDD was found to mediate 31% of this effect and SCZ 12%, collectively accounting for 46% of the total effect.

Conclusions

Early sexual intercourse is associated with an increased risk of intentional self‐harm, potentially mediated by psychiatric disorders. These findings emphasize the need for mental health screening and early intervention in adolescents with early sexual debuts.
Evaluation of the Clinical Safety of the Low‐Cost Warburg Therapy for the Treatment of Patients With Advanced Cancers
Authors: Lu Peihua , Tsang Tom , Badowski Michael S. , Pennington Michael E. , Meade‐Tollin Linda C.
Published: December 2024

Background

Rising cancer care costs are becoming cost prohibitive for lower income people worldwide. We developed the Warburg protocol as a low‐cost option for the treatment of cancer that was inspired. It was developed to exploit an Achilles heel which is a hallmark of cancer cells; the metabolic requirement for higher levels of glucose than normal cells.

Objective

The purpose of this report is to assess the clinical safety and affordability of the Warburg therapy as an option for patients with advanced cancers.

Methods

Between 2021 and 2023, 251 patients with advanced cancers received a total of 8542 treatments with the Warburg therapy. To restrict the supply of blood glucose to cancerous tumors, regular human insulin was administered (IV) sufficient to reduce blood glucose concentrations to hypoglycemic levels for 40–60 min. Subroutine doses of fluorouracil and cyclophosphamide were administered intravenously during this hypoglycemic period. Food or intravenous glucose was given as needed to return blood glucose to euglycemic levels after treatment. Patient symptoms, status, vitals, blood glucose, and hypoglycemic symptoms were monitored throughout treatment. Various blood parameters were measured before and after patients' course of treatment.

Results

There were no irreversible adverse reactions in advanced tumor patients of different ages and different cancer types after treatment. There was no significant fluctuation in blood glucose levels in diabetic and non‐diabetic patients after treatment, and the weight, vital index and blood biochemical index of patients before and after multiple treatments exhibited little variation.

Conclusion

Warburg therapy for the treatment of advanced tumors is clinically feasible, and safe for multiple treatments. It is inexpensive and widely applicable to different patient groups.
Consumer Adoption of Internet of Things
Authors: Ladeira Wagner Junior , Lim Weng Marc , de Oliveira Santini Fernando , Rasul Tareq , Frantz Bernardo , de Oliveira Rosa Jean Carlos , Azhar Mohd
Published: December 2024

The Internet of Things (IoT), a pivotal technology in enhancing user connectivity, faces a paradox: its widespread potential yet limited consumer adoption. This study addresses this dichotomy by synthesizing a large‐scale meta‐analytic structural equation modeling (MASEM) and hierarchical linear meta‐analysis (HiLMA) of 2736 effect sizes from 52,629 respondents across 138 studies. We propose an integrated and heterogeneous model, underpinned by appraisal theory and the technology acceptance model (TAM), to explain the dynamics of IoT adoption among consumers across heterogeneous settings. Our findings reveal that consumers' primary appraisals of IoT, influenced significantly by hedonic motivation and social influence, are instrumental in forming perceptions of IoT's ease of use and usefulness. These perceptions subsequently guide consumers in navigating the complexities of IoT, such as privacy, risk, and trust issues. These layered appraisals inform consumers' attitudes and intentions toward IoT adoption, wherein its efficacy is heightened in contexts involving critical services versus non‐critical ones, in Eastern versus Western regions, within healthcare rather than fashion sectors, and among more experienced and younger demographics, particularly students over the general public. The study also underscores the distinct impact of branded IoT devices over unbranded ones, delineating a heterogeneous understanding of IoT adoption. Therefore, the interpretation of heterogeneities in the combination of effect sizes from extant studies is a seminal attempt to address the IoT paradox by demonstrating which factors explain the variations in the relationship between attitude and intention toward IoT from the consumer's perspective.
Synthesis of Thiazolidinedione‐ and Triazole‐Linked Organoselenocyanates and Evaluation of Anticancer Activities Against Breast Cancer with Mechanistic Investigations
Authors: Pal Nikita , Banerjee Kaustav , Sarkar Shilpi , Mandal Tapas K. , Bhabak Krishna P.
Published: December 2024

Organoselenocyanates are important classes of organoselenium compounds having potential pharmaceutical applications in cancer biology. In the present study, two different series of organoselenocyanates (15 a–15 c and 16 a–16 c) incorporating crucial heterocyclic pharmacophores such as 2,4‐thiazolidine‐1,3‐dione and 1,2,3‐triazole were rationally designed. The organoselenocyanates were synthesized using multi‐step organic synthesis and investigated for their anticancer activities against triple‐negative breast cancer cells. Based on the preliminary anti‐proliferative activities and the selectivity index towards cancer cells over the normal cells, 2,4‐thiazolidine‐1,3‐dione‐based selenocyanate 15 a was identified as the lead analogue for detailed investigations. In addition to the anti‐migratory activity, compound 15 a induced G1‐phase arrest of the cell cycle and led to early apoptosis. Further studies on the redox balance of MDA‐MB‐231 cells indicated the antioxidant nature of 15 a with the quenching of ROS level and upregulation of TrxR1 expression. Detailed mechanistic investigations with the expression levels of key‐cancer marker proteins revealed that the selenocyanate 15 a induced the activation of ERK pathway by upregulating p‐ERK expression with the subsequent downregulation of p‐Akt and c‐Myc levels leading to the inhibition of cellular proliferation. Therefore, the primary outcomes of the study would be valuable in the development of chemotherapeutic agents towards the treatment of triple‐negative breast cancer.
pH Controlled Transient Cyclization of Peptides for Increased Stability towards Oral Delivery
Authors: Paprocki Maciej P. , Sørensen Kasper K. , Jensen Knud J.
Published: December 2024

Peptides are highly efficient for treatment of many diseases, especially in oncology and diabetes. Oral delivery of peptides is desirable, but is challenged by low bioavailability and new chemical methods to enable oral delivery are needed. Here, we developed pH responsive linearization as a strategy for transient protection of peptides to extend their half‐life in model systems. Peptides were cyclized to increase their stability at the low pH in the stomach, while they linearize at neutral pH to form the active peptide. We developed ester based responsive linkers with a protonable amine for O‐to‐N acyl shift, which allowed linearization strategies based on pyroglutamoyl (pGlu) or diketopiperazine (DKP) formation. After coupling of the linker, peptides were cyclized by CuAAC. We studied the stability against simulated gastric fluid (SGF) at different pH and the ability of cyclic peptides to linearize. This led to PYY3–36 analogues with pH responsive linearization for increased stability.
Reusable Iron‐Copper Catalyzed Cross‐Coupling of Primary Amides with Aryl and Alkyl Halides: Access to N‐Arylamides as Potential Antibacterial and Anticancer Agents
Authors: Roy Keya , Saha Anay , Saha Bijay , Banerjee Subhrajyoti , Mukhopadhyay Chitrangada Das , Sahu Sumanta Kumar , Adak Laksmikanta
Published: December 2024

We present, for the first time, an efficient ligand‐free iron‐copper catalyzed cross‐coupling reaction involving a variety of aryl, heteroaryl halides (including chlorides, bromides, and iodides), and alkyl bromides with diverse aryl and aliphatic primary amides, conducted under solvent‐minimized conditions. This economically competitive protocol successfully yielded the corresponding cross‐coupling products, N‐arylamides and N‐alkylamides, in good to excellent yields with broad substrate scope (65 examples) and tolerance to several sensitive functionalities (including heterocycles). No conventional work‐up is required for this protocol, and the developed method is applicable for gram‐scale synthesis. Notably, the catalyst is inexpensive, environmentally friendly, and can be reused at least four times with minimal loss of catalytic activity. A series of experiments, including X‐ray photoelectron spectroscopy (XPS), UV spectroscopy, cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and X‐ray diffraction (XRD) were conducted to identify the oxidation state of active catalytic species and radical clock experiment was performed using a radical probe to investigate the reaction mechanism. Furthermore, we evaluated the antibacterial and anticancer properties of selected synthesized products (3 ii, 3 xii, and 3 xxxx) in‐vitro. The results indicated that the prepared compounds exhibited promising antibacterial and anticancer activities (MTT and Molecular Docking).
At‐Home Self‐Collection of Pharmacokinetic Data: Design and Results From a Phase 1 Open‐Label Feasibility Trial
Authors: Raoufinia Arash , Shoaf Susan E. , Rothman Brian , Ye Chelsea , Chung Chris
Published: December 2024

Pharmacokinetic (PK) studies pose unique technical challenges. We present the design of a Phase 1, open‐label, fixed‐sequence, PK trial that aimed to compare the timing accuracy of participant‐ versus staff‐collected data, and we provide safety and tolerability outcomes for centanafadine treatment. Healthy adults aged 18‐55 years received a single 100‐mg centanafadine sustained‐release tablet at Visits 1, 2, and 4. PK samples (venous sampling and blood microsampling) and safety assessments (12‐lead electrocardiograms [ECGs] and vital signs) were collected by clinical site staff only at Visit 1. At Visit 2, site staff collected venous blood, and participants obtained blood microsamples, a 6‐lead ECG, and vital signs under staff supervision. At Visit 4, participants obtained blood microsamples, a 6‐lead ECG, and vital signs remotely. The absolute differences between actual and scheduled collection times for PK samples, ECGs, and vital signs are reported descriptively. Of the 20 participants, at least 75% obtained blood microsamples within 10 minutes of the planned nominal time. Absolute differences between actual and scheduled collection times of ECGs and vital signs were small. No adverse events were related to treatment. Overall, results support the feasibility of at‐home collection of PK samples, ECGs, and vital signs.
The effect of the board of directors, audit committee, and institutional ownership on carbon disclosure quality: The moderating effect of environmental committee
Authors: Adam Abbas Abdelrahman , Salleh Zalailah , Alahdal Waleed M. , Hussien Asaad Mubarak , Bajaher Mohammed , Baatwah Saeed Rabea
Published: December 2024

This study investigates the impact of the board of directors' effectiveness (BODEF), audit committee effectiveness (AUDEF), and institutional ownership (IO) on carbon disclosure quality (CDQ) and examines the moderating effect of the environmental committee (EC) on such impacts. Thus, to evaluate CDQ, a self‐constructed index was established based on standards and recommendations stated in several Malaysian and international guidelines related to carbon reporting. This study employs panel data analysis on 200 publicly listed Malaysian firms observed from 2015 to 2019. The findings showed a significant positive effect of BODEF, AUDEF, and IO on CDQ. Additionally, the results showed that EC has an insignificant moderating influence on the impact of BODEF and AUDEF on CDQ; meanwhile, it strengthens the effect of IO on CDQ. The reported findings offer valuable insights to policymakers, enhancing their awareness of carbon disclosure practices in Malaysia and emphasizing the significance of corporate governance in this context.
Further Validation for a Measure of Disordered Eating in an Independent Sample of Male and Female Elite Athletes: The Athletic Disordered Eating (ADE) Scale
Authors: Fatt Scott J. , Prnjak Katarina , Buckley Georgina L. , George Emma , Hay Phillipa , Jeacocke Nikki , Mitchison Deborah
Published: December 2024

Background

Elite athletes experience unique pressures and cognitions associated with disordered eating, which may not be appropriately captured by existing tools. The Athletic Disordered Eating (ADE) scale is a recently developed and first measure of disordered eating specifically developed and validated in current and former athletes. This study aimed to provide further validation for the ADE in an independent sample of elite athletes.

Method

Participants were 237 elite athletes (MAge = 26.1, SDAge = 8.6; 75.9% female; 73.0% current athletes) participating in various sports across Australia and the United States. Participants completed an online survey including the ADE, demographic questions, and other measures of eating disorder symptoms (Eating Disorder Examination—Questionnaire Short‐form, Clinical Impairment Assessment), and related constructs. Twenty‐five athletes also completed a clinical interview to determine eating disorder caseness.

Results

The four‐factor structure of the ADE from the original validation was confirmed. Further, the ADE demonstrated adequate measurement invariance across male and female current and former athletes; internal consistency for the total score and each subscale; convergent and discriminant validity; and criterion‐related validity—with a score of 40 balancing sensitivity and specificity against other scales with established cut‐offs for a likely eating disorder. The high‐risk cut‐off (ADE ≥ 33) had high sensitivity but low specificity in identifying eating disorder cases, as confirmed by the clinical interview.

Discussion

The ADE is a low‐time‐burden screening tool for disordered eating, validated in independent samples of diverse athletes. It should be considered for future use in screening, early identification, and monitoring treatment progress in elite athletes.
Conversion of tropical forests to water buffalo pastures in lower Amazonia: Carbon losses and social carbon costs
Authors: Kauffman J. Boone , Souza Fernanda M. , Costa Rodolfo F. , Barreto da Silva Antonio Elves , Ferreira Tiago O. , Megonigal J. Patrick , Ritonga Rasis , Gangga Adi , Novita Nisa , Pacheco Carla F. O. , Bernardino Angelo Fraga
Published: December 2024

Tropical peat swamp forests provide many important ecosystem services, especially their function as global carbon sinks. These carbon‐rich wetlands are widespread in South America, yet few studies have examined carbon stocks or losses due to land use change. In the lower Amazon, they are being converted to pastures largely utilized by domestic water buffalo (Bubalus bubalis). We quantified carbon stocks in intact peat forests and recently converted pastures (<10 years) at the Lago Piratuba Biosphere Reserve (LPBR) in the lower Amazon of Brazil. The soils of intact forests were typified by shallow organic (peat) horizons at the soil surface. The mean total ecosystem carbon stock (TECS) in intact forests was 354 ± 28 Mg C ha−1. In contrast, the TECS of disturbed sites was significantly lower (p = 0.02) with a mean of 248 ± 17 Mg C ha−1. We estimated greenhouse gas (GHG) emissions from water buffalo (due to enteric fermentation and manure deposition) to be 7.5 Mg CO2e ha−1 year−1. Considering GHG emissions from this land use, the social carbon costs (SCCs) arising from the degradation of coastal Amazon peatlands are as high as US$2742 ha−1 year−1. The SCC of meat produced from this land use is as high as US$100/kg of meat produced, which far exceeds the economic returns from livestock. Based on the estimated numbers of water buffalo for the southern portion of the LPBR and the time since initial disturbance, the annual GHG emissions from this land use are estimated to be 602,846 Mg CO2e year−1 with an SCC as high as US$111,526,524 million year−1. This land use also eliminates opportunity values and services of carbon storage and biodiversity that would be possible from a regenerating biosphere reserve.
Identification of Multiple Thermal Events in High‐Grade Metacarbonate Rocks Using Carbon Isotope Thermometry: An Example From the Sør Rondane Mountains, East Antarctica
Authors: Satish‐Kumar M. , Kiran Sasidharan , Higashino Fumiko , Kawakami Tetsuo , Hokada Tomokazu
Published: December 2024

Nine metacarbonate layers from the regionally metamorphosed terrane of the Sør Rondane Mountains in the Eastern Dronning Maud Land in East Antarctica were examined in detail for constraining the thermal events using carbon isotope exchange between dolomite/calcite and graphite. Equilibrium carbon isotope fractionation between dolomite and graphite suggested peak metamorphic temperature conditions reaching up to 802°C ± 29°C were estimated at the Balchenfjella locality, where multiple samples from six thick layers of metacarbonate rocks were examined. However, some of the samples exhibit lower carbon isotope fractionation reflecting the possibility of ultrahigh‐temperature metamorphic conditions, which is consistent with recent reports. Furthermore, several metacarbonate rock samples display large variations in δ13CVPDB values for graphite grains, despite dolomite and calcite showing homogeneous carbon and oxygen isotopic composition indicating signatures of retrograde metamorphism and fluid infiltration events. Detailed textural observation suggested alteration of δ13CVPDB values of graphite during retrograde metamorphism might have resulted due to the overgrowth of graphite crystals by the infiltration of low δ13CVPDB‐bearing fluids, the extent of alteration being a direct function of the fluid–rock ratio. Field evidence indicates the presence of carbonate veins cutting across the metacarbonate rocks suggesting that carbon isotope thermometry can also be utilised to understand the effect of external fluid infiltration. At Perlebandet locality the metamorphic temperature conditions were estimated to be around 915°C, whereas those from Tanngarden and Menipa gave lower temperature estimates. Detailed textural analysis of graphite in combination with isotopic composition provided clear evidence for retrograde events. Thus, our results provide tight constraints of peak and post‐peak metamorphic temperature conditions and a regional thermal structure for the Sør Rondane Mountains and further testify the usefulness of carbon isotope thermometry in polymetamorphic terrains.