bluuebunny/crossref_metadata_2025 huggingface dataset:
Actividad antibacteriana y antifúngica de extractos de guayusa (Ilex guayusa Loes.) obtenidos mediante técnicas de alta presión y solventes polares
Authors:   Universidad Técnica de Ambato, Cadena Carrera Santiago Esmiro , Tramontin Deise Parolo ,   Instituto Federal Catarinense, Núñez Villacis Lorena ,   Universidad Técnica de Ambato, Bella Cruz Alexandre ,   Universidade do Vale do Itajaí
Published: January 2024

La resistencia a los antimicrobianos (RAM) representa unos de los problemas más importantes de salud mundial. En países en desarrollo, como América Latina, la RAM provoca miles de muertes cada año debido al bajo o limitado acceso a antibióticos y/o cuidado básico de salud. En esta región, la Amazonía alberga una gran biodiversidad que podría ser fuente para el descubrimiento de nuevas substancias antimicrobianas que podrían ayudar a enfrentar la RAM. La guayusa (Ilex guayusa Loes.) ha sido usada durante milenos por los nativos de esta región, y se ha reportado como fuente de compuestos bioactivos. Sin embargo, los compuestos bioactivos obtenidos, han sido mediante la aplicación de técnicas convencionales, pocas investigaciones han aplicado técnicas no convencionales de extracción como fluido supercrítico (ESC) o líquido presurizado (ELP) usando solventes o cosolventes polares. En el presente estudio evaluó la actividad antibacteriana y antifúngica de extractos de guayusa obtenidos mediante técnicas no convencionales ESC y PLE aplicando solventes/cosolventes polares y comparada con la técnica convencional de extracción por maceración. Los solventes/cosolventes usados en las diferentes extracciones fueron: CO2/agua, CO2/etanol/agua, etanol/agua o agua. A partir de la evaluación de la concentración inhibitoria mínima (CIM) de los extractos, se evidenció que presentaron actividad antifúngica contra diferentes dermatofitos: Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes and Trichophyton rubrum en el rango 1000 µg mL-1 a 62.5 µg mL-1. El presente estudio demostró el promisor potencial de los extractos de hojas de guayusa obtenidos mediante baja y alta presión para combatir problemas asociados a dermatofitos.
AlignScape, displaying sequence similarity using self-organizing maps
Authors: Filella-Merce Isaac , Mallet Vincent , Durand Eric , Nilges Michael , Bouvier Guillaume , Pellarin Riccardo
Published: January 2024

The current richness of sequence data needs efficient methodologies to display and analyze the complexity of the information in a compact and readable manner. Traditionally, phylogenetic trees and sequence similarity networks have been used to display and analyze sequences of protein families. These methods aim to shed light on key computational biology problems such as sequence classification and functional inference. Here, we present a new methodology, AlignScape, based on self-organizing maps. AlignScape is applied to three large families of proteins: the kinases and GPCRs from human, and bacterial T6SS proteins. AlignScape provides a map of the similarity landscape and a tree representation of multiple sequence alignments These representations are useful to display, cluster, and classify sequences as well as identify functional trends. The efficient GPU implementation of AlignScape allows the analysis of large MSAs in a few minutes. Furthermore, we show how the AlignScape analysis of proteins belonging to the T6SS complex can be used to predict coevolving partners.
Towards using bacterial microcompartments as a platform for spatial metabolic engineering in the industrially important and metabolically versatile Zymomonas mobilis
Authors: Doron Lior , Raval Dhairya , Kerfeld Cheryl A.
Published: January 2024

Advances in synthetic biology have enabled the incorporation of novel biochemical pathways for the production of high-value products into industrially important bacterial hosts. However, attempts to redirect metabolic fluxes towards desired products often lead to the buildup of toxic or undesirable intermediates or, more generally, unwanted metabolic cross-talk. The use of shells derived from self-assembling protein-based prokaryotic organelles, referred to as bacterial microcompartments (BMCs), as a scaffold for metabolic enzymes represents a sophisticated approach that can both insulate and integrate the incorporation of challenging metabolic pathways into industrially important bacterial hosts. Here we took a synthetic biology approach and introduced the model shell system derived from the myxobacterium Haliangium ochraceum (HO shell) into the industrially relevant organism Zymomonas mobilis with the aim of constructing a BMC-based spatial scaffolding platform. SDS-PAGE, transmission electron microscopy, and dynamic light scattering analyses collectively demonstrated the ability to express and purify empty capped and uncapped HO shells from Z. mobilis. As a proof of concept to internally load or externally decorate the shell surface with enzyme cargo, we have successfully targeted fluorophores to the surfaces of the BMC shells. Overall, our results provide the foundation for incorporating enzymes and constructing BMCs with synthetic biochemical pathways for the future production of high-value products in Z. mobilis.
Financial stress in emerging adults with type 1 diabetes: a mini review integrating lessons from cancer research
Authors: Wentzell Katherine , Nagel Kathryn E.
Published: January 2024

Amongst adults in the United States, those ages 18-30 have the highest unemployment rates, the lowest incomes, and are the most likely to be uninsured. Achieving financial independence is a core developmental task for this age group, but for those with type 1 diabetes (T1D), the high costs of insulin and diabetes supplies as well as an employment-based insurance model with minimal safety net can make this a formidable challenge. Cost-related non-adherence to diabetes management is particularly high in emerging adults with T1D and is associated with severe consequences, such as diabetic ketoacidosis (DKA) and even death. Objective financial burden and subjective financial distress related to illness are not unique to diabetes; in cancer care this construct is termed financial toxicity. Researchers have identified that emerging adults with cancer are particularly vulnerable to financial toxicity. Such research has helped inform models of care for cancer patients to mitigate cost-related stress. This mini review aims to briefly describe the state of the science on financial stress for emerging adults with T1D and explore parallels in cancer scholarship that can help guide future work in diabetes care to reduce health inequity, drive research forward, improve clinical care, and inform policy debates.
Case Report: The woman with the big heart—an imaging-guided attempt of surgical reduction
Authors: Huenges Katharina , Langguth Patrick , Grothusen Christina , Hoffmann Grischa , Kapahnke Julia , Haneya Assad , Strotmann Jörg , Cremer Jochen
Published: January 2024

In a female patient with acute cardiac decompensation, an auxiliary finding of a giant left atrium emerged. The surgical therapy of the atrial reduction, in addition to a mitral valve replacement and a coronary artery bypass grafting, is hereby presented.
Venoarterial extracorporeal membrane oxygenation for vasoplegic shock after treprostinil refill of an implanted intravenous pump: a case report
Authors: Valencia Lucía , López Sergio , Olivas Ana , Becerra Ángel , Alemán-Segura María Desirée , Évora-García Marta , Ojeda Nazario , Cabrera Leonardo , Rodríguez-Pérez Aurelio , Pérez-Peñate Gregorio
Published: January 2024

Introduction

Venoarterial extracorporeal membrane oxygenation (ECMO) is a rescue therapy that can stabilize patients with hemodynamic compromise. Indications continue to evolve, including drug overdose. However, the indication merely for vasoplegic shock following drug overdose is controversial.

Case summary

We report a case of a 57-year-old male with high-risk idiopathic pulmonary arterial hypertension treated with upfront triple combination therapy (sildenafil, bosentan, and intravenous treprostinil infusion via subcutaneous abdominal implantable pump). In one of the refills of the drug reservoir, accidental administration of 1 months's supply of treprostinil (200 mg) into the subcutaneous tissue occurred, causing refractory vasoplegic shock. He required urgent VA-ECMO for 96 h, surviving to discharge 28 days later.

Discussion

Treprostinil poisoning is rare due to its less frequent use but is life-threatening. ECMO may be considered in vasoplegic shock due to overdose of vasodilatory medication. It allows organ perfusion to be maintained, with the knowledge that recovery is as rapid as drug elimination.
A framework towards digital twins for type 2 diabetes
Authors: Zhang Yue , Qin Guangrong , Aguilar Boris , Rappaport Noa , Yurkovich James T. , Pflieger Lance , Huang Sui , Hood Leroy , Shmulevich Ilya
Published: January 2024

Introduction

A digital twin is a virtual representation of a patient's disease, facilitating real-time monitoring, analysis, and simulation. This enables the prediction of disease progression, optimization of care delivery, and improvement of outcomes.

Methods

Here, we introduce a digital twin framework for type 2 diabetes (T2D) that integrates machine learning with multiomic data, knowledge graphs, and mechanistic models. By analyzing a substantial multiomic and clinical dataset, we constructed predictive machine learning models to forecast disease progression. Furthermore, knowledge graphs were employed to elucidate and contextualize multiomic–disease relationships.

Results and discussion

Our findings not only reaffirm known targetable disease components but also spotlight novel ones, unveiled through this integrated approach. The versatile components presented in this study can be incorporated into a digital twin system, enhancing our grasp of diseases and propelling the advancement of precision medicine.
Conducting and interpreting disproportionality analyses derived from spontaneous reporting systems
Authors: Cutroneo Paola Maria , Sartori Daniele , Tuccori Marco , Crisafulli Salvatore , Battini Vera , Carnovale Carla , Rafaniello Concetta , Capuano Annalisa , Poluzzi Elisabetta , Moretti Ugo , Raschi Emanuel
Published: January 2024

Spontaneous reporting systems remain pivotal for post-marketing surveillance and disproportionality analysis (DA) represents a recognized approach for early signal detection. Although DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient, their role remain irreplaceable for rapid detection of rare and unpredictable adverse drug reactions with strong drug-attributable component (e.g., designated medical events), especially when developed by a multidisciplinary team and combined with a careful case-by-case analysis (individual inspection of reports for causality assessment or to uncover reporting patterns and clinical features). In the recent past, a remarkable increase in publications of pharmacovigilance studies using DAs was observed, albeit the quality was debated: several publications contained “spin”, namely, misinterpretation of results to infer causality, calculate incidence, or provide risk stratification, which may ultimately result in unjustified alarm. The development of dedicated Guidelines by the international READUS-PV project (https://readus-statement.org/) will allow reproducible and transparent publication of accurate DAs, thus supporting their real transferability and exploitation by regulators and clinicians. This review offered a perspective on methodological aspects (and understanding) of DAs, their rationale, design, reporting, and interpretation.
Deep gold prospectivity modeling in the Jiaojia gold belt, Jiaodong Peninsula, eastern China using machine learning of geometric and geodynamic variables
Authors: Chen Guanghuan , Liu Zhankun , Chen Guodong , Xie Shaofeng , Yang Xin , Li Xiao , Chen Yudong , Hao Zihe , Zhong Huiting , Jiang Liqun
Published: January 2024

Gold mineralization in the Jiaojia gold belt was formed in a structurally-dominant hydrothermal mineral system showing a close spatial association with the Jiaojia detachment fault. This study delves into the Jiaojia gold belt from the perspective of coupled spatial association and ore-forming processes by employing spatial analysis of three-dimensional (3D) models, 3D ore-forming numerical modeling, and 3D prospectivity modeling using machine learning techniques (random forest (RF) and multilayer perceptron (MLP)). The overarching goal is to gain insight into the structural-hydrothermal gold system and pinpoint potential areas of deep-seated gold deposits for future exploration endeavors. The spatial analysis of ore-controlling faults uncovers a close correlation between gold enrichment and specific fault geometrical attributes, including a dip angle ranging from 20° to 40°, minimal variations in dip angle (less than 5°), and convex topographical features. These attributes likely stem from the influence of fault morphology on the flow and pooling of fluids. In conjunction with this, 3D ore-forming numerical modeling of structural deformation and fluid flow reveals that gold mineralization is intertwined with moderate volumetric strain and shear strain of rock and fluid divergence. This interaction seems particularly pronounced in areas characterized by channel-like or gentle features. Consequently, it is plausible that gold distribution in the Jiaojia region is the outcome of a comprehensive coupling process involving strain localization, rock deformation, fluid flow, heat transfer and/or interaction. The deep gold prospectivity models of RF and MLP for the Jiaojia district jointly using the predictive variables of fault geometry features and ore-forming simulation data (volume strain, shear strain, temperature variation, and fluid flux) exhibit higher AUC (area under the curve) values compared to models employing individual predictor variable datasets. This improvement underscores their enhanced predictive capability. The prospectivity results thus were used for identifying gold potential within the Jiaojia region, where five promising gold targets at depth were ultimately determined.
The relationship between diabetic retinopathy and diabetic nephropathy in type 2 diabetes
Authors: Wang Qian , Cheng Haimei , Jiang Shuangshuang , Zhang Li , Liu Xiaomin , Chen Pu , Liu Jiaona , Li Ying , Liu Xiaocui , Wang Liqiang , Li Zhaohui , Cai Guangyan , Chen Xiangmei , Dong Zheyi
Published: January 2024

Context

Diabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear.

Objective

To investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM)

Methods

Patients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored.

Results

DN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p<0.001) significantly increased with increasing severity of DR. The presence of KW nodules, lower hemoglobin levels, and younger age were independent risk factors associated with more severe DR in patients with DN.

Conclusion

DR was a good predictor of DN. In DN patients, the severity of DR was associated with glomerular injury, and presence of KW nodules, lower hemoglobin levels and younger age were independent risk factors associated with more severe DR.

Trial registration

ClinicalTrails.gov, NCT03865914.
Implications of SNP-triggered miRNA dysregulation in Schizophrenia development
Authors: Mohamed Fadumo Abdullahi , Freude Kristine
Published: January 2024

This review examines the substantial involvement of Single Nucleotide Polymorphisms (SNPs) and microRNAs (miRNAs) in the etiology and susceptibility to Schizophrenia, with particular emphasis on the dopaminergic, glutamatergic, and GABAergic systems. It elucidates the potential of SNPs to disrupt miRNA-mRNA interactions, leading to alterations in the regulatory mechanisms of Schizophrenia risk genes and subsequently influencing the susceptibility to Schizophrenia. Specific attention is given to the impact of SNPs in DICER, DROSHA, and DGCR8, as well as the potential for changes in DRD2 gene expression driven by miR-9 and miR-326, heightening the likelihood of Schizophrenia development. Furthermore, the review explores genetic alterations in the glutamatergic system, focusing on modifications linked to GRIN2A and its associated miRNAs, which have been reported to have a notable impact on the occurrence of Schizophrenia. Knowledge of the involvement of SNPs within miRNAs in influencing the expression of essential genes within the GABA system are emerging and described in this review, including their potential consequences for Schizophrenia.
Acceptance and hesitancy of COVID-19 vaccination among Saudi pregnant women
Authors: Hawsawi Sereen , Orabi Abeer , Alnajjar Hend
Published: January 2024

Introduction

Since the COVID-19 pandemic started, it has significantly impacted health systems and societies worldwide. Pregnancy increases the risk of severe illness when associated with COVID-19. Pregnant women are likely to experience COVID-19-related pregnancy complications however many of them were hesitant to receive the vaccine. This study aimed to assess the acceptance and hesitancy of COVID-19 vaccination among pregnant women in Jeddah.

Methods

The present study utilized a descriptive cross-sectional research design to include pregnant women through convenience sampling at the obstetrics and gynecology outpatient department and antenatal ward at King Abdul-Aziz Medical City, Jeddah. Data was collected from August to October 2022 using a structured questionnaire.

Results

Approximately one-third of the 264 participants (36.4%) strongly disagreed that they had developed immunity against COVID-19. More than half of them (61% and 66.3% respectively) had heard that the vaccine was unsafe for them and their babies during pregnancy, and it would contain the COVID-19 virus. However, half of them 50% agreed that vaccination would ease precautionary measures. A high acceptance score toward COVID-19 vaccination was observed among pregnant women working in the health sector. The most frequently reported reason for vaccination refusal was the belief that it was unsafe for the mother and her baby during pregnancy.

Discussion

Most of the participants perceived their susceptibility to COVID-19 infection as low and were hesitant to take the vaccine because of their worry about its effectiveness. However, they indicated a willingness to take the vaccine if it was mandatory and if they received adequate information about it. These findings correspond with previous studies conducted in Saudi Arabia that explore the reluctance of pregnant and breastfeeding women to receive COVID-19 vaccination.
An overview of the mechanisms and potential roles of extracellular vesicles in septic shock
Authors: Cao Meiling , Shi Mingyue , Zhou Boru , Jiang Hongkun
Published: January 2024

Septic shock, a subset of sepsis, is a fatal condition associated with high morbidity and mortality. However, the pathophysiology of septic shock is not fully understood. Moreover, the diagnostic markers employed for identifying septic shock lack optimal sensitivity and specificity. Current treatment protocols for septic shock have not been effective in lowering the mortality rate of patients. Most cells exhibit the capability to release extracellular vesicles (EVs), nanoscale vesicles that play a vital role in intercellular communication. In recent years, researchers have investigated the potential role of EVs in the pathogenesis, diagnosis, and treatment of different diseases, such as oncological, neurological, and cardiovascular diseases, as well as diabetes and septic shock. In this article, we present an overview of the inhibitory and facilitative roles that EVs play in the process of septic shock, the potential role of EVs in the diagnosis of septic shock, and the potential therapeutic applications of both native and engineered EVs in the management of septic shock.
Increased circulating regulatory T cells and decreased follicular T helper cells are associated with colorectal carcinogenesis
Authors: Meng Qiao , Zhao Yang , Xu Miao , Wang Pingzhang , Li Jun , Cui Rongli , Fu Weiwei , Ding Shigang
Published: January 2024

Objective

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and is associated with high morbidity and mortality rates. Colorectal carcinogenesis occurs via the conventional adenoma-to-carcinoma and serrated pathways. Conventional T helper (Th) and innate lymphoid cells (ILCs) play vital roles in maintaining intestinal homeostasis. However, the contribution of these two major lymphoid cell populations and their associated cytokines to CRC development is unclear. Therefore, we aimed to analyze peripheral lymphocyte profiles during colorectal carcinogenesis.

Methods

We collected 86 blood samples concurrently, and pathologists confirmed the presence of various pathological conditions (i.e., HPs, adenoma, and carcinoma) using hematoxylin and eosin staining. Ten healthy donors were recruited as healthy controls (HCs) from the physical examination center. We performed flow cytometry on peripheral blood mononuclear cells collected from patients with various pathological conditions and the HCs, and cytokines (interleukin-2, interleukin-4, interleukin-5, interleukin-13, interleukin-17A, interleukin-17F, interleukin-22, interferon-γ, and tumor necrosis factor-α) were quantified. We also analyzed the published single-cell RNA sequence data derived from tissue samples from different stages of colorectal carcinogenesis.

Results

The cytokine response in peripheral CD4+ T cells was upregulated during the carcinoma process. The frequency of peripheral regulatory T cells (Tregs) increased in the adenoma and carcinoma stages. While the T follicular helper (Tfh) cell proportion was downregulated in the adenoma and carcinoma processes. Thus, Th cell subsets, especially Tregs and Tfh cells, were involved in colonic diseases. Moreover, the immunological profile characteristics in the HPs were clarified.

Conclusion

We comprehensively analyzed circulating ILCs and adaptive T-cell lymphocyte subtypes in colorectal carcinoma progression. Our results show the immunological profile characteristics and support the involvement of Th subsets, especially Treg and Tfh cell populations, in colonic diseases. These findings significantly enhance our understanding of the immune mechanisms underlying CRC and its precancerous lesions. Further investigation of the Treg and Tfh cells’ function in colorectal disease development will provide potential therapeutic targets for monitoring and preventing CRC development.
Geometric parameters that affect the behavior of logic-gated CAR T cells
Authors: Partin Alexander C. , Bruno Richele , Shafaattalab Sanam , Vander Mause Erica , Winters Aaron , Daris Mark , Gahrs Casey , Jette Claudia A. , DiAndreth Breanna , Sandberg Mark L. , Hamburger Agnes E. , Kamb Alexander , Riley Timothy P.
Published: January 2024

Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod™, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.
Role of the intestinal microbiome and its therapeutic intervention in cardiovascular disorder
Authors: Luqman Ameer , Hassan Adil , Ullah Mehtab , Naseem Sahar , Ullah Mehraj , Zhang Liyuan , Din Ahmad Ud , Ullah Kamran , Ahmad Waqar , Wang Guixue
Published: January 2024

The gut microbiome is a heterogeneous population of microbes comprising viruses, bacteria, fungi, and protozoa. Such a microbiome is essential for sustaining host equilibrium, and its impact on human health can be altered by a variety of factors such as external variables, social behavior, age, nutrition, and genetics. Gut microbes’ imbalances are related to a variety of chronic diseases including cancer, obesity, and digestive disorders. Globally, recent findings show that intestinal microbes have a significant role in the formation of cardiovascular disease (CVD), which is still the primary cause of fatalities. Atherosclerosis, hypertension, diabetes, inflammation, and some inherited variables are all cardiovascular risk variables. However, studies found correlations between metabolism, intestinal flora, and dietary intake. Variations in the diversity of gut microbes and changes in their activity are thought to influence CVD etiology. Furthermore, the gut microbiota acts as an endocrine organ, producing bioactive metabolites such as TMA (trimethylamine)/TMAO (trimethylamine N-oxide), SCFA (short-chain fatty acids), and bile acids, which have a substantial impact on host wellness and disease by multiple mechanisms. The purpose of this overview is to compile current evidence highlighting the intricate links between gut microbiota, metabolites, and the development of CVD. It focuses on how intestinal dysbiosis promotes CVD risk factors such as heart failure, hypertension, and atherosclerosis. This review explores the normal physiology of intestinal microbes and potential techniques for targeting gut bacteria for CVD treatment using various microbial metabolites. It also examines the significance of gut bacteria in disease treatment, including supplements, prebiotics, probiotics, antibiotic therapies, and fecal transplantation, which is an innovative approach to the management of CVD. As a result, gut bacteria and metabolic pathways become increasingly attractive as potential targets for CVD intervention.
The pathogenesis of influenza in intact alveoli: virion endocytosis and its effects on the lung’s air-blood barrier
Authors: Hook Jaime L. , Bhattacharya Jahar
Published: January 2024

Lung infection by influenza A virus (IAV) is a major cause of global mortality from lung injury, a disease defined by widespread dysfunction of the lung’s air-blood barrier. Endocytosis of IAV virions by the alveolar epithelium – the cells that determine barrier function – is central to barrier loss mechanisms. Here, we address the current understanding of the mechanistic steps that lead to endocytosis in the alveolar epithelium, with an eye to how the unique structure of lung alveoli shapes endocytic mechanisms. We highlight where future studies of alveolar interactions with IAV virions may lead to new therapeutic approaches for IAV-induced lung injury.
Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein
Authors: Kroenke Mark A. , Starcevic Manning Marta , Zuch de Zafra Christina L. , Zhang Xinwen , Cook Kevin D. , Archer Michael , Lolkema Martijn P. , Wang Jin , Hoofring Sarah , Saini Gurleen , Aeffner Famke , Ahern Elizabeth , Cabanas Elena Garralda , Govindan Ramaswamy , Hui Mun , Gupta Shalini , Mytych Daniel T.
Published: January 2024

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.
Transcriptomic profiling of immune cells in murine polymicrobial sepsis
Authors: Murao Atsushi , Jha Alok , Aziz Monowar , Wang Ping
Published: January 2024

Introduction

Various immune cell types play critical roles in sepsis with numerous distinct subsets exhibiting unique phenotypes even within the same cell population. Single-cell RNA sequencing (scRNA-seq) enables comprehensive transcriptome profiling and unbiased cell classification. In this study, we have unveiled the transcriptomic landscape of immune cells in sepsis through scRNA-seq analysis.

Methods

We induced sepsis in mice by cecal ligation and puncture. 20 h after the surgery, the spleen and peritoneal lavage were collected. Single-cell suspensions were processed using a 10× Genomics pipeline and sequenced on an Illumina platform. Count matrices were generated using the Cell Ranger pipeline, which maps reads to the mouse reference transcriptome, GRCm38/mm10. Subsequent scRNA-seq analysis was performed using the R package Seurat.

Results

After quality control, we subjected the entire data set to unsupervised classification. Four major clusters were identified as neutrophils, macrophages, B cells, and T cells according to their putative markers. Based on the differentially expressed genes, we identified activated pathways in sepsis for each cell type. In neutrophils, pathways related to inflammatory signaling, such as NF-κB and responses to pathogen-associated molecular patterns (PAMPs), cytokines, and hypoxia were activated. In macrophages, activated pathways were the ones related to cell aging, inflammatory signaling, and responses to PAMPs. In B cells, pathways related to endoplasmic reticulum stress were activated. In T cells, activated pathways were the ones related to inflammatory signaling, responses to PAMPs, and acute lung injury. Next, we further classified each cell type into subsets. Neutrophils consisted of four clusters. Some subsets were activated in inflammatory signaling or cell metabolism, whereas others possessed immunoregulatory or aging properties. Macrophages consisted of four clusters, namely, the ones with enhanced aging, lymphocyte activation, extracellular matrix organization, or cytokine activity. B cells consisted of four clusters, including the ones possessing the phenotype of cell maturation or aging. T cells consisted of six clusters, whose phenotypes include molecular translocation or cell activation.

Conclusions

Transcriptomic analysis by scRNA-seq has unveiled a comprehensive spectrum of immune cell responses and distinct subsets in the context of sepsis. These findings are poised to enhance our understanding of sepsis pathophysiology, offering avenues for targeting novel molecules, cells, and pathways to combat infectious diseases.
Carbonate budgets induced by coral restoration of a Great Barrier Reef site following cyclone damage
Authors: Nuñez Lendo C. Isabel , Suggett David J. , Boote Chloë , McArdle Alicia , Nicholson Freda , Fisher Eric E. , Smith David , Camp Emma F.
Published: January 2024

Coral carbonate production is fundamental to reef accretion and, consequently, the preservation of essential reef ecosystem services, such as wave attenuation and sustained reef biodiversity. However, the unprecedented loss of coral reefs from anthropogenic impacts has put these valuable ecosystem services at risk. To counteract this loss, active rehabilitation of degraded reef sites has accelerated globally. A variety of restoration practices exist, tailored to local site needs and reef types. For sites where there is a significant unconsolidated substrate, Mars Assisted Reef Restoration System (MARRS, or “Reef Stars”) has been utilised to contribute toward rubble stabilisation and reef accretion. However, the effect of the Reef Stars on the local carbonate budgets and structural complexity has not been assessed. For that purpose, we assess coral cover and reef complexity through a census-based approach to identify the contribution of carbonate producers and eroders alongside studying coral skeletal properties to estimate current carbonate budgets on a rehabilitated site compared to natural unrehabilitated reef and rubble patches on the mid-Great Barrier Reef. Our research identified positive ecological processes and ecological functions such as increased carbonate budget, coral cover and structural complexity at the restored site compared to the non-intervened reef and rubble patches. In general, no impacts on skeletal rigour relative to this active reef restoration were found for two key coral species and the Acropora rubble for most of the skeletal traits. However, Pocillopora damicornis hardness seemed to decrease on the restored site compared to the other sites, demonstrating different performances of coral species during restoration activities that should be considered to maximise return-on-effort of restoration activities. Overall, our data demonstrate that consideration of carbonate budgets is important for measuring success of coral restoration initiatives and that coral restoration can be a relevant tool to recover lost local carbonate budgets.
Use of mesocosm and field studies to assess the effects of nutrient levels on phytoplankton population dynamics in Korean coastal waters
Authors: Yoon Ji Nam , Lim Young Kyun , Hong Seongjin , Baek Seung Ho
Published: January 2024

We integrated data from field observations during April and March with data from a 2-week mesocosm experiment to investigate changes in phytoplankton populations in southern Korean coastal waters (KCWs) following nutrient enrichment during early spring of 2021. The mesocosm experiments used 1000 L cylindrical plastic containers that had natural seawater (control), a low nutrient (LN) treatment, or a high nutrient (HN) treatment. The field observations showed that increased freshwater runoff following spring rainfall led to elevated levels of dissolved inorganic nitrogen and silicate and a significant increase in total phytoplankton abundance. In March, nutrient enrichment from water mixing and terrestrial runoff led to dominance of cryptophyte Cryptomonas spp. In April, higher nutrient levels than March (p< 0.05) resulting from increased terrestrial runoff after rainfall and dominant species were Skeletonema spp., and Cryptomonas spp. In the mesocosm experiment, a succession from E. zodiacus initially to Chaetoceros spp. in the middle stage, and then to Cylindrotheca closterium and Pseudo-nitzschia spp. finally was observed, depending on the species-specific nutrient availability after nutrient addition. In principal component analysis, the negative correlation between C. closterium and nutrient levels supports their nutrient availability, which is an adaptation to low-nutrient conditions. The combined data from the field observations and mesocosm experiments indicated that nutrient supplementation from terrestrial runoff and tidal mixing played a crucial role in determining the dynamics of phytoplankton populations during early spring in the KCWs.
Climate change enables invasion of the portunid crab Charybdis bimaculata into the southern Bohai Sea
Authors: Zhang Xiaomin , Shi Yongchuang , Li Shaowen , Yang Yanyan , Xu Bingqing , Wang Xiuxia , Su Haixia , Li Fan
Published: January 2024

In May 2020, a bottom-trawl survey in the southern Bohai Sea collected the portunid crab Charybdis bimaculata, a species formerly found in the northern Yellow Sea. In subsequent surveys, C. bimaculata was found to be abundant and likely to occupy habitats and niches of native species. To study the suitability of habitat in the southern Bohai Sea for this crab, nine trawl surveys were conducted between 2020 and 2022 to monitor its dispersal. Using Biomod2 software and combining species occurrence and environmental data, a distribution model for C. bimaculata in the southern Bohai Sea is developed. We analyze relationships between this and other crustacean species by comparing niche widths and their overlap. A random forest model outperforms eight others, and has the highest evaluation indices among single algorithm species-distribution models. The evaluation index of an ensemble model is significantly higher than those of single algorithm models, indicating its greater accuracy and robustness. We report suitable habitat for C. bimaculata to occur mainly in central and northeastern Laizhou Bay, and for this habitat suitability to shift over years from the middle to northeastern waters. Niche width showed a negative trend from 2020 to 2022, and is greater in May than August for each year. Niche overlaps between C. bimaculata and other major crustaceans in the southern Bohai Sea exist. We consider that increased sea surface temperature caused by climate change enabled invasion of C. bimaculata from northern Yellow Sea waters into the southern Bohai Sea, where it can overwinter and complete its life cycle. These results provide a scientific basis upon which monitoring of C. bimaculata in the Bohai Sea can be strengthened to better cope with its invasion and any negative impact on local biodiversity.
Kinase signalling adaptation supports dysfunctional mitochondria in disease
Authors: Skalka George L. , Tsakovska Mina , Murphy Daniel J.
Published: January 2024

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.
Global burden of stroke attributable to secondhand smoke in 204 countries and territories from 1990 to 2019: analysis of the global burden of disease study
Authors: Yang Xinyue , Sun Jiayi , Zhang Wenjuan
Published: January 2024

Background

Secondhand smoke (SHS) continues a significant public health concern globally. This study aimed to assess the global burden of stroke attributable to SHS exposure during 1990–2019.

Methods

This analysis utilized data on stroke morbidity and mortality from the Global Burden of Disease (GBD) 2019 study covering 204 countries and territories. We estimated stroke burden indicators attributable to SHS exposure, including age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life-year rate (ASDR), stratified by age, sex, region, and stroke subtype.

Results

In 2019, global SHS exposure accounted for 2.01 [95% uncertainty interval (UI): 1.49–2.58] million stroke mortality. The ASMR and ASDR were 2.5 (95% UI: 1.9–3.2) and 61.5 (95% UI: 46–78.8) per 100,000 population, respectively. The disease burden was higher among women than men and higher among the elderly than younger populations. Intracerebral hemorrhage and ischemic stroke had a more significant burden than subarachnoid hemorrhage. From 1990 to 2019, the ASMR and ASDR declined [estimated annual percentage change: −2.08 (95% CI: −2.21% to −1.95%) and −2.08% (95% CI: −2.19% to −1.97%) for each], but the absolute number of mortalities increased along with population growth. Substantial disparities existed across regions and sociodemographic groups.

Conclusion

Despite declining ASMR and ASDR over time, the absolute number of stroke deaths attributable to SHS continued to rise globally, imposing a considerable stroke burden worldwide. These findings can inform targeted interventions and policies aimed at SHS control.
Early and late basilar artery thrombectomy time window outcomes
Authors: Mierzwa Adam T. , Rao Rahul , Al Kasab Sami , Nelson Ashley , Ortega-Gutierrez Santiago , Vivanco-Suarez Juan , Farooqui Mudassir , Jadhav Ashutosh P. , Desai Shashvat , Toth Gabor , Alrohimi Anas , Nguyen Thanh N. , Klein Piers , Abdalkader Mohamad , Salahuddin Hisham , Pandey Aditya , Wilseck Zachary , Koduri Sravanthi , Vora Nirav , Aladamat Nameer , Gharaibeh Khaled , Afreen Ehad , Zaidi Syed , Jumaa Mouhammad
Published: January 2024

Importance

Stroke-to-recanalization time is a strong predictor of outcomes in anterior circulation large-vessel occlusion (LVO). The authors aimed to evaluate functional outcomes in early (<6 h) vs. late (6–24 h) time windows for thrombectomy-treated basilar artery occlusions.

Methods

Patients were derived from the Posterior Circulation Ischemic Stroke Evaluation: Analyzing Radiographic and Intra-procedural Predictors of Mechanical Thrombectomy (PC-SEARCH) Registry and retrospectively analyzed early and late basilar artery thrombectomy time windows cohorts. Patients were dichotomized based on the last known well and correlated to 90-day functional outcomes (mRS 0–3). A multiple logistic regression analysis was performed.

Results

A total of 405 patients were included in this study: 216 and 189 patients in the early and late time windows, respectively. Baseline demographic, stroke, radiographic, and intraprocedural characteristics were similar between the groups. A total of 99 (46%) and 79 (42%) patients in the early and late time windows, respectively, achieved favorable functional outcomes at 90 days (p = 0.41), and multiple logistic regression analysis did not reveal differences between cohorts (OR: 0.74; 95% CI: 0.46–1.19; p = 0.22). Symptomatic hemorrhage (7% vs. 5%; p = 0.69) and neurological complications (8% vs. 9%; p = 0.83) were similar between the groups; however, hospital complications were more common in the early time window cohort (22% vs. 13%; p = 0.01).

Conclusion

The early and late thrombectomy time windows can achieve similar rates of 90-day favorable functional outcomes. However, timely thrombectomy influences the likelihood of achieving excellent functional outcomes (mRS ≤ 2) within the early time window.
Sodium intake and the risk of heart failure and hypertension: epidemiological and Mendelian randomization analysis
Authors: Yuan Miao , Yan Dingyi , Wang Yu , Qi Mengyao , Li Kexin , Lv Zhi , Gao Dengfeng , Ning Ning
Published: January 2024

Background

This study aimed to analysis the relationship between sodium intake and the risk of heart failure and hypertension through epidemiological studies and Mendelian randomization analysis.

Methods and result

We initially conducted an analysis using data from the National Health and Nutrition Examination Survey (NHANES) database to examine the relationship between sodium intake and heart failure, hypertension, systolic blood pressure, and diastolic blood pressure. After adjusting for confounding factors, we found a non-linear association between sodium intake and heart failure (p nonlinear = 0.0448). Subsequently, we utilized Mendelian randomization (MR) analysis by utilizing urinary sodium as a proxy for sodium intake to investigate the relationships between sodium and heart failure, hypertension, systolic blood pressure, and diastolic blood pressure. The results indicated that with increasing urinary sodium, there is an increase in systolic and diastolic blood pressure, as well as an elevated risk of heart failure and hypertension.

Conclusion

The evidence provided by this study suggests that higher sodium intake is associated with an increased risk of heart failure and hypertension. However, excessively low sodium intake may not necessarily be beneficial, as there may be maximum benefits at a sodium intake level of around 3,000 mg/d.