bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Heart Failure in ECG Data With Artificial Intelligence—A Meta-Analysis
Authors: Grün Dimitri , Rudolph Felix , Gumpfer Nils , Hannig Jennifer , Elsner Laura K. , von Jeinsen Beatrice , Hamm Christian W. , Rieth Andreas , Guckert Michael , Keller Till
Published: February 2021

Introduction: Electrocardiography (ECG) is a quick and easily accessible method for diagnosis and screening of cardiovascular diseases including heart failure (HF). Artificial intelligence (AI) can be used for semi-automated ECG analysis. The aim of this evaluation was to provide an overview of AI use in HF detection from ECG signals and to perform a meta-analysis of available studies.

Methods and Results: An independent comprehensive search of the PubMed and Google Scholar database was conducted for articles dealing with the ability of AI to predict HF based on ECG signals. Only original articles published in peer-reviewed journals were considered. A total of five reports including 57,027 patients and 579,134 ECG datasets were identified including two sets of patient-level data and three with ECG-based datasets. The AI-processed ECG data yielded areas under the receiver operator characteristics curves between 0.92 and 0.99 to identify HF with higher values in ECG-based datasets. Applying a random-effects model, an sROC of 0.987 was calculated. Using the contingency tables led to diagnostic odds ratios ranging from 3.44 [95% confidence interval (CI) = 3.12–3.76] to 13.61 (95% CI = 13.14–14.08) also with lower values in patient-level datasets. The meta-analysis diagnostic odds ratio was 7.59 (95% CI = 5.85–9.34).

Conclusions: The present meta-analysis confirms the ability of AI to predict HF from standard 12-lead ECG signals underlining the potential of such an approach. The observed overestimation of the diagnostic ability in artificial ECG databases compared to patient-level data stipulate the need for robust prospective studies.
Investigation of the Effect of the Dataset Size and Type in the Earthquake-Triggered Landslides Mapping: A Case Study for the 2018 Hokkaido Iburu Landslides
Authors: Comert Resul
Published: February 2021

Rapid mapping of landslides that occur after an earthquake is important for rapid crisis management. In this study, experimental research was conducted on the size of the model area and the data types used in developing classifiers for the supervised classification approaches used in rapid landslide mapping. The Hokkaido Iburu earthquake zone that occurred on September 6, 2018, was selected as the study area. PlanetScope pre-event and post-event images and ALOS-PALSAR Digital Elevation Model (DEM) were used in the analysis processes. In this context, five model areas with different sizes and one test area were determined. Object-based image analysis (OBIA) was used as a landslide mapping approach. Random Forest classifier, which is a supervised classification algorithm, was performed in the mapping of image objects produced by the segmentation stage of OBIA. Two different data sets were created for landslide mapping: change-based dataset and post-event dataset. The change-based dataset is generated from change data such as the difference of normalized difference vegetation index (δNDVI), change detection Image (CDI), princiable component analysis (PCA), and Independent component analysis (ICA) which are used in change detection applications. The post-event dataset was created from data generated from post-event image bands. When the obtained results were examined, higher accuracy results were obtained with the post-event dataset. Increasing the size of the model area, in other words, increasing the training data slightly increases the accuracy of landslide mapping. However, a model area that represents the region to be mapped in small sizes to make rapid decisions provides a 94% F-measure accuracy for earthquake-triggered landslide detection.
Instructional Leadership as a Vehicle for Teacher Collaboration and Student Achievement. What the German PISA 2015 Sample Tells Us
Authors: Mora-Ruano Julio Gregorio , Schurig Michael , Wittmann Eveline
Published: February 2021

We investigated the effects of principal instructional leadership (IL) on the frequency of two forms of teacher collaboration (TC) namely exchange and coordination of teaching (EXCHT) and professional collaboration (PROFCOLT) and their influence on student achievement (SA). Using data from the representative German PISA 2015 sample, we carry out structural equation modeling analysis to estimate the direct effects of IL on TC and of TC on SA, as well as the indirect effects of IL on SA. The analyses were conducted at the school level and only teachers belonging to the non-science group in PISA 2015 were included. After testing for the factorial validity of the instrument, only the collaboration form (EXCHT) could be retained. Our analysis suggests that principal instructional leadership can positively influence teachers’ collaboration frequency and that the remaining form of teacher collaboration is not positively related to student achievement. Our study builds on and extends research on student achievement by adding evidence about the relations between principal leadership and teacher collaboration in Germany.
A Focused Review of the Metabolic Side-Effects of Clozapine
Authors: Yuen Jessica W. Y. , Kim David D. , Procyshyn Ric M. , Panenka William J. , Honer William G. , Barr Alasdair M.
Published: February 2021

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.
Insulin Requirements and Carbohydrate to Insulin Ratio in Normal Weight, Overweight, and Obese Women With Type 1 Diabetes Under Pump Treatment During Pregnancy: A Lesson From Old Technologies
Authors: Festa Camilla , Fresa Raffaella , Visalli Natalia , Bitterman Olimpia , Giuliani Chiara , Suraci Concetta , Bongiovanni Marzia , Napoli Angela
Published: February 2021

Aim

The primary aim of this study was to assess insulin requirements and carbohydrate to insulin ratio (CHO/IR) in normal weight, overweight, and obese pregnant women with type 1 diabetes across early, middle, and late pregnancy.

Methods

In this multicenter, retrospective, observational study we evaluated 86 of 101 pregnant Caucasian women with type 1 diabetes under pump treatment. The women were trained to calculate CHO/IR daily by dividing CHO grams of every single meal by insulin units injected. Since the purpose of the study was to identify the CHO/IR able to reach the glycemic target, we only selected the CHO/IR obtained when glycemic values were at target. Statistics: SPSS 20.

Results

We studied 45 normal weight, 31 overweight, and 10 obese women. Insulin requirements increased throughout pregnancy (p < 0.0001 and <0.001 respectively) in the normal and overweight women, while it remained unchanged in the obese women. Insulin requirements were different between groups when expressed as an absolute value, but not when adjusted for body weight. Breakfast CHO/IR decreased progressively throughout pregnancy in the normal weight women, from 13.3 (9.8–6.7) at the first stage of pregnancy to 6.2 (3.8–8.6) (p = 0.01) at the end stage, and in the overweight women from 8.5 (7.1–12.6) to 5.2 (4.0–8.1) (p = 0.001), while in the obese women it remained stable, moving from 6.0 (5.0–7.9) to 5.1 (4.1–7.4) (p = 0.7). Likewise, lunch and dinner CHO/IR decreased in the normal weight and overweight women (p < 0.03) and not in the obese women. The obese women gained less weight than the others, especially in early pregnancy when they even lost a median of 1.25 (−1 −1.1) kg (p = 0.005). In early pregnancy, we found a correlation between pregestational BMI and insulin requirements (IU/day) or CHO/IR at each meal (p < 0.001 and p = 0.001, respectively). In late pregnancy, a relationship between pre-gestational BMI and CHO/IR change was found (P = 0.004), as well as between weight gain and CHO/IR change (p=0.02). The significance was lost when both variables were included in the multiple regression analysis. There was no difference in pregnancy outcomes except for a higher pre-term delivery rate in the obese women.

Conclusion

Pre-gestational BMI and weight gain may play a role in determining CHO/IR during pregnancy in women with type 1 diabetes under pump treatment.
Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway
Authors: Duez Hélène , Pourcet Benoit
Published: February 2021

The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia–reperfusion and brain diseases.
Harnessing Proliferation for the Expansion of Stem Cell-Derived Pancreatic Cells: Advantages and Limitations
Authors: Oakie Amanda , Nostro Maria Cristina
Published: February 2021

Restoring the number of glucose-responsive β-cells in patients living with diabetes is critical for achieving normoglycemia since functional β-cells are lost during the progression of both type 1 and 2 diabetes. Stem cell-derived β-cell replacement therapies offer an unprecedented opportunity to replace the lost β-cell mass, yet differentiation efficiencies and the final yield of insulin-expressing β-like cells are low when using established protocols. Driving cellular proliferation at targeted points during stem cell-derived pancreatic progenitor to β-like cell differentiation can serve as unique means to expand the final cell therapeutic product needed to restore insulin levels. Numerous studies have examined the effects of β-cell replication upon functionality, using primary islets in vitro and mouse models in vivo, yet studies that focus on proliferation in stem cell-derived pancreatic models are only just emerging in the field. This mini review will discuss the current literature on cell proliferation in pancreatic cells, with a focus on the proliferative state of stem cell-derived pancreatic progenitors and β-like cells during their differentiation and maturation. The benefits of inducing proliferation to increase the final number of β-like cells will be compared against limitations associated with driving replication, such as the blunted capacity of proliferating β-like cells to maintain optimal β-cell function. Potential strategies that may bypass the challenges induced by the up-regulation of cell cycle-associated factors during β-cell differentiation will be proposed.
Innate and Adaptive Immunity in Giant Cell Arteritis
Authors: Akiyama Mitsuhiro , Ohtsuki Shozo , Berry Gerald J. , Liang David H. , Goronzy Jörg J. , Weyand Cornelia M.
Published: February 2021

Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4+ T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4+ T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8+ T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.
Biomechanics of T Cell Dysfunctions in Chronic Diseases
Authors: Gunasinghe Sachith D. , Peres Newton G. , Goyette Jesse , Gaus Katharina
Published: February 2021

Understanding the mechanisms behind T cell dysfunctions during chronic diseases is critical in developing effective immunotherapies. As demonstrated by several animal models and human studies, T cell dysfunctions are induced during chronic diseases, spanning from infections to cancer. Although factors governing the onset and the extent of the functional impairment of T cells can differ during infections and cancer, most dysfunctional phenotypes share common phenotypic traits in their immune receptor and biophysical landscape. Through the latest developments in biophysical techniques applied to explore cell membrane and receptor–ligand dynamics, we are able to dissect and gain further insights into the driving mechanisms behind T cell dysfunctions. These insights may prove useful in developing immunotherapies aimed at reinvigorating our immune system to fight off infections and malignancies more effectively. The recent success with checkpoint inhibitors in treating cancer opens new avenues to develop more effective, targeted immunotherapies. Here, we highlight the studies focused on the transformation of the biophysical landscape during infections and cancer, and how T cell biomechanics shaped the immunopathology associated with chronic diseases.
The Roles of Sclerostin in Immune System and the Applications of Aptamers in Immune-Related Research
Authors: Sun Meiheng , Chen Zihao , Wu Xiaoqiu , Yu Yuanyuan , Wang Luyao , Lu Aiping , Zhang Ge , Li Fangfei
Published: February 2021

Wnt signaling is one of the fundamental pathways that play a major role in almost every aspect of biological systems. In addition to the well-known influence of Wnt signaling on bone formation, its essential role in the immune system also attracted increasing attention. Sclerostin, a confirmed Wnt antagonist, is also proven to modulate the development and differentiation of normal immune cells, particularly B cells. Aptamers, single-stranded (ss) oligonucleotides, are capable of specifically binding to a variety of target molecules by virtue of their unique three-dimensional structures. With in-depth study of those functional nucleic acids, they have been gradually applied to diagnostic and therapeutic area in immune diseases due to their various advantages over antibodies. In this review, we focus on several issues including the roles of Wnt signaling and Wnt antagonist sclerostin in the immune system. For the sake of understanding, current examples of aptamers applications for the immune diseases are also discussed. At the end of this review, we propose our ideas for the future research directions.
Adipose Extracellular Vesicles in Intercellular and Inter-Organ Crosstalk in Metabolic Health and Diseases
Authors: Huang Zhe , Xu Aimin
Published: February 2021

Adipose tissue (AT) is a highly heterogeneous and dynamic organ that plays important roles in regulating energy metabolism and insulin sensitivity. In addition to its classical roles in nutrient sensing and energy storage/dissipation, AT secretes a large number of bioactive molecules (termed adipokines) participating in immune responses and metabolic regulation through their paracrine and/or endocrine actions. Adipose-derived extracellular vesicles (ADEVs), including exosomes, microvesicles (MVs), and apoptotic bodies, have recently emerged as a novel class of signal messengers, mediating intercellular communications and inter-organ crosstalk. In AT, ADEVs derived from adipocytes, immune cells, mesenchymal stem cells, endothelial cells are actively involved in modulation of immune microenvironment, adipogenesis, browing of white adipose tissue, adipokine release and tissue remodeling. Furthermore, ADEVs exert their metabolic actions in distal organs (such as liver, skeletal muscle, pancreas and brain) by sending genetic information (mainly in the form of microRNAs) to their target cells for regulation of gene expression. Here, we provide an updated summary on the nature and composition of ADEVs, and their pathophysiological functions in regulating immune responses, whole-body insulin sensitivity and metabolism. Furthermore, we highlight the latest clinical evidence supporting aberrant production and/or function of ADEVs as a contributor to obesity-related chronic inflammation and metabolic complications and discuss the opportunities and challenges in developing novel therapies by targeting ADEVs.
Dietary Oxalate Loading Impacts Monocyte Metabolism and Inflammatory Signaling in Humans
Authors: Kumar Parveen , Patel Mikita , Oster Robert A. , Yarlagadda Vidhush , Ambrosetti Adam , Assimos Dean G. , Mitchell Tanecia
Published: February 2021

Diet has been associated with several metabolic diseases and may impact immunity. Increased consumption of meals with high oxalate content may stimulate urinary calcium oxalate (CaOx) crystals, which are precursors to CaOx kidney stones. We previously reported that CaOx stone formers have decreased monocyte cellular bioenergetics compared to healthy participants and oxalate reduces monocyte metabolism and redox status in vitro. The purpose of this study was to investigate whether dietary oxalate loading impacts monocyte cellular bioenergetics, mitochondrial complex activity, and inflammatory signaling in humans. Healthy participants (n = 40; 31.1 ± 1.3 years) with a BMI of 24.9 ± 0.6 kg/m2 consumed a controlled low oxalate diet for 3 days before drinking a blended preparation of fruits and vegetables containing a large amount of oxalate. Blood and urine were collected before (pre-oxalate) and for 5 h after the oxalate load to assess urinary oxalate levels, monocyte cellular bioenergetics and mitochondrial complex activity, and plasma cytokine/chemokine levels. Urinary oxalate levels significantly increased in post-oxalate samples compared to pre-oxalate samples. Monocyte cellular bioenergetics, mitochondrial complex I activity, and plasma cytokine and chemokine levels were altered to varying degrees within the study cohort. We demonstrate for the first time that dietary oxalate loading may impact monocyte metabolism and immune response in a cohort of healthy adults, but these response are variable. Further studies are warranted to understand oxalate mediated mechanisms on circulating monocytes and how this potentially influences CaOx kidney stone formation.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03877276.
Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
Authors: Lee Lydia , Alrasheed Nouf , Khandelwal Garima , Fitzsimons Evelyn , Richards Huw , Wilson William , Chavda Selina J. , Henry Jake , Conde Lucia , De Massy Marc Robert , Chin Melody , Galas-Filipowicz Daria , Herrero Javier , Chain Benny , Quezada Sergio A. , Yong Kwee
Published: February 2021

The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), examining phenotype and T cell receptor (TCR) repertoire, seeking correlations with timing of relapse. Compared to healthy donors (HD), we observed an increase in regulatory T cells (CD4+FoxP3+, Tregs) with reduction in CD4 T cells, leading to lower CD4:8 ratios. Compared to paired pre-treatment marrow, both CD4 and CD8 compartments showed a reduction in naïve, and increase in effector memory subsets, suggestive of a more differentiated phenotype. This was supported by increased levels of several immune-regulatory and activation proteins (ICOS, PD-1, LAG-3, CTLA-4 and GzmB) when compared with HD. Unsupervised analysis identified a patient subgroup with shorter PFS (p=0.031) whose BM contained increased Tregs, and higher immune-regulatory markers (ICOS, PD-1, LAG-3) on effector T cells. Using single feature analysis, higher frequencies of marrow PD-1+ on CD4+FoxP3- cells and Ki67+ on CD8 cells were independently associated with early relapse. Finally, studying paired pre-treatment and post-ASCT BM (n=5), we note reduced abundance of TCR sequences at day+100, with a greater proportion of expanded sequences indicating a more focused persistent TCR repertoire. Our findings indicate that, following induction chemotherapy and ASCT, marrow T cells demonstrate increased activation and differentiation, with TCR repertoire focusing. Pending confirmation in larger series, higher levels of immune-regulatory proteins on T cell effectors at day+100 may indicate early relapse.
Phenotype Definition for “Resisters” to Mycobacterium tuberculosis Infection in the Literature—A Review and Recommendations
Authors: Gutierrez Jesús , Kroon Elouise E. , Möller Marlo , Stein Catherine M.
Published: February 2021

Tuberculosis (TB) remains a worldwide problem. Despite the high disease rate, not all who are infected with Mycobacterium Tuberculosis (Mtb) develop disease. Interferon-γ (IFN-γ) specific T cell immune assays such as Quantiferon and Elispot, as well as a skin hypersensitivity test, known as a tuberculin skin test, are widely used to infer infection. These assays measure immune conversion in response to Mtb. Some individuals measure persistently negative to immune conversion, despite high and prolonged exposure to Mtb. Increasing interest into this phenotype has led to multiple publications describing various aspects of these responses. However, there is a lack of a unified “resister” definition. A universal definition will improve cross study data comparisons and assist with future study design and planning. We review the current literature describing this phenotype and make recommendations for future studies.
Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques
Authors: Venkatasubramaniam Arundhathi , Liao Grant , Cho Eunice , Adhikari Rajan P. , Kort Tom , Holtsberg Frederick W. , Elsass Karen E. , Kobs Dean J. , Rudge Thomas L. , Kauffman Keith D. , Lora Nickiana E. , Barber Daniel L. , Aman M. Javad , Karauzum Hatice
Published: February 2021

Staphylococcus aureus is a leading cause of significant morbidity and mortality and an enormous economic burden to public health worldwide. Infections caused by methicillin-resistant S. aureus (MRSA) pose a major threat as MRSA strains are becoming increasingly prevalent and multi-drug resistant. To this date, vaccines targeting surface-bound antigens demonstrated promising results in preclinical testing but have failed in clinical trials. S. aureus pathogenesis is in large part driven by immune destructive and immune modulating toxins and thus represent promising vaccine targets. Hence, the objective of this study was to evaluate the safety and immunogenicity of a staphylococcal 4-component vaccine targeting secreted bi-component pore-forming toxins (BCPFTs) and superantigens (SAgs) in non-human primates (NHPs). The 4-component vaccine proved to be safe, even when repeated vaccinations were given at a dose that is 5 to 10- fold higher than the proposed human dose. Vaccinated rhesus macaques did not exhibit clinical signs, weight loss, or changes in hematology or serum chemistry parameters related to the administration of the vaccine. No acute, vaccine-related elevation of serum cytokine levels was observed after vaccine administration, confirming the toxoid components lacked superantigenicity. Immunized animals demonstrated high level of toxin-specific total and neutralizing antibodies toward target antigens of the 4-component vaccine as well as cross-neutralizing activity toward staphylococcal BCPFTs and SAgs that are not direct targets of the vaccine. Cross-neutralization was also observed toward the heterologous streptococcal pyogenic exotoxin B. Ex vivo stimulation of PBMCs with individual vaccine components demonstrated an overall increase in several T cell cytokines measured in supernatants. Immunophenotyping of CD4 T cells ex vivo showed an increase in Ag-specific polyfunctional CD4 T cells in response to antigen stimulation. Taken together, we demonstrate that the 4-component vaccine is well-tolerated and immunogenic in NHPs generating both humoral and cellular immune responses. Targeting secreted toxin antigens could be the next-generation vaccine approach for staphylococcal vaccines if also proven to provide efficacy in humans.
Recurrent Sepsis Exacerbates CD4+ T Cell Exhaustion and Decreases Antiviral Immune Responses
Authors: He Wanxue , Xiao Kun , Xu Jiaruo , Guan Wei , Xie Sheling , Wang Kaifei , Yan Peng , Fang Min , Xie Lixin
Published: February 2021

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.
Reactive Oxygen Species in Autoimmune Cells: Function, Differentiation, and Metabolism
Authors: Lin Weiji , Shen Pan , Song Yaqin , Huang Ying , Tu Shenghao
Published: February 2021

Accumulated reactive oxygen species (ROS) directly contribute to biomacromolecule damage and influence various inflammatory responses. Reactive oxygen species act as mediator between innate and adaptive immune cells, thereby influencing the antigen-presenting process that results in T cell activation. Evidence from patients with chronic granulomatous disease and mouse models support the function of ROS in preventing abnormal autoimmunity; for example, by supporting maintenance of macrophage efferocytosis and T helper 1/T helper 2 and T helper 17/ regulatory T cell balance. The failure of many anti-oxidation treatments indicates that ROS cannot be considered entirely harmful. Indeed, enhancement of ROS may sometimes be required. In a mouse model of rheumatoid arthritis (RA), absence of NOX2-derived ROS led to higher prevalence and more severe symptoms. In patients with RA, naïve CD4+T cells exhibit inhibited glycolysis and enhanced pentose phosphate pathway (PPP) activity, leading to ROS exhaustion. In this “reductive” state, CD4+T cell immune homeostasis is disrupted, triggering joint destruction, together with oxidative stress in the synovium.
Effects of Detached Seaweeds on Structure and Function of Arctic Intertidal Soft-Bottom Communities
Authors: Díaz María José , Buschbaum Christian , Renaud Paul E. , Molis Markus
Published: February 2021

Expected lower sea-ice cover and increased storm frequency have led to projections of an increase in seaweed detritus in Arctic marine systems in the near future. To assess whether detached seaweed affects structural and functional traits of species assemblages in soft-bottom habitats, comparable experiments were run in two intertidal sites (Longyearbyen and Thiisbukta) on Svalbard. At each site, we fixed nets containing the locally dominating seaweeds Saccharina latissima and Desmarestia aculeata (Thiisbukta) or Fucus sp. (Longyearbyen) to intertidal mud flats. Empty nets were fixed as procedural controls at both sites. After 2.5 months, one sediment core was taken from each manipulated plot and the number of individuals, dry mass, and average length of each encountered animal taxon were recorded. The same measurements were taken from cores collected from unmanipulated areas at each site, both at the start and end of the experiment. Abundance data were used to calculate estimates of diversity (Shannon-index, evenness, and taxon richness), while initial and final average length measurements were used to estimate taxon-specific growth. Log response ratios of initial and final abundance in unmanipulated areas were used to estimate magnitude and direction of the effect of change in community traits over time, serving as a reference to log response ratios estimating manipulated seaweed effects. In Longyearbyen, the presence of detached seaweeds reduced abundance and dry mass by, on average, 46 and 70%, respectively, compared to unmanipulated benthic communities. In Thiisbukta, the presence of seaweeds enhanced evenness, on average by 16%, but reduced abundance and growth of benthic fauna by, on average, 31 and 86%, respectively. Seaweed effects were generally smaller in Thiisbukta than in Longyearbyen. At both sites, time effects were generally opposite in direction to those caused by the seaweed treatments, yet of similar or larger magnitude. Through reversing temporal dynamics of several of the tested community traits, detached seaweeds strongly modified the structure and functioning of soft-bottom species assemblages at both intertidal sites. We suggest that the detected effects possibly result from seaweed-induced changes in environmental conditions and/or physical disturbance as underlying processes.
The Role of a Dipeptide Transporter in the Virulence of Human Pathogen, Helicobacter pylori
Authors: Xu Xiaohong , Chen Junwei , Huang Xiaoxing , Feng Shunhang , Zhang Xiaoyan , She Feifei , Wen Yancheng
Published: February 2021

Helicobacter pyloriharbors a dipeptide (Dpp) transporter consisting of a substrate-binding protein (DppA), two permeases (DppB and C), and two ATPases (DppD and F). The Dpp transporter is responsible for the transportation of dipeptides and short peptides. We found that its expression is important for the growth ofH.pylori. To understand the role of the Dpp transporter in the pathogenesis ofH.pylori, the expression of virulence factors andH.pylori-induced IL-8 production were investigated inH. pyloriwild-type and isogenicH. pyloriDpp transporter mutants. We found that expression of CagA was downregulated, while expression of type 4 secretion system (T4SS) components was upregulated in Dpp transporter mutants. The DppA mutant strain expressed higher levels of outer membrane proteins (OMPs), including BabA, HopZ, OipA, and SabA, and showed a higher adhesion level to gastric epithelial AGS cells compared with theH.pylori26695 wild-type strain. After infection of AGS cells,H.pyloriΔdppAinduced a higher level of NF-κB activation and IL-8 production compared with wild-type. These results suggested that in addition to supporting the growth ofH.pylori, the Dpp transporter causes bacteria to alter the expression of virulence factors and reducesH.pylori-induced NF-κB activation and IL-8 production in gastric epithelial cells.
Reverse Microbiomics: A New Reverse Dysbiosis Analysis Strategy and Its Usage in Prediction of Autoantigens and Virulent Factors in Dysbiotic Gut Microbiomes From Rheumatoid Arthritis Patients
Authors: Wang Haihe , Ong Edison , Kao John Y. , Sun Duxin , He Yongqun
Published: February 2021

Alterations in the gut microbiome have been associated with various human diseases. Most existing gut microbiome studies stopped at the stage of identifying microbial alterations between diseased or healthy conditions. As inspired by reverse vaccinology (RV), we developed a new strategy called Reverse Microbiomics (RM) that turns this process around: based on the identified microbial alternations, reverse-predicting the molecular mechanisms underlying the disease and microbial alternations. Our RM methodology starts by identifying significantly altered microbiota profiles, performing bioinformatics analysis on the proteomes of the microbiota identified, and finally predicting potential virulence or protective factors relevant to a microbiome-associated disease. As a use case study, this reverse methodology was applied to study the molecular pathogenesis of rheumatoid arthritis (RA), a common autoimmune and inflammatory disease. Those bacteria differentially associated with RA were first identified and annotated from published data and then modeled and classified using the Ontology of Host-Microbiome Interactions (OHMI). Our study identified 14 species increased and 9 species depleted in the gut microbiota of RA patients. Vaxign was used to comparatively analyze 15 genome sequences of the two pairs of species: Gram-negative Prevotella copri (increased) and Prevotella histicola (depleted), as well as Gram-positive Bifidobacterium dentium (increased) and Bifidobacterium bifidum (depleted). In total, 21 auto-antigens were predicted to be related to RA, and five of them were previously reported to be associated with RA with experimental evidence. Furthermore, we identified 94 potential adhesive virulence factors including 24 microbial ABC transporters. While eukaryotic ABC transporters are key RA diagnosis markers and drug targets, we identified, for the first-time, RA-associated microbial ABC transporters and provided a novel hypothesis of RA pathogenesis. Our study showed that RM, by broadening the scope of RV, is a novel and effective strategy to study from bacterial level to molecular level factors and gain further insight into how these factors possibly contribute to the development of microbial alterations under specific diseases.
Cellular Senescence in Brain Aging
Authors: Sikora Ewa , Bielak-Zmijewska Anna , Dudkowska Magdalena , Krzystyniak Adam , Mosieniak Grazyna , Wesierska Malgorzata , Wlodarczyk Jakub
Published: February 2021

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.
The Influence of Moderate Physical Activity on Brain Monoaminergic Responses to Binge-Patterned Alcohol Ingestion in Female Mice
Authors: Buhr Trevor J. , Reed Carter H. , Shoeman Allyse , Bauer Ella E. , Valentine Rudy J. , Clark Peter J.
Published: February 2021

Monoamine neurotransmitter activity in brain reward, limbic, and motor areas play key roles in the motivation to misuse alcohol and can become modified by exercise in a manner that may affect alcohol craving. This study investigated the influence of daily moderate physical activity on monoamine-related neurochemical concentrations across the mouse brain in response to high volume ethanol ingestion. Adult female C57BL/6J mice were housed with or without 2.5 h of daily access to running wheels for 30 days. On the last 5 days, mice participated in the voluntary binge-like ethanol drinking procedure, “Drinking in the dark” (DID). Mice were sampled immediately following the final episode of DID. Monoamine-related neurochemical concentrations were measured across brain regions comprising reward, limbic, and motor circuits using ultra High-Performance Liquid Chromatography (UHPLC). The results suggest that physical activity status did not influence ethanol ingestion during DID. Moreover, daily running wheel access only mildly influenced alcohol-related norepinephrine concentrations in the hypothalamus and prefrontal cortex, as well as serotonin turnover in the hippocampus. However, access to alcohol during DID eliminated wheel running-related decreases of norepinephrine, serotonin, and 5-HIAA content in the hypothalamus, but also to a lesser extent for norepinephrine in the hippocampus and caudal cortical areas. Finally, alcohol access increased serotonin and dopamine-related neurochemical turnover in the striatum and brainstem areas, regardless of physical activity status. Together, these data provide a relatively thorough assessment of monoamine-related neurochemical levels across the brain in response to voluntary binge-patterned ethanol drinking, but also adds to a growing body of research questioning the utility of moderate physical activity as an intervention to curb alcohol abuse.
Target Recognition of Industrial Robots Using Machine Vision in 5G Environment
Authors: Jin Zhenkun , Liu Lei , Gong Dafeng , Li Lei
Published: February 2021

The purpose is to solve the problems of large positioning errors, low recognition speed, and low object recognition accuracy in industrial robot detection in a 5G environment. The convolutional neural network (CNN) model in the deep learning (DL) algorithm is adopted for image convolution, pooling, and target classification, optimizing the industrial robot visual recognition system in the improved method. With the bottled objects as the targets, the improved Fast-RCNN target detection model's algorithm is verified; with the small-size bottled objects in a complex environment as the targets, the improved VGG-16 classification network on the Hyper-Column scheme is verified. Finally, the algorithm constructed by the simulation analysis is compared with other advanced CNN algorithms. The results show that both the Fast RCN algorithm and the improved VGG-16 classification network based on the Hyper-Column scheme can position and recognize the targets with a recognition accuracy rate of 82.34%, significantly better than other advanced neural network algorithms. Therefore, the improved VGG-16 classification network based on the Hyper-Column scheme has good accuracy and effectiveness for target recognition and positioning, providing an experimental reference for industrial robots' application and development.
Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke
Authors: Liu Huiyong , Reiter Sydney , Zhou Xiangyue , Chen Hanmin , Ou Yibo , Lenahan Cameron , He Yue
Published: February 2021

Strokes are the most common types of cerebrovascular disease and remain a major cause of death and disability worldwide. Cerebral ischemic stroke is caused by a reduction in blood flow to the brain. In this disease, two major zones of injury are identified: the lesion core, in which cells rapidly progress toward death, and the ischemic penumbra (surrounding the lesion core), which is defined as hypoperfusion tissue where cells may remain viable and can be repaired. Two methods that are approved by the Food and Drug Administration (FDA) include intravenous thrombolytic therapy and endovascular thrombectomy, however, the narrow therapeutic window poses a limitation, and therefore a low percentage of stroke patients actually receive these treatments. Developments in stem cell therapy have introduced renewed hope to patients with ischemic stroke due to its potential effect for reversing the neurological sequelae. Over the last few decades, animal tests and clinical trials have been used to treat ischemic stroke experimentally with various types of stem cells. However, several technical and ethical challenges must be overcome before stem cells can become a choice for the treatment of stroke. In this review, we summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. We also discuss new developing trends in this field.
Thymectomy in Juvenile Myasthenia Gravis Is Safe Regarding Long Term Immunological Effects
Authors: Popperud Trine H. , Gul Kiran A. , Brunborg Cathrine , Olaussen Richard W. , Abrahamsen Tore G. , Osnes Liv T. , Kerty Emila
Published: February 2021

Thymectomy is an established treatment in adult MG and also recommended for the treatment of post-pubertal onset juvenile MG. Whether the youngest children should be thymectomized is still debated. Signs of premature aging of the immune system have been shown in studies on early perioperative thymectomy in children with congenital heart defect. In this retrospective cohort study the objective was to investigate the long-term effects of treatment related thymectomy on T cell subsets and T cell receptor rearrangement excision circles (TRECs) in peripheral blood of juvenile myasthenia gravis (MG) patients, as well as clinical occurrence of autoimmune disorders, malignancies and infectious diseases. Forty-seven patients with onset of myasthenia gravis before the age of 19 years were included; 32 (68.1%) had been thymectomized and 15 (31.8%) had not. They were studied at varying times after thymectomy (7–26 years). We found a significant lower number of naïve helper T cells (CD4+CD45RA+) with an increased proportion of memory helper T cells (CD4+CD45RO+), and a significant lower number of naïve cytotoxic T cells (CD8+CD27+CD28+) in the thymectomized patients. In addition they showed a significant reduction in the number of TRECs and proportion of recent thymic emigrants (RTE) compared to non-thymectomized patients. In none of them an increased frequency of malignancies or infections was found. Our findings indicate a premature aging of the immune system after thymectomy in juvenile MG, but associated clinical consequences could not be verified.