bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Wang Ruxin , Ye Haowen , Ma Li , Wei Jinjing , Wang Ying , Zhang Xiaofang , Wang Lihong
Published: July 2022

Background and Objective

Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias.

Methods and Results

RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73–0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51–0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37–0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32–0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48–0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47–0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74–1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83–1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82–1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias.

Conclusion

Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.
Sex Differences in Clinical Characteristics and Prognosis in Primary Thrombotic Antiphospholipid Syndrome
Authors: Huang Yongfa , Liu Huazhen , Qi Wanting , Du Le , Li Mengtao , Zeng Xiaofeng , Guo Xiaoxiao , Zhao Jiuliang , Zhang Shuyang
Published: July 2022

Objectives

This study aimed to investigate whether there are sex differences in clinical characteristics and prognosis in patients with primary thrombotic antiphospholipid syndrome (ptAPS).

Methods

From January 2013 to July 2021, 154 consecutive patients diagnosed with ptAPS were prospectively recruited. Multivariable Cox regression was used to evaluate the association between gender and the composite endpoint including thromboembolic recurrence or all-cause death during follow-up.

Results

Totally, 80 (52%) male and 74 (48%) female patients with ptAPS were included, and men had a higher percentage of smokers/ex-smokers [50 (62%) vs. 6 (8%), p < 0.001] and hyperhomocysteinemia [26 (32%) vs. 9 (12%), p = 0.003]. The baseline thromboembolic events were similar in two genders, except for limb ischemia [15 (19%) in men vs. 1 (1%) in women, p < 0.001]. During a median follow-up of 42 months, the composite endpoint occurred in 30 (38%) male and 15 (20%) female patients (p = 0.019). Male gender [HR 2.499, 95% CI (1.316, 4.743), p = 0.005] and warfarin administration [HR 0.482, 95% CI (0.257, 0.905), p = 0.023] remained independent risk factors for the composite endpoint. Male gender [HR 3.699, 95% CI (1.699, 8.246), p = 0.001] and isolated lupus anticoagulant positivity [HR 2.236, 95% CI (1.039, 4.811), p = 0.040] were independent risk factors for thromboembolic recurrence.

Conclusion

There are sex disparities in the clinical characteristics in patients with ptAPS and the male gender is an independent risk factor for the poor prognosis. Male patients with isolated lupus anticoagulant (LA) positivity have the highest risk of thromboembolic recurrence.
How Functional Genomics Can Keep Pace With VUS Identification
Authors: Anderson Corey L. , Munawar Saba , Reilly Louise , Kamp Timothy J. , January Craig T. , Delisle Brian P. , Eckhardt Lee L.
Published: July 2022

Over the last two decades, an exponentially expanding number of genetic variants have been identified associated with inherited cardiac conditions. These tremendous gains also present challenges in deciphering the clinical relevance of unclassified variants or variants of uncertain significance (VUS). This review provides an overview of the advancements (and challenges) in functional and computational approaches to characterize variants and help keep pace with VUS identification related to inherited heart diseases.
Global Landslide Forecasting System for Hazard Assessment and Situational Awareness
Authors: Khan Sana , Kirschbaum Dalia B. , Stanley Thomas A. , Amatya Pukar M. , Emberson Robert A.
Published: July 2022

Landslides triggered by extreme rainfall can be devastating, resulting in loss of life, property, and infrastructure. Landslide forecasting systems provide an opportunity to build awareness of potential hazards and ultimately take preemptive measures. There is currently a dearth of forecasting systems that provide regional or global coverage, but these systems can offer important situational awareness in data-sparse, ungauged, or large-scale catchments. A near global, primarily satellite-based system called the Landslide Hazard Assessment for Situational Awareness (LHASA) provides near real-time estimates of potential landslide hazard and exposure around the world. In this work, a precipitation forecast module is introduced into LHASA to complement the existing LHASA framework and provide an estimate of landslide hazard up to 3 days in advance at 1 km resolution. The model-based Goddard Earth Observing System-Forward Processing (GEOS-FP) precipitation forecast product is used as the forcing input for the model in place of the satellite-based Integrated Multi-satellitE Retrievals for Global Precipitation Mission product. Soil moisture and snow depth from the GEOS-FP assimilated product are also incorporated. The study period January 2020–January 2021 is used to test the model performance against the LHASA near real-time estimates at multiple spatiotemporal scales. Validation of the model is carried out using a collection of rainfall-triggered landslide inventories from around the world as case studies to demonstrate the potential utility and limitations of this system. The rescaling of the GEOS-FP precipitation product is a critical step in incorporating the forecasted precipitation data within LHASA-Forecast (LHASA-F). Combining different streams of forecasted data within the LHASA-F framework shows promise, particularly for larger events at the 1- and 2-days lead time for events. Results indicate that for the case studies evaluated, the LHASA-F is generally able to resolve major landslide events triggered by extreme rainfall, such as from tropical cyclones. The analysis shows that landslide forecast outputs may be represented differently depending on the user’s needs. This framework serves as a first milestone in providing a global predictive view of landslide hazard.
Early Cretaceous Slump Deposits in Laiyang Group (Lingshan Island, East China): New Constraints for Provenance Identification and Tectonic Evolution
Authors: Wang Yuzhe , Qiu Longwei , Yang Yongqiang , Yang Baoliang , Dong Daotao , Khan Danish , Guo Zhongren
Published: July 2022

The sedimentary strata in the Lingshan Island area are gaining attention because of their unique sedimentary and tectonic characteristics. However, the provenance and the depositional and tectonic setting in this area remain the focus of controversy. There is a significant slump deposit with lateral length up to 250 m in the Laohuzui section at the top of the Laiyang Group, which differs from the underlying turbidite deposits in morphology and composition. The sandstone in the Laohuzui section was continuously sampled and analyzed for major trace and rare earth elements. The results showed that the Laohuzui section is mixed with a continental margin provenance from the re-cyclic deposition in the arid region, which is different from the continental island arc provenance in the lower part of the Laiyang Group. Through the geochemical study of the igneous gravel contained in the olistolite and the comparison with the igneous rocks in the surrounding area, it is observed that the properties of the igneous gravel are most like those of the igneous rock deposit in the Zhucheng-Taolin area. In addition, the Lingshan Island and the Zhucheng-Taolin areas have similar sedimentary processes, suggesting that both received provenance from the Jiaonan uplift at the end of the Early Cretaceous. This study clarified the depositional processes of the later period of the Laiyang Group deposition in the Lingshan Island area.
Morphology Evolution of Three-Dimensional Scours Under Submerged Jets
Authors: Chen Ke-ling , Wei Wang-ru , Deng Jun
Published: July 2022

Through physical model tests, the three-dimensional morphological features and their scale changes with time were measured and comparatively analyzed during the scouring of a homogeneous granular bed surface using submerged oblique jets. The effects of various flow velocities and water cushion depths on the depth, length, and width of the scour hole were studied. At the early stage of scour formation, the morphological scales changed more dramatically, and the jet impact flow velocity had a more significant effect on the scour hole relative to the depth of the water cushion; for the final scales in all three directions of the scour, the scour depth developed at a more significant rate relative to the length and width of the scour. The correlation between the depth, length, and width of scour hole formation was achieved based on the time-domain variation pattern of scour hole scales. As the jet velocity increased and the depth of the water cushion decreased, the scour gradually developed from a wide-shallow morphology to a narrow-deep morphology; the impact of three-dimensional morphological features of the scour on hole depth gradually became obvious, appearing to inhibit the development of scour depth. The results of the present experimental tests offered an exploratory study of the effect of three-dimensional morphological features on the formation of jet scours, having constituted the basis for more rational analysis and evaluation of energy dissipation for the hydraulic operation in water conservancy projects.
Text Mining to Alleviate the Cold-Start Problem of Adaptive Comparative Judgments
Authors: De Vrindt Michiel , Van den Noortgate Wim , Debeer Dries
Published: July 2022

Comparative judgments permit the assessment of open-ended student works by constructing a latent quality scale through repeated pairwise comparisons (i.e., which works “win” or “lose”). Adaptive comparative judgments speed up the judgment process by maximizing the Fisher information of the next comparison. However, at the start of a judgment process, such an adaptive algorithm will not perform well. In order to reliably approximate the Fisher Information of possible pairs well, multiple comparisons are needed. In addition, adaptive comparative judgments have been shown to inflate the scale separation coefficient, which is a reliability estimator for the quality estimates. Current methods to solve the inflation issue increase the number of required comparisons. The goal of this study is to alleviate the cold-start problem of adaptive comparative judgments for essays or other textual assignments, but also to minimize the bias of the scale separation coefficient. By using text-mining techniques, which can be performed before the first judgment, essays can be adaptively compared from the start. More specifically, we propose a selection rule that is based both on a high (1) cosine similarity of the vector representations and (2) Fisher Information of essay pairs. At the start of the judgment process, the cosine similarity has the highest weight in the selection rule. With more judgments, this weight decreases progressively, whereas the weight of the Fisher Information increases. Using simulated data, the proposed strategy is compared with existing approaches. The results indicate that the proposed selection rule can mitigate both the cold-start. That is, fewer judgments are needed to obtain accurate and reliable quality estimates. In addition, the selection rule was found to reduce the inflation of the scale separation reliability.
Impact of Covid-19 Pandemic on the Effectiveness of Outpatient Counseling in Childhood Obesity Management
Authors: Corica Domenico , Li Pomi Alessandra , Curatola Selenia , Pepe Giorgia , Giandalia Annalisa , Tropeano Angelo , Alibrandi Angela , Aversa Tommaso , Wasniewska Malgorzata
Published: July 2022

The Covid-19 pandemic drastically modified social life and lifestyle, in particular, among children and adolescents, promoting sedentary behaviors and unhealthy eating habits. The aims of this study were to assess the rate and the factors associated with outpatient drop-out in childhood obesity management, and to evaluate how the Covid-19 pandemic influenced weight status and lifestyle of children and adolescents with obesity. One hundred and forty-five children and adolescents with obesity were identified, including 80 subjects evaluated before the Covid-19 pandemic (group A) and 65 subjects in the period straddling the Covid-19 pandemic (group B). Anamnestic (family history of obesity, dietary habits, physical activity, screen time), socio-cultural (economic status, employment and schooling of parents, household composition, place of living) and clinical (weight, height, BMI, waist circumference) data were retrospectively analyzed for each subject in both groups at baseline (V0) and 12-months (V1) at in-person assessment. Glycemic and lipid profiles were assessed at V0. Drop-out rate did not differ significantly between the two groups. BMI SDS at V0 (OR=2.52; p=0.004), female sex (OR=0.41; p=0.035), and the presence of a single parent in the household (OR=5.74; p=0.033) significantly influenced drop-out in both groups. Weight loss between V0 and V1 was significantly greater among group A patients compared to group B (p=0.031). In group B, hours spent in physical activity significantly decreased from V0 to V1, being significantly lower than group A at V1; on the contrary, screen time significantly increased in the same period. The consumption of sugary drinks and snacks was significantly greater in group B than group A at V1. Our study documented that the Covid-19 pandemic, although not affecting the drop-out rate of obese children in a follow-up program, negatively influenced lifestyle and reduced the effectiveness of outpatient counseling in childhood obesity treatment.
The Lipid Profiles in Different Characteristics of Women with PCOS and the Interaction Between Dyslipidemia and Metabolic Disorder States: A Retrospective Study in Chinese Population
Authors: Guo Fei , Gong Zhentao , Fernando Taniya , Zhang Lingshan , Zhu Xiaoyong , Shi Yingli
Published: July 2022

Purpose

To exhibit the lipid profiles in PCOS women with different characteristics and to access correlations between alternation of key lipid parameters and characteristics of PCOS.

Design

A retrospective study.

Participants

A total of 700 PCOS women were included.

Methods

Retrospective study on 700 women (age 24.6 ± 4.7 years), diagnosed with PCOS in the outpatient department of Obstetrics and Gynecology Hospital of Fudan University according to Rotterdam criteria. Anthropometric features, hormone levels, lipid levels, and metabolic parameters were measured and compared between PCOS patients with different characteristics.

Results

There was a high prevalence of dyslipidemia among Chinese PCOS patients (41.3%), and the most common pattern was low HDL. Patients with clinical hyperandrogenism presented with significantly decreased HDL and Apo-A levels. The levels of TG, LDL, Apo-B, TG/HDL, and Apo-B/Apo-A were significantly increased in the insulin resistance subgroup. The levels of TC and TG were significantly increased in the dysglycemia and T2DM women. And in general, the levels of TG, and Apo-B had an increasing trend with BMI. Moreover, AI, TG/HDL, and Apo-B/Apo-A ratios were associated with some characteristics of PCOS, such as insulin resistance, and obesity.

Conclusion

The PCOS women with different characteristics presented with different lipid profiles, and there is a complex correlation between lipid metabolism and PCOS characteristics, which may explain the increased risk of long-term cardiovascular disease. Regular screening of blood lipids is essential for PCOS women. Identification of optimal subgroups in PCOS patients that need lipid-lowering treatment and therapeutic effectiveness is worth exploring.
Case Study of Successfully Staged Acid Fracturing on the Ultra-Deep Horizontal Well for the Qixia Fm HTHP Tight Carbonate Gas Reservoir in China
Authors: Liu Fei , Fan Yu , Li Li , Li Jinsui , Chen Yan , Lv Zefei , He Tingting
Published: July 2022

The lower Permian Qixia formation gas reservoir is characterized by ultra-deep buried, high temperature and high pressure (HTHP), low porosity and permeability, ultra-high closure pressure, and thin thickness in the western Sichuan Basin, China. Acid fracturing has been adopted as the main well stimulation technology. The average test production of the acid-fractured vertical well was 46 × 104 m3/d. The horizontal well with staged acid fracturing is considered a reliable measure to enhance gas production. However, the staged acid fracturing on the ultra-deep horizontal well has been challenged. The reaction rates of conventional, self-diverting, and gelled acid and the acid-etched fracture conductivity experiments under HTHP are measured to optimize the acid fracturing technique. The reaction rate of gelled acid with Qixia Fm limy dolomite at 150°C is 3.4–6.7 times faster than that with dolomite and similar to that with limestone. The gelled acid with better retardation and friction reduction performance is selected as the main acid to increase the effective acid-etched fracture length. The acid-etched fracture conductivity can be greatly enhanced by using gelled acid, increasing acid volume, and closed fracture acidizing (CFA) under a closure stress of 50 MPa. Moreover, the feasibility of staged acid fracturing for ultra-deep horizontal wells is discussed. The first stage is assembled by fracturing sleeve, spared ball drop sleeve, and circulating valve to ensure activation of the fracturing channel. The tested production is significantly enhanced with temporary plugging and open-hole packer and sliding sleeve staged acid fracturing.
Soil Structural Quality and Relationships With Root Properties in Single and Integrated Farming Systems
Authors: Cavalieri-Polizeli Karina Maria Vieira , Marcolino Feliciano Canequetela , Tormena Cássio Antonio , Keller Thomas , Moraes Anibal de
Published: July 2022

Single farming systems (SFS) such as monocultures may negatively affect soil structural quality. This study tested the hypothesis that integrated farming systems (IFS), i.e., the combination of cropping and forestry and/or livestock farming, improves soil structural quality, root development and soil organic carbon. An experimental area was set up in 2012 at the Canguiri experimental farm belonging to the Federal University of Paraná, Southern Brazil. The soils are predominantly Ferralsols. The experimental treatments representing different farming systems, organized in a random block design with three replicates, were: Forestry (F), Conventional Crop Production (C), Livestock (L), and integrated Crop-Forestry (CF), Crop-Livestock (CL), Livestock-Forestry (LF), and Crop-Livestock-Forestry (CLF). In situ measurements and sampling were carried out in the 0–0.3 m layer during summer 2019/20, and included soil penetration resistance (PR), soil structural quality based on visual evaluation of soil structure (SqVESS scores), root length (RL), root volume (RV) and soil organic carbon content (SOC). Soil structural quality, penetration resistance, root length and volume, and SOC varied between farming systems, but no significant differences were found between single (C, L, F) and integrated farming systems (CF, CL, LF, CLF). The single system Forestry (F) and the integrated systems including forestry (LF, CF, CLF) tended to have higher SqVESS scores, i.e. poorer soil structural quality, and higher PR, which we associate with the generally drier soil conditions that are due to higher soil water uptake and higher interception and reduce the frequency of wetting-drying cycles. Roots were concentrated in the shallow soil layer (0–0.1 m depth), and this was especially pronounced in the Crop (C) single farming system. Based on the measured values, our results suggest an acceptable soil structural quality in all farming systems. Our data revealed strong, significant relationships between soil structural quality, penetration resistance, root growth and SOC, demonstrating that improvements in soil structure results in lower soil penetration resistance, higher root volumes and higher SOC, and vice versa. Soil PR was positively correlated with SqVESS (R2 = 0.84), indicating that better soil structural quality resulted in lower soil mechanical resistance. This, in turn, increased root length and volume, which increases carbon input to soil and therefore increases SOC in the long run.
Inter- and Intraspecific Trait Compensation of Behavioural and Morphological Defences in a Damselfly Genus
Authors: Mühlenhaupt Max , Jiang Bin , Brauner Oliver , Mikolajewski Dirk J.
Published: July 2022

Predation is a key driver of phenotypic diversification with prey having evolved sets of correlated anti-predator traits. Changes in anti-predator traits can be studied on an evolutionary as well as on a developmental timescale. Using a common garden setup, we studied inter- and intraspecific correlations of behavioural and morphological defences in four damselfly species that either occur in habitats dominated by predatory fish (fish habitats) or fishless habitats by raising larvae either with predatory fish or in a control treatment. We found inter- as well as intraspecific trait compensation (negative correlations) between behavioural and morphological defences. Compared to fishless habitat species, fish habitat species invested more in behavioural defences and less in morphological defences. This was mirrored by fish habitat species investing more in behavioural defences and less in morphological defences when reared with predatory fish whereas fishless habitat species invested less in morphological defences only. Our results emphasise the role of context-specific combinations of defensive traits to avoid predation. We suggest, considering changes in multiple correlated traits on different timescales when studying the evolution of anti-predator traits.
Exome/Genome-Wide Testing in Newborn Screening: A Proportionate Path Forward
Authors: Rahimzadeh Vasiliki , Friedman Jan M. , de Wert Guido , Knoppers Bartha M.
Published: July 2022

Population-based newborn screening (NBS) is among the most effective public health programs ever launched, improving health outcomes for newborns who screen positive worldwide through early detection and clinical intervention for genetic disorders discovered in the earliest hours of life. Key to the success of newborn screening programs has been near universal accessibility and participation. Interest has been building to expand newborn screening programs to also include many rare genetic diseases that can now be identified by exome or genome sequencing (ES/GS). Significant declines in sequencing costs as well as improvements to sequencing technologies have enabled researchers to elucidate novel gene-disease associations that motivate possible expansion of newborn screening programs. In this paper we consider recommendations from professional genetic societies in Europe and North America in light of scientific advances in ES/GS and our current understanding of the limitations of ES/GS approaches in the NBS context. We invoke the principle of proportionality—that benefits clearly outweigh associated risks—and the human right to benefit from science to argue that rigorous evidence is still needed for ES/GS that demonstrates clinical utility, accurate genomic variant interpretation, cost effectiveness and universal accessibility of testing and necessary follow-up care and treatment. Confirmatory or second-tier testing using ES/GS may be appropriate as an adjunct to conventional newborn screening in some circumstances. Such cases could serve as important testbeds from which to gather data on relevant programmatic barriers and facilitators to wider ES/GS implementation.
Genome-Wide Identification and Characterization of Receptor-Like Protein Kinase 1 (RPK1) Gene Family in Triticum aestivum Under Drought Stress
Authors: Rahim Amna Abdul , Uzair Muhammad , Rehman Nazia , Rehman Obaid Ur , Zahra Nageen , Khan Muhammad Ramzan
Published: July 2022

Receptor-like protein kinase1 (RPK1) genes play crucial roles in plant growth and development processes, root architecture, and abiotic stress regulation. A comprehensive study of the RPK1 gene family has not been reported in bread wheat (Triticum aestivum). Here, we reported the genome-wide identification, characterization, and expression patterns of the RPK1 gene family in wheat. Results confirmed 15 TaRPK1 genes, classified mainly into three sub-clades based on a phylogenetic tree. The TaRPK1 genes were mapped on chromosomes 1–3 in the respective A, B, and D genomes. Gene structure, motif conservation, collinearity prediction, and synteny analysis were carried out systematically. A Gene ontology study revealed that TaRPK1 genes play a vital role during molecular and biological processes. We also identified 18 putative miRNAs targeting TaRPK1 genes, suggesting their roles in growth, development, and stress responses. Cis-Regulatory elements interpreted the presence of light-related elements, hormone responsiveness, and abiotic stress-related motifs in the promoter regions. The SWISS_MODEL predicted the successful models of TaRPK1 proteins with at least 30% identity to the template, a widely accepted threshold for successful modeling. In silico expression analysis in different tissues and stages suggested that TaRPK1 genes exhibited the highest expression in root tissues. Moreover, qRT-PCR further validated the higher expression of TaRPK1 genes in roots of drought-tolerant varieties compared to the drought-susceptible variety. Collectively, the present study renders valuable information on the functioning of TaRPK1 genes in wheat that will be useful in further functional validation of these genes in future studies.
CIEGAN: A Deep Learning Tool for Cell Image Enhancement
Authors: Sun Qiushi , Yang Xiaochun , Guo Jingtao , Zhao Yang , Liu Yi
Published: July 2022

Long-term live-cell imaging technology has emerged in the study of cell culture and development, and it is expected to elucidate the differentiation or reprogramming morphology of cells and the dynamic process of interaction between cells. There are some advantages to this technique: it is noninvasive, high-throughput, low-cost, and it can help researchers explore phenomena that are otherwise difficult to observe. Many challenges arise in the real-time process, for example, low-quality micrographs are often obtained due to unavoidable human factors or technical factors in the long-term experimental period. Moreover, some core dynamics in the developmental process are rare and fleeting in imaging observation and difficult to recapture again. Therefore, this study proposes a deep learning method for microscope cell image enhancement to reconstruct sharp images. We combine generative adversarial nets and various loss functions to make blurry images sharp again, which is much more convenient for researchers to carry out further analysis. This technology can not only make up the blurry images of critical moments of the development process through image enhancement but also allows long-term live-cell imaging to find a balance between imaging speed and image quality. Furthermore, the scalability of this technology makes the methods perform well in fluorescence image enhancement. Finally, the method is tested in long-term live-cell imaging of human-induced pluripotent stem cell-derived cardiomyocyte differentiation experiments, and it can greatly improve the image space resolution ratio.
ISR8/IRF1-AS1 Is Relevant for IFNα and NF-κB Responses
Authors: Barriocanal Marina , Prats-Mari Laura , Razquin Nerea , Prior Celia , Unfried Juan Pablo , Fortes Puri
Published: July 2022

The study of the interferon (IFN) α-induced cell transcriptome has shown altered expression of several long non-coding RNAs (lncRNAs). ISR8/IRF1-AS1 (IFN stimulated RNA 8), located close to IFN regulatory factor 1 (IRF1) coding gene, transcribes a lncRNA induced at early times after IFNα treatment or IRF1 or NF-κB activation. Depletion or overexpression of ISR8 RNA does not lead to detected deregulation of the IFN response. Surprisingly, disruption of ISR8 locus with CRISPR-Cas9 genome editing results in cells that fail to induce several key ISGs and pro-inflammatory cytokines after a trigger with IFNα or overexpression of IRF1 or the NF-κB subunit RELA. This suggests that the ISR8 locus may play a relevant role in IFNα and NF-κB pathways. Interestingly, IFNα, IRFs and NF-κB-responding luciferase reporters are normally induced in ISR8-disrupted cells when expressed from a plasmid but not when integrated into the genome. Therefore, IFNα and NF-κB pathways are functional to induce the expression of exogenous episomic transcripts but fail to activate transcription from genomic promoters. Transcription from these promoters is not restored with silencing inhibitors, by decreasing the levels of several negative regulators or by overexpression of inducers. Transcriptome analyses indicate that ISR8-disrupted cells have a drastic increase in the levels of negative regulators such as XIST and Zinc finger proteins. Our results agree with ISR8 loci being an enhancer region that is fundamental for proper antiviral and proinflammatory responses. These results are relevant because several SNPs located in the ISR8 region are associated with chronic inflammatory and autoimmune diseases including Crohn’s disease, inflammatory bowel disease, ulcerative colitis or asthma.
Increased Development of Th1, Th17, and Th1.17 Cells Under T1 Polarizing Conditions in Juvenile Idiopathic Arthritis
Authors: Patrick Anna E. , Shoaff Kayla , Esmond Tashawna , Patrick David M. , Flaherty David K. , Graham T Brent , Crooke Philip S. , Thompson Susan , Aune Thomas M.
Published: July 2022

In juvenile idiopathic arthritis (JIA) inflammatory T cells and their produced cytokines are drug targets and play a role in disease pathogenesis. Despite their clinical importance, the sources and types of inflammatory T cells involved remain unclear. T cells respond to polarizing factors to initiate types of immunity to fight infections, which include immunity types 1 (T1), 2 (T2), and 3 (T17). Polarizing factors drive CD4+ T cells towards T helper (Th) cell subtypes and CD8+ T cells towards cytotoxic T cell (Tc) subtypes. T1 and T17 polarization are associated with autoimmunity and production of the cytokines IFNγ and IL-17 respectively. We show that JIA and child healthy control (HC) peripheral blood mononuclear cells are remarkably similar, with the same frequencies of CD4+ and CD8+ naïve and memory T cell subsets, T cell proliferation, and CD4+ and CD8+ T cell subsets upon T1, T2, and T17 polarization. Yet, under T1 polarizing conditions JIA cells produced increased IFNγ and inappropriately produced IL-17. Under T17 polarizing conditions JIA T cells produced increased IL-17. Gene expression of IFNγ, IL-17, Tbet, and RORγT by quantitative PCR and RNA sequencing revealed activation of immune responses and inappropriate activation of IL-17 signaling pathways in JIA polarized T1 cells. The polarized JIA T1 cells were comprised of Th and Tc cells, with Th cells producing IFNγ (Th1), IL-17 (Th17), and both IFNγ-IL-17 (Th1.17) and Tc cells producing IFNγ (Tc1). The JIA polarized CD4+ T1 cells expressed both Tbet and RORγT, with higher expression of the transcription factors associated with higher frequency of IL-17 producing cells. T1 polarized naïve CD4+ cells from JIA also produced more IFNγ and more IL-17 than HC. We show that in JIA T1 polarization inappropriately generates Th1, Th17, and Th1.17 cells. Our data provides a tool for studying the development of heterogeneous inflammatory T cells in JIA under T1 polarizing conditions and for identifying pathogenic immune cells that are important as drug targets and diagnostic markers.
T and B Cell Composition and Cytokine Producing Capacity Before and After Bariatric Surgery
Authors: Wijngaarden L. H. , Taselaar A. E. , Nuijten F. , Harst E. van der , Klaassen R. A. , Kuijper T. M. , Jongbloed F. , Ambagtsheer G. , Klepper M. , IJzermans J. N. M. , de Bruin R. W. F. , Litjens N. H. R.
Published: July 2022

Morbid obesity is associated with a chronic state of low-grade inflammation, which may lead to accelerated differentiation of T and B cells. These differentiated immune cells are strongly cytotoxic and have an increased pro-inflammatory cytokine producing capacity. Furthermore, the anti-inflammatory function of the T and B cells decreases. The aim of this study was to evaluate the effect of morbid obesity on the subset profile and cytokine producing capacity of T and B cells. Subsequently, we assessed whether bariatric surgery affected the subset profile and cytokine producing capacity of these cells. We determined the proportion of T and B cell subsets and their cytokine producing capacity in peripheral blood collected from 23 morbidly obese patients before and three months after bariatric surgery using flow-cytometry. We compared this with the results of 25 lean controls. Both CD4+ and CD8+ T cells showed a more differentiated subset profile in morbidly obese patients as compared to lean controls, which was not recovered three months after bariatric surgery. The B cell composition of morbidly obese patients after bariatric surgery adjusted towards the profile of lean controls. However, the IL-2 and IFN-γ producing capacity of CD8+ T cells and the IL-2, IFN-γ, TNF-α and IL-10 producing capacity of B cells was not restored three months after bariatric surgery. In conclusion, the data suggest that the immune system has the capacity to recover from the detrimental effects of morbid obesity within three months after bariatric surgery in terms of cell composition; however, this was not seen in terms of cytokine producing capacity. The full restoration of the immune system after bariatric surgery may thus take longer.
Proteomic Changes of Osteoclast Differentiation in Rheumatoid and Psoriatic Arthritis Reveal Functional Differences
Authors: Kovács Orsolya Tünde , Tóth Eszter , Ozohanics Olivér , Soltész-Katona Eszter , Marton Nikolett , Buzás Edit Irén , Hunyady László , Drahos László , Turu Gábor , Nagy György
Published: July 2022

Background

Osteoclasts play a crucial role in the maintenance, repair, and remodeling of bones of the adult vertebral skeleton due to their bone resorption capability. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are associated with increased activity of osteoclasts.

Objectives

Our study aimed to investigate the dynamic proteomic changes during osteoclast differentiation in healthy donors, in RA, and PsA.

Methods

Blood samples of healthy donors, RA, and PsA patients were collected, and monocytes were isolated and differentiated into osteoclasts in vitro using macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANK-L). Mass spectrometry-based proteomics was used to analyze proteins from cell lysates. The expression changes were analyzed with Gene Set Enrichment Analysis (GSEA).

Results

The analysis of the proteomic changes revealed that during the differentiation of the human osteoclasts, expression of the proteins involved in metabolic activity, secretory function, and cell polarity is increased; by contrast, signaling pathways involved in the immune functions are downregulated. Interestingly, the differences between cells of healthy donors and RA/PsA patients are most pronounced after the final steps of differentiation to osteoclasts. In addition, both in RA and PsA the differentiation is characterized by decreased metabolic activity, associated with various immune pathway activities; furthermore by accelerated cytokine production in RA.

Conclusions

Our results shed light on the characteristic proteomic changes during human osteoclast differentiation and expression differences in RA and PsA, which reveal important pathophysiological insights in both diseases.
White Spot Syndrome Virus Triggers a Glycolytic Pathway in Shrimp Immune Cells (Hemocytes) to Benefit Its Replication
Authors: Ng Yen Siong , Lee Der-Yen , Liu Chun-Hung , Tung Cheng-Yi , He Shu-Ting , Wang Han-Ching
Published: July 2022

White spot syndrome virus (WSSV) is the causative agent of a shrimp disease that inflicts in huge economic losses in shrimp-farming industry. WSSV triggers aerobic glycolysis in shrimp immune cells (hemocytes), but how this virus regulates glycolytic enzymes or pathway is yet to be characterized. Therefore, mRNA levels and activity of four important glycolytic enzymes, Hexokinase (HK), Phosphofructokinase (PFK), Pyruvate kinase (PK), and Lactate dehydrogenase (LDH), were measured in WSSV-infected shrimp hemocytes. Gene expression of HK and PFK, but not LDH or PK, was increased at the viral genome replication stage (12 hpi); furthermore, activity of these enzymes, except HK, was concurrently increased. However, there was no increased enzyme activity at the viral late stage (24 hpi). In vivo dsRNA silencing and glycolysis disruption by 2-DG further confirmed the role of glycolysis in virus replication. Based on tracing studies using stable isotope labeled glucose, glycolysis was activated at the viral genome replication stage, but not at the viral late stage. This study demonstrated that WSSV enhanced glycolysis by activating glycolytic enzyme at the viral genome replication stage, providing energy and biomolecules for virus replication.
Carbohydrates Metabolic Signatures in Immune Cells: Response to Infection
Authors: Awad Kareem , Maghraby Amany Sayed , Abd-Elshafy Dina Nadeem , Bahgat Mahmoud Mohamed
Published: July 2022

Introduction

Metabolic reprogramming in immune cells is diverse and distinctive in terms of complexity and flexibility in response to heterogeneous pathogenic stimuli. We studied the carbohydrate metabolic changes in immune cells in different types of infectious diseases. This could help build reasonable strategies when understanding the diagnostics, prognostics, and biological relevance of immune cells under alternative metabolic burdens.

Methods

Search and analysis were conducted on published peer-reviewed papers on immune cell metabolism of a single pathogen infection from the four known types (bacteria, fungi, parasites, and viruses). Out of the 131 selected papers based on the PIC algorithm (pathogen type/immune cell/carbohydrate metabolism), 30 explored immune cell metabolic changes in well-studied bacterial infections, 17 were on fungal infections of known medical importance, and 12 and 57 were on parasitic and viral infections, respectively.

Results and Discussion

While carbohydrate metabolism in immune cells is signaled by glycolytic shift during a bacterial or viral infection, it is widely evident that effector surface proteins are expressed on the surface of parasites and fungi to modulate metabolism in these cells.

Conclusions

Carbohydrate metabolism in immune cells can be categorized according to the pathogen or the disease type. Accordingly, this classification can be used to adopt new strategies in disease diagnosis and treatment.
Neddylation Inhibition Causes Impaired Mouse Embryo Quality and Blastocyst Hatching Failure Through Elevated Oxidative Stress and Reduced IL-1β
Authors: Yang Guangping , Chen Jianhua , He Yanni , Luo Hui , Yuan Hongxia , Chen Liangliang , Huang Lingli , Mao Fei , Hu Saifei , Qian Yun , Miao Congxiu , Feng Ruizhi
Published: July 2022

Mammalian blastocyst hatching is an essential prerequisite for successful embryo implantation. As the rate-limiting step of current assisted reproductive technology, understanding the key factors regulating blastocyst hatching would be significantly helpful to improve the performance of the assisted reproductive practice. In early embryo development, the fine-tuned elimination of maternal materials and the balanced protein turnover are inevitable for the competent to hatch and implant into endometrium. Neddylation, a ubiquitination-like protein modification, has been shown to be involved in oocyte maturation and early embryo development. In this study, aiming to discover an unknown role of neddylation in the blastocyst hatching process, we provided functional evidence of neddylation in mammalian embryo quality and blastocyst hatching. Treatment with MLN4924, a specific neddylation inhibitor, lowered the embryo quality and dramatically reduced the hatching rate in mouse blastocysts. The transcriptional profile showed the upregulation of oxidative stress-related genes and aberrant expression of immune-related genes. The elevated oxidative stress was validated by qPCR and markers of apoptosis, DNA damage, reactive oxygen species, and cytoskeleton. Moreover, we found the secreted IL-1β level was reduced in an NF-κB-independent manner, leading to the final poor embryo quality and blastocyst hatching failure. This is the first report of neddylation being of great importance in the mammalian blastocyst hatching process. Further investigations uncovering more detailed molecular mechanisms of neddylation regulation in blastocyst hatching would greatly promote not only the understanding of this crucial biological process but also the clinical application in reproductive centers.
Relationship Between Gender Differences and Clinical Outcome in Patients With the Antiphospholipid Syndrome
Authors: Truglia Simona , Capozzi Antonella , Mancuso Silvia , Manganelli Valeria , Rapino Luca , Riitano Gloria , Recalchi Serena , Colafrancesco Serena , Ceccarelli Fulvia , Garofalo Tina , Alessandri Cristiano , Longo Agostina , Misasi Roberta , Conti Fabrizio , Sorice Maurizio
Published: July 2022

Antiphospholipid syndrome (APS), characterized by artherial and/or venous thrombosis, pregnancy morbidity and “antiphospholipid” antibodies (aPLs), is more common in women than in men, with a female to male ratio of about 3.5:1. Only few studies have investigated the clinical differences between male and female patients with APS. Therefore, this study was aimed to analyze the differences of clinical manifestations and laboratory tests, at diagnosis, between female and male APS patients and the clinical outcome. We enrolled 191 consecutive APS patients (125 with primary APS, PAPS, and 66 with secondary APS, SAPS) with a female predominant ratio of approximately 3:1 (142 vs 49). The prevalence of PAPS was higher in males than females (p<0.001). The analysis of aPL profile revealed that high IgM anti-cardiolipin (aCL) and high-medium IgG aCL titers were more frequent in males. In thrombotic APS peripheral arterial thrombosis was more common in male than female patients (p=0.049), as well as myocardial infarction (p=0.031). Multivariate analysis to correct for cardiovascular risk factors, high titer of aPLs and triple positivity for aPLs, revealed that the odds ratio for myocardial infarction in male was 3.77. Thus, APS may be considered as a disease in which serological (IgM titer) and clinical profiles are influenced by gender.
The Neonatal Innate Immune Response to Sepsis: Checkpoint Proteins as Novel Mediators of This Response and as Possible Therapeutic/Diagnostic Levers
Authors: Hensler Emily , Petros Habesha , Gray Chyna C. , Chung Chun-Shiang , Ayala Alfred , Fallon Eleanor A.
Published: July 2022

Sepsis, a dysfunctional immune response to infection leading to life-threatening organ injury, represents a significant global health issue. Neonatal sepsis is disproportionately prevalent and has a cost burden of 2-3 times that of adult patients. Despite this, no widely accepted definition for neonatal sepsis or recommendations for management exist and those created for pediatric patients are significantly limited in their applicability to this unique population. This is in part due to neonates’ reliance on an innate immune response (which is developmentally more prominent in the neonate than the immature adaptive immune response) carried out by dysfunctional immune cells, including neutrophils, antigen-presenting cells such as macrophages/monocytes, dendritic cells, etc., natural killer cells, and innate lymphoid regulatory cell sub-sets like iNKT cells, γδ T-cells, etc.

Immune checkpoint inhibitors are a family of proteins with primarily suppressive/inhibitory effects on immune and tumor cells and allow for the maintenance of self-tolerance. During sepsis, these proteins are often upregulated and are thought to contribute to the long-term immunosuppression seen in adult patients. Several drugs targeting checkpoint inhibitors, including PD-1 and PD-L1, have been developed and approved for the treatment of various cancers, but no such therapeutics have been approved for the management of sepsis. In this review, we will comparatively discuss the role of several checkpoint inhibitor proteins, including PD-1, PD-L1, VISTA, and HVEM, in the immune response to sepsis in both adults and neonates, as well as posit how they may uniquely propagate their actions through the neonatal innate immune response. We will also consider the possibility of leveraging these proteins in the clinical setting as potential therapeutics/diagnostics that might aid in mitigating neonatal septic morbidity/mortality.
Translating MSC Therapy in the Age of Obesity
Authors: Boland Lauren , Bitterlich Laura Melanie , Hogan Andrew E. , Ankrum James A. , English Karen
Published: July 2022

Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.