bluuebunny/crossref_metadata_2025 huggingface dataset:
Notch Signaling Pathway Is Activated by Sulfate Reducing Bacteria
Authors: Singh Sudha B. , Coffman Cristina N. , Carroll-Portillo Amanda , Varga Matthew G. , Lin Henry C.
Published: July 2021

Sulfate Reducing Bacteria (SRB), usually rare residents of the gut, are often found in increased numbers (called a SRB bloom) in inflammatory conditions such as Inflammatory Bowel Disease (IBD), pouchitis, and periodontitis. However, the underlying mechanisms of this association remain largely unknown. Notch signaling, a conserved cell-cell communication pathway, is usually involved in tissue development and differentiation. Dysregulated Notch signaling is observed in inflammatory conditions such as IBD. Lipolysaccharide and pathogens also activate Notch pathway in macrophages. In this study, we tested whether Desulfovibrio, the most dominant SRB genus in the gut, may activate Notch signaling. RAW 264.7 macrophages were infected with Desulfovibrio vulgaris (DSV) and analyzed for the expression of Notch signaling pathway-related proteins. We found that DSV induced protein expression of Notch1 receptor, Notch intracellular domain (NICD) and p21, a downstream Notch target, in a dose-and time-dependent manner. DSV also induced the expression of pro-IL1β, a precursor of IL-1β, and SOCS3, a regulator of cytokine signaling. The gamma secretase inhibitor DAPT or Notch siRNA dampened DSV-induced Notch-related protein expression as well the expression of pro-IL1β and SOCS3. Induction of Notch-related proteins by DSV was not affected by TLR4 -IN -C34(C34), a TLR4 receptor antagonist. Additionally, cell-free supernatant of DSV-infected macrophages induced NICD expression in uninfected macrophages. DSV also activated Notch pathway in the human epithelial cell line HCT116 and in mouse small intestine. Thus, our study uncovers a novel mechanism by which SRB interact with host cells by activating Notch signaling pathway. Our study lays a framework for examining whether the Notch pathway induced by SRB contributes to inflammation in conditions associated with SRB bloom and whether it can be targeted as a therapeutic approach to treat these conditions.
Bearing-Only Adaptive Formation Control Using Back-Stepping Method
Authors: Li Sulong , Wang Qin , Wang Enci , Chen Yangyang
Published: July 2021

In this paper, the bearing-only formation control problem of a class of second-order system with unknown disturbance is investigated, where the control law merely depends on the relative bearings between neighboring agents. In order to offset the effect of unknown disturbance on the system, adaptive estimation is introduced. In the design of the control law, the back-stepping design method and the negative gradient method are used. The Barbalat’s lemma is used to prove the global stability of the system. The simulation results prove the effectiveness of the proposed formation control algorithm.
Contribution of Congenital Heart Disorders Associated With Copy Number Variants in Mediating Risk for Brain Developmental Disorders: Evidence From 20-Year Retrospective Cohort Study
Authors: Dowden Luke , Tucker David , Morgan Sian , Uzun Orhan , Syed Yasir Ahmed
Published: July 2021

Rare pathogenic copy number variants (CNVs) are genetic rearrangements that have been associated with an increased risk for congenital heart disorders (CHDs). However, the association of CNVs with atypical brain development, leading to neurodevelopmental disorders (NDDs), in the presence of CHDs remains unclear. We attempted to explore this association by establishing the prevalence and burden of CNVs associated with CHD in a Welsh population and by studying the effect of rare CNVs associated with CHDs in mediating the risk of NDDs. Toward this goal, we analyzed data from the Congenital Anomaly Register for Wales (CARIS), referred from hospitals in Wales between 1998 and 2018, which included 1,113 subjects in total. Of these, 785 subjects were included in the study following application of the exclusion criteria, and a total of 28 rare CNVs associated with CHD were analyzed. The findings from this cohort study identified 22q11.2 deletion as the most prominent CNV across the cohort. Our data demonstrates that the survival rate of the cohort after 3 years was 99.9%, and mortality fell significantly between 1 and 2 years and between 2 and 3 years [F(1,27) = 10, p = 0.0027; F(1,27) = 5.8, p = 0.0222]. Importantly, the data set revealed a positive correlation between the incidence of congenital heart disease and the incidence of neurodevelopmental abnormalities in patients with CNVs across the whole cohort [95% CI (0.4062, 0.8449), p < 0.0001, r = 0.6829]. Additionally, we identified significant CNVs that result in the co-morbidity of CHD and NDD and show that septal defects and global developmental delay are major congenital defects. Further research should identify a common molecular mechanism leading to the phenotypic comorbidity of CHDs and NDDs, arising from a common CNV, which can have an implication for improving risk classification and for fetal neuroprotection strategies in the affected children and in precision medicine.
Clinical Significance of Ventricular Tachyarrhythmias in Patients Undergoing Valve Replacement: A Nationwide Population-Based Study
Authors: Li Guan-Yi , Chen Yun-Yu , Chien Kuo-Liong , Lin Yenn-Jiang , Kuo Tzu-Ting , Chung Fa-Po
Published: July 2021

Background: The clinical significance and outcomes of ventricular tachyarrhythmias (VTa) in patients undergoing valve replacement have rarely been reported.

Objective: This study aimed to investigate the incidence and outcome of VTa after surgical valve replacement.

Methods: We conducted a population-based retrospective cohort study using data obtained from the Taiwan National Health Insurance Research Database. In total, 10,212 patients were selected after 1:1 propensity-score matching based on the type of prosthetic valve used (mechanical vs. bioprosthetic). Various outcomes during long-term follow-up were analyzed.

Results: After a median follow-up period of 59.6 months, the crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased after surgery. Furthermore, the occurrences of VTa after valve replacement significantly increased the risk of cardiovascular (CV) death (P < 0.001, HR 1.67, 95% CI 1.41–1.96), stroke- (P < 0.001, HR 1.66, 95% CI 1.37–2.01), atrial fibrillation- (P < 0.001, HR 2.80, 95% CI 2.42–3.24), and congestive heart failure-related hospitalization (P < 0.001, HR 2.61, 95% CI 2.30–2.95). Among patients with VTa, all-cause mortality (P = 0.001, HR 0.49, 95% CI 0.32–0.75) and CV death (P = 0.047, HR 0.58, 95% CI 0.34–0.99) in those with implantable cardioverter-defibrillator (ICD) implantation were lower than those without.

Conclusion: The crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased during follow-up. The presence of VTa after surgical valve replacement increases hospitalization and CV death, while ICD implantation reduced the mortality rate in these patients.
Prognostic Value of Diastolic Dysfunction Derived From D-SPECT in Coronary Artery Disease Patients With Normal Ejection Fraction
Authors: Xu Bin , Liu Lu , Abdu Fuad A. , Yin Guoqing , Mohammed Abdul-Quddus , Xu Siling , Lv Xian , Fan Rui , Feng Cailin , Shi Tingting , Zhang Wen , Xu Yawei , Cai Haidong , Yu Fei , Che Wenliang
Published: July 2021

Diastolic dysfunction (DD) with normal systolic function has been elucidated to be associated with heart failure and worse prognosis. The recently introduced single photon emission computed tomography (SPECT) with dedicated cardiac cadmium-zinc-telluride (CZT) cameras (D-SPECT) is a novel method to quantitate left ventricular functional parameters. We aimed to evaluate the prognostic value of DD derived from D-SPECT in coronary artery disease (CAD) patients with normal ejection fraction. All CAD patients who underwent D-SPECT and invasive coronary angiography within 3 months were considered. DD was defined as peak filling rate (PFR) <2.1 end diastolic volume (EDV, ml)/s according to the D-SPECT results. Patients were divided into three groups: group 1 (n = 226)—normal PFR; group 2 (n = 67)—ischemia-related DD (abnormal stress PFR and normal rest PFR); and group 3 (n = 106)—rest DD (abnormal rest PFR). The primary clinical endpoint of the present study was a composite of heart failure events (HFE). A total of 399 consecutive CAD patients with normal systolic function undergoing stress D-SPECT were analyzed. The incidence rates of HFE among the three groups were 4.0, 7.5, and 11.3%, respectively. Cox regression analysis showed that the multivariate predictors of HFE were rest PFR, diabetes mellitus, obesity, and old age. DD derived from D-SPECT in CAD patients with normal ejection fraction is predictive of HFE.
Cognitive Impairments in Schizophrenia: A Study in a Large Clinical Sample Using Natural Language Processing
Authors: Mascio Aurelie , Stewart Robert , Botelle Riley , Williams Marcus , Mirza Luwaiza , Patel Rashmi , Pollak Thomas , Dobson Richard , Roberts Angus
Published: July 2021

Background: Cognitive impairments are a neglected aspect of schizophrenia despite being a major factor of poor functional outcome. They are usually measured using various rating scales, however, these necessitate trained practitioners and are rarely routinely applied in clinical settings. Recent advances in natural language processing techniques allow us to extract such information from unstructured portions of text at a large scale and in a cost effective manner. We aimed to identify cognitive problems in the clinical records of a large sample of patients with schizophrenia, and assess their association with clinical outcomes.

Methods: We developed a natural language processing based application identifying cognitive dysfunctions from the free text of medical records, and assessed its performance against a rating scale widely used in the United Kingdom, the cognitive component of the Health of the Nation Outcome Scales (HoNOS). Furthermore, we analyzed cognitive trajectories over the course of patient treatment, and evaluated their relationship with various socio-demographic factors and clinical outcomes.

Results: We found a high prevalence of cognitive impairments in patients with schizophrenia, and a strong correlation with several socio-demographic factors (gender, education, ethnicity, marital status, and employment) as well as adverse clinical outcomes. Results obtained from the free text were broadly in line with those obtained using the HoNOS subscale, and shed light on additional associations, notably related to attention and social impairments for patients with higher education.

Conclusions: Our findings demonstrate that cognitive problems are common in patients with schizophrenia, can be reliably extracted from clinical records using natural language processing, and are associated with adverse clinical outcomes. Harvesting the free text from medical records provides a larger coverage in contrast to neurocognitive batteries or rating scales, and access to additional socio-demographic and clinical variables. Text mining tools can therefore facilitate large scale patient screening and early symptoms detection, and ultimately help inform clinical decisions.
Insights from Fumarole Gas Geochemistry on the Recent Volcanic Unrest of Pico do Fogo, Cape Verde
Authors: Melián Gladys V. , Hernández Pedro A. , Pérez Nemesio M. , Asensio-Ramos María , Padrón Eleazar , Alonso Mar , Padilla Germán D. , Barrancos José , Sortino Francesco , Sumino Hirochicka , Rodríguez Fátima , Amonte Cecilia , Silva Sonia , Cardoso Nadir , Pereira José M.
Published: July 2021

We report the results of the geochemical monitoring of the fumarolic discharges at the Pico do Fogo volcano in Cape Verde from 2007 to 2016. During this period Pico do Fogo experienced a volcanic eruption (November 23, 2014) that lasted 77 days, from a new vent ∼2.5 km from the fumaroles. Two fumaroles were sampled, a low (F1∼100°C) and a medium (F2∼300°C) temperature. The variations observed in the δ18O and δ2H in F1 and F2 suggest different fluid source contributions and/or fractionation processes. Although no significant changes were observed in the outlet fumarole temperatures, two clear increases were observed in the vapor fraction of fumarolic discharges during the periods November 2008–2010 and 2013–2014. Also, two sharp peaks were observed in CO2/CH4ratios at both fumaroles, in November 2008 and November 2013. This confirms that gases with a strong magmatic component rose towards the surface within the Pico do Fogo system during 2008 and 2013. Further, F2 showed two CO2/Stotalpeaks, the first in late 2010 and the second after eruption onset, suggesting the occurrence of magmatic pulses into the volcanic system. Time series of He/CO2, H2/CO2and CO/CO2ratios are low in 2008–2009, and high in 2013–2014 period, supporting the hypothesis of fluid input from a deeper magmatic source. Regarding to the isotopic composition, increases in air-corrected3He/4He ratios are observed in both fumaroles; F1 showed a peak in 2010 from a minimum in 2009 during the first magmatic reactivation onset and another in late 2013, while F2 displayed a slower rise to its maximum in late 2013. The suite of geochemical species analyzed have considerably different reactivities, hence these integrated geochemical time-series can be used to detect the timing of magmatic arrivals to the base of the system, and importantly, indicate the typical time lags between gas release periods at depth and their arrival at the surface. The high3He/4He ratios in both fumaroles in the range observed for mid-ocean ridge basalts, indicating that He is predominantly of upper mantle origin. This work supports that monitoring of the chemical and isotopic composition of the fumaroles of the Pico do Fogo volcano is a very important tool to understand the processes that take place in the magmatic-hydrothermal system and to be able to predict future episodes of volcanic unrest and to mitigate volcanic risk.
Differential Gene Expression and Biological Analyses of Primary Hepatocytes Following D-Chiro-Inositol Supplement
Authors: Cheng Feier , Yun Shao-jun , Cao Jin-ling , Chang Ming-chang , Meng Jun-long , Liu Jing-yu , Cheng Yan-fen , Feng Cui-ping
Published: July 2021

Dietary supplements have improved the prevention of insulin resistance and metabolic diseases, which became a research hotspot in food science and nutrition. Obesity and insulin resistance, caused by a high-fat diet, eventually result in severe metabolic diseases, can be prevented with the dietary supplement D-chiro-inositol (DCI). In this work, we isolated mice primary hepatocytes with palmitic acid stimulation and DCI was applied to compare and contrast its effects of in primary hepatocyte biology. Before and after intervention with DCI, we used RNA-Seq technology to establish a primary hepatocyte transcriptome gene profile. We found that both PA and DCI cause a wide variation in gene expression. Particularly, we found that DCI plays critical role in this model by acting on glycolysis and gluconeogenesis. Overall, we generated extensive transcripts from primary hepatocytes and uncovered new functions and gene targets for DCI.
Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer
Authors: Fullmer Tanner , Cabanillas Maria E. , Zafereo Mark
Published: July 2021

Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.
Phased Impacts of China’s Dual-Credit Policy on R&D
Authors: Li Xu , Xiong Qing Y.
Published: July 2021

As a sustainability policy in emerging markets, the dual-credit policy was implemented in China to promote automakers expanding investment in research and development, and ultimately achieve the energy-saving and emission-reduction goals of the auto industry. We regard the dual-credit policy as a quasi-natural experiment, use the difference-in-difference model to divide Chinese automakers into an experimental group (the passenger vehicle group) and a control group (the commercial vehicle group), and analyze the impacts of the dual-credit policy in the brewing period (2014–2016) and the implementation period on the scale, intensity, and structure of research and development investment. We found that the dual-credit policy has significantly promoted the research and development investment of automakers, and the heterogeneity of automakers has a moderating effect on the policy effects. In addition, we also found that there are certain differences in the significance and stability of the effects of the dual-credit policy during the brewing period and the implementation period. Finally, we presented some management insights into the response to the dual-credit policy.
Increasing Renewable Energy Consumption Coordination With the Monthly Interprovincial Transaction Market
Authors: Cai Ye , Liu Ying , Tang Xiafei , Tan Yudong , Cao Yijia
Published: July 2021

The limited regulation capacity of the power grid, coupled with the imperfect market mechanism, has squeezed the space for renewable energy consumption in China. This article proposes a renewable energy consumption mechanism through the monthly interprovincial transaction market, to balance the revenue of each market participant and improve the consumption of renewable energy. A new player named “interprovincial traders” is introduced to serve as the middleman for the renewable generation, users, and the power grid company. The main function of “interprovincial traders” is to coordinate and match the user load with the output of renewable energy. In such a market mechanism, the social factors, influenced by the revenue of each trading cycle, are considered in the user responding model from the perspective of consumer psychology. Finally, a two-phase optimization model is proposed to promote renewable energy consumption coordination with the monthly interprovincial market. The optimization model is simulated in a provincial power grid example. The results show that the model can effectively increase the consumption of renewable energy as well as improve the profit of power grid companies and users.
Insights Into the Prevalence and Impacts of Phthalate Esters in Aquatic Ecosystems
Authors: Baloyi N. D. , Tekere M. , Maphangwa K. W. , Masindi V.
Published: July 2021

Phthalate esters (PEs) are by far the most produced and extensively used synthetic organic chemicals with notable applications in many industrial products such as vinyl upholstery, adhesives, food containers, packaging materials, printing inks, adhesives, cosmetics, paints, pharmaceuticals munitions, and insecticides among other. PEs have long been recognised as ubiquitous organic pollutants of prime environmental concern, with urbanisation amongst the main cause and source of these compounds. Due to their notoriety, these compounds are known to pose devastating effects to living organisms including humans. The presence of PEs and their metabolites in the aquatic ecosystems is of concern primarily due to their endocrine disrupting and carcinogenicity properties. Several research studies have reported prevalence, exposure pathways, toxicity, and impacts of PEs in aquatic ecosystems and humans. Their principal routes of exposure could be direct or indirect, of which the direct route include contact, eating, and drinking contaminated foods, and the indirect route constitute aerosols, leaching and other forms of environmental contamination. PEs find way into water systems through means such as effluent discharges, urban and agricultural land runoff, leaching from waste dumps and other diffuse sources. High-end instrumentation and improved methodologies on the other hand have resulted in increased ability to measure trace levels (μg/L) of PEs and their metabolites in different matrices and ecological compartments of water or aquatic ecosystems such as lakes, oceans, rivers, sediments, wetlands and drinking water samples. In light of the above, this article provides an informed and focused information on the prevalence of phthalate esters in aquatic systems and related effects on living organisms and humans. Furthermore, techniques that have enabled the extraction and analysis of these PEs in aquatic samples are also explained. Future research outlooks and needs are also highlighted in this manuscript. This information will be used to better understand their temporal and spatial distributions in the aquatic systems and aid in devising prudent means to curtail their ecological footprints.
The Evolutionary Ecology of Dormancy in Nature and in Cancer
Authors: Miller Anna K. , Brown Joel S. , Enderling Heiko , Basanta David , Whelan Christopher J.
Published: July 2021

Dormancy is an inactive period of an organism’s life cycle that permits it to survive through phases of unfavorable conditions in highly variable environments. Dormancy is not binary. There is a continuum of dormancy phenotypes that represent some degree of reduced metabolic activity (hypometabolism), reduced feeding, and reduced reproduction or proliferation. Similarly, normal cells and cancer cells exhibit a range of states from quiescence to long-term dormancy that permit survival in adverse environmental conditions. In contrast to organismal dormancy, which entails a reduction in metabolism, dormancy in cells (both normal and cancer) is primarily characterized by lack of cell division. “Cancer dormancy” also describes a state characterized by growth stagnation, which could arise from cells that are not necessarily hypometabolic or non-proliferative. This inconsistent terminology leads to confusion and imprecision that impedes progress in interdisciplinary research between ecologists and cancer biologists. In this paper, we draw parallels and contrasts between dormancy in cancer and other ecosystems in nature, and discuss the potential for studies in cancer to provide novel insights into the evolutionary ecology of dormancy.
A Field-Based Experiment on the Influence of Stand Density Reduction on Watershed Processes at the Caspar Creek Experimental Watersheds in Northern California
Authors: Dymond Salli F. , Richardson Paul W. , Webb Lynn A. , Keppeler Elizabeth T. , Arismendi Ivan , Bladon Kevin D. , Cafferata Peter H. , Dahlke Helen E. , Longstreth David L. , Brand Patrick K. , Ode Peter R. , Surfleet Christopher G. , Wagenbrenner Joseph W.
Published: July 2021

Forests are integral to sustaining clean water resources and healthy watersheds. It is critical, therefore, that managers fully understand the potential impacts of their actions on myriad ecosystem services provided by forested watersheds. While forest hydrologists have long used paired-watershed experiments to elucidate the complex interactions between forest management and watershed biogeochemical and ecohydrological processes, there is still much to learn from these studies. Here, we present an overview of the process for designing a paired-watershed study using a large harvesting experiment at the Caspar Creek Experimental Watersheds in coastal California as an example. We detail many considerations when designing such an experiment and highlight the wide range of scientific investigations that are part of the larger experiment. Paired watershed studies are a great example of community engaged scholarship and offer the unique opportunity to work with land managers to solve applied problems while simultaneously discovering new fundamental knowledge about how watersheds function.
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis
Authors: Nordin Jessika , Pettersson Mats , Rosenberg Lina Hultin , Mathioudaki Argyri , Karlsson Åsa , Murén Eva , Tandre Karolina , Rönnblom Lars , Kastbom Alf , Cedergren Jan , Eriksson Per , Söderkvist Peter , Lindblad-Toh Kerstin , Meadows Jennifer R. S.
Published: July 2021

Objectives

To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.

Methods

High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.

Results

Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.

Conclusion

Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.
SIRT4 and SIRT6 Serve as Novel Prognostic Biomarkers With Competitive Functions in Serous Ovarian Cancer
Authors: Wang Huihuan , Li Juan , Huang Rui , Fang Lei , Yu Shan
Published: July 2021

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that include seven members and are widely expressed in mammals. Accumulating evidence shows that sirtuins may have contradictory roles in various malignancies. They mainly participate in metabolic homeostasis, DNA damage repair, cell survival, and differentiation, as well as other cancer-related biological processes. To better understand their prognostic role and biological functions, we used comprehensive bioinformatic analyses to demonstrate the expression and mutation of sirtuin family member genes in ovarian cancer (OC), with a detailed focus on prognostic prediction, including the effectiveness of anti-OC drugs. Furthermore, the co-expression genes of SIRT4 and SIRT6 with contradictory survival prediction values in both overall and progression-free survival (PFS) times were further analyzed through Gene Ontology enrichment and Kyoto Encyclopedia annotation. Additionally, we performed and obtained the immunohistochemical staining patterns of these two biomarkers from the serous OC patient database and clinical patient samples to demonstrate their potential applicability in clinical pathology. According to our findings, SIRT4 and SIRT6 are novel prognostic biomarkers that may serve as contradictory competitors for OC cell survival. They are also sensitive biomarkers for the prediction of Avastin’s anticancer effect. While SIRT4 is related to the immune response during oocyte maturation, SIRT6 participates in immune-related disease pathways and mitochondrial metabolism-mediated DNA translation. These findings contribute to the novel hypothesis that SIRT4 and SIRT6 act as contradictory competitors in the regulation of OC behavior. Further studies are required to validate our hypothesis.
Identification of HCC-Related Genes Based on Differential Partial Correlation Network
Authors: Gao Yuyao , Chang Xiao , Xia Jie , Sun Shaoyan , Mu Zengchao , Liu Xiaoping
Published: July 2021

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death, but its pathogenesis is still unclear. As the disease is involved in multiple biological processes, systematic identification of disease genes and module biomarkers can provide a better understanding of disease mechanisms. In this study, we provided a network-based approach to integrate multi-omics data and discover disease-related genes. We applied our method to HCC data from The Cancer Genome Atlas (TCGA) database and obtained a functional module with 15 disease-related genes as network biomarkers. The results of classification and hierarchical clustering demonstrate that the identified functional module can effectively distinguish between the disease and the control group in both supervised and unsupervised methods. In brief, this computational method to identify potential functional disease modules could be useful to disease diagnosis and further mechanism study of complex diseases.
PacBio Iso-Seq Improves the Rainbow Trout Genome Annotation and Identifies Alternative Splicing Associated With Economically Important Phenotypes
Authors: Ali Ali , Thorgaard Gary H. , Salem Mohamed
Published: July 2021

Rainbow trout is an important model organism that has received concerted international efforts to study the transcriptome. For this purpose, short-read sequencing has been primarily used over the past decade. However, these sequences are too short of resolving the transcriptome complexity. This study reported a first full-length transcriptome assembly of the rainbow trout using single-molecule long-read isoform sequencing (Iso-Seq). Extensive computational approaches were used to refine and validate the reconstructed transcriptome. The study identified 10,640 high-confidence transcripts not previously annotated, in addition to 1,479 isoforms not mapped to the current Swanson reference genome. Most of the identified lncRNAs were non-coding variants of coding transcripts. The majority of genes had multiple transcript isoforms (average ∼3 isoforms/locus). Intron retention (IR) and exon skipping (ES) accounted for 56% of alternative splicing (AS) events. Iso-Seq improved the reference genome annotation, which allowed identification of characteristic AS associated with fish growth, muscle accretion, disease resistance, stress response, and fish migration. For instance, an ES inGVIN1gene existed in fish susceptible to bacterial cold-water disease (BCWD). Besides, under five stress conditions, there was a commonly regulated exon in prolyl 4-hydroxylase subunit alpha-2 (P4HA2) gene. The reconstructed gene models and their posttranscriptional processing in rainbow trout provide invaluable resources that could be further used for future genetics and genomics studies. Additionally, the study identified characteristic transcription events associated with economically important phenotypes, which could be applied in selective breeding.
Combined Analysis of MicroRNAs and Target Genes Revealed miR156-SPLs and miR172-AP2 Are Involved in a Delayed Flowering Phenomenon After Chromosome Doubling in Black Goji (Lycium ruthencium)
Authors: Rao Shupei , Li Yue , Chen Jinhuan
Published: July 2021

Polyploidy, which is widely distributed in angiosperms, presents extremely valuable commercial applications in plant growth and reproduction. The flower development process of higher plants is essential for genetic improvement. Nevertheless, the reproduction difference between polyploidy and the polyploid florescence regulatory network from the perspective of microRNA (miRNA) remains to be elucidated. In this study, the autotetraploid of Lycium ruthenicum showed late-flowering traits compared with the progenitor. Combining the association of miRNA and next-generation transcriptome technology, the late-flowering characteristics triggered by chromosome duplication may be caused by the age pathway involved in miR156-SPLs and miR172-AP2, which inhibits the messenger RNA (mRNA) transcripts of FT in the leaves. Subsequently, FT was transferred to the shoot apical meristem (SAM) to inhibit the expression of the flowering integration factor SOC1, which can eventually result in delayed flowering time. Our exploration of the flowering regulation network and the control of the flowering time are vital to the goji producing in the late frost area, which provides a new perspective for exploring the intrinsic molecular mechanism of polyploid and the reproductive development of flowering plants.
Barriers to Contraceptive Use Among Urban Adolescents and Youth in Conakry, in 2019, Guinea
Authors: Dioubaté Nafissatou , Manet Hawa , Bangoura Charlotte , Sidibé Sidikiba , Kouyaté Mariama , Kolie Delphin , Ayadi Alison M. El , Delamou Alexandre
Published: July 2021

Background: Despite efforts to improve access to family planning, contraceptive prevalence remains relatively low among adolescents and youth in Guinea. The objective of this study was to understand the barriers to the use of modern contraceptive methods among urban adolescents and youth (15–24 years) in Conakry, Guinea.

Methods: This was a qualitative study using an exploratory design. It was conducted in the capital city of Guinea, Conakry in 2019. Respondents included adolescents and youth aged 15–24 years, health care providers, and parents of adolescents and youth. In-depth individual interviews (IDIs) and focus group discussions (FGDs) were used to collect the data. Sixty IDIs and ten FGDs were planned in Conakry. These data were recorded and transcribed, when applicable, from the local languages into French in an anonymous manner. The data were analyzed using a mixed (inductive and deductive) thematic approach following the elements of the socio-ecological model.

Results: Overall, 56 IDIs and 10 FGDs were conducted with 136 participants and included in this analysis. Respondents were adolescents (16%), youth (30%), and key informants (54%) who were health care providers (public and private), decision-makers, parents of adolescents and youth, and neighbors. Among adolescent respondents, 75% were female, and of the youth, 61% were female. Our analysis indicates various and interrelated barriers that limit the access and use of contraceptives by adolescents and youth. These included the individual (fear of side effects, cost, and rumor-related misinformation), interpersonal or family (spouse perception and sexuality taboo and perception of sexual activity before marriage), sociocultural (religious prohibitions and ethnicity), and health care system (breakdown of contraceptive methods in public health facilities, perception of service delivery, provider attitudes, visiting hours, geographic proximity of services, and quality of training received by health care providers) barriers.

Conclusion: In our context, the use of modern contraceptive methods by adolescents and youth is influenced by an interaction of various barriers, including individual, interpersonal, sociocultural, and health care system factors. Strengthening contraceptive uptake interventions by involving different stakeholders, including adolescents, parents, religious, and community leaders, and improving the quality of sexual and reproductive health services would help in reducing barriers to contraceptive use among adolescents and youth.
Targeting Neoepitopes to Treat Solid Malignancies: Immunosurgery
Authors: de Sousa Eric , Lérias Joana R. , Beltran Antonio , Paraschoudi Georgia , Condeço Carolina , Kamiki Jéssica , António Patrícia Alexandra , Figueiredo Nuno , Carvalho Carlos , Castillo-Martin Mireia , Wang Zhe , Ligeiro Dário , Rao Martin , Maeurer Markus
Published: July 2021

Successful outcome of immune checkpoint blockade in patients with solid cancers is in part associated with a high tumor mutational burden (TMB) and the recognition of private neoantigens by T-cells. The quality and quantity of target recognition is determined by the repertoire of ‘neoepitope’-specific T-cell receptors (TCRs) in tumor-infiltrating lymphocytes (TIL), or peripheral T-cells. Interferon gamma (IFN-γ), produced by T-cells and other immune cells, is essential for controlling proliferation of transformed cells, induction of apoptosis and enhancing human leukocyte antigen (HLA) expression, thereby increasing immunogenicity of cancer cells. TCR αβ-dependent therapies should account for tumor heterogeneity and availability of the TCR repertoire capable of reacting to neoepitopes and functional HLA pathways. Immunogenic epitopes in the tumor-stroma may also be targeted to achieve tumor-containment by changing the immune-contexture in the tumor microenvironment (TME). Non protein-coding regions of the tumor-cell genome may also contain many aberrantly expressed, non-mutated tumor-associated antigens (TAAs) capable of eliciting productive anti-tumor immune responses. Whole-exome sequencing (WES) and/or RNA sequencing (RNA-Seq) of cancer tissue, combined with several layers of bioinformatic analysis is commonly used to predict possible neoepitopes present in clinical samples. At the ImmunoSurgery Unit of the Champalimaud Centre for the Unknown (CCU), a pipeline combining several tools is used for predicting private mutations from WES and RNA-Seq data followed by the construction of synthetic peptides tailored for immunological response assessment reflecting the patient’s tumor mutations, guided by MHC typing. Subsequent immunoassays allow the detection of differential IFN-γ production patterns associated with (intra-tumoral) spatiotemporal differences in TIL or peripheral T-cells versus TIL. These bioinformatics tools, in addition to histopathological assessment, immunological readouts from functional bioassays and deep T-cell ‘adaptome’ analyses, are expected to advance discovery and development of next-generation personalized precision medicine strategies to improve clinical outcomes in cancer in the context of i) anti-tumor vaccination strategies, ii) gauging mutation-reactive T-cell responses in biological therapies and iii) expansion of tumor-reactive T-cells for the cellular treatment of patients with cancer.
Risk of HBV Reactivation in Patients With Resolved HBV Infection Receiving Anti-CD19 Chimeric Antigen Receptor T Cell Therapy Without Antiviral Prophylaxis
Authors: Li Ping , Zhou Lili , Ye Shiguang , Zhang Wenjun , Wang Junbang , Tang Xiaochen , Liu Jie , Xu Yangyang , Qian Wenbin , Liang Aibin
Published: July 2021

Background

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for hematologic malignancies and is predicted to experience widespread use in the near future. However, not all risks associated with this novel approach are well defined. There are few data in the risk of HBV reactivation and limited experience in management in patients with resolved HBV infection who undergo CAR-T cell therapy.

Methods

We performed a post-hoc analysis of a prospective clinical trial of anti-CD19 CAR-T (CART19) cell therapy in patients with relapsed or refractory (r/r) B-cell malignancies, and aimed at exploring the actual risk of HBV reactivation in a cohort of patients with resolved HBV infection receiving CART19 cell therapy in the absence of antiviral prophylaxis.

Results

In this study, we investigated the risk of HBV reactivation after CART19 cell therapy in 30 consecutive patients with B-cell malignancies and resolved HBV infection without antiviral prophylaxis, in the Tongji Hospital of Tongji University. In this cohort, two patients developed HBV reactivation 2 months and 14 months after CAR-T cell infusion, respectively, the latter of whom developed severe hepatitis. These findings showed that the incidence of HBV reactivation was 6.67% (95% CI, 0.8–22.1). Specifically, none of the 21 patients who were HBsAb positive (0.0%) versus two of nine patients who were HBsAb negative (22.2%) experienced HBV reactivation (p = 0.03), suggesting HbsAb seronegativity at baseline is a possible risk factor in this population. Although use of tocilizumab or corticosteroids has been associated with increased risk of HBV reactivation, none of the patients who received these agents had HBV reactivation in this study.

Conclusion

This is the first and largest study to assess the true incidence of HBV reactivation in patients with resolved HBV infection receiving CART19 cell therapy without antiviral prophylaxis. This study highlights that this population are at risk of developing HBV reactivation and indicates that close monitoring of HBV DNA is required in the absence of antiviral prophylaxis. In addition, antiviral prophylaxis is recommended in the HBsAb-negative subpopulation.
Identifying Bacterial and Host Factors Involved in the Interaction of Mycobacterium bovis with the Bovine Innate Immune Cells
Authors: Blanco Federico Carlos , Gravisaco María José , Bigi María Mercedes , García Elizabeth Andrea , Marquez Cecilia , McNeil Mike , Jackson Mary , Bigi Fabiana
Published: July 2021

Bovine tuberculosis is an important animal and zoonotic disease caused by Mycobacterium bovis. The innate immune response is the first line of defense against pathogens and is also crucial for the development of an efficient adaptive immune response. In this study we used an in vitro co-culture model of antigen presenting cells (APC) and autologous lymphocytes derived from peripheral blood mononuclear cells to identify the cell populations and immune mediators that participate in the development of an efficient innate response capable of controlling the intracellular replication of M. bovis. After M. bovis infection, bovine immune cell cultures displayed upregulated levels of iNOS, IL-22 and IFN-γ and the induction of the innate immune response was dependent on the presence of differentiated APC. Among the analyzed M. bovis isolates, only a live virulent M. bovis isolate induced an efficient innate immune response, which was increased upon stimulation of cell co-cultures with the M. bovis culture supernatant. Moreover, we demonstrated that an allelic variation of the early secreted protein ESAT-6 (ESAT6 T63A) expressed in the virulent strain is involved in this increased innate immune response. These results highlight the relevance of the compounds secreted by live M. bovis as well as the variability among the assessed M. bovis strains to induce an efficient innate immune response.
Chronic Obstructive Pulmonary Disease Patients Have Increased Levels of Plasma Inflammatory Mediators Reported Upregulated in Severe COVID-19
Authors: Acevedo Nathalie , Escamilla-Gil Jose Miguel , Espinoza Héctor , Regino Ronald , Ramírez Jonathan , Florez de Arco Lucila , Dennis Rodolfo , Torres-Duque Carlos A. , Caraballo Luis
Published: July 2021

Background

Chronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.

Methods

Ninety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the “COVID-19 Drug and Gene Set Library” and with experimentally tested protein biomarkers of severe COVID-19.

Results

Forty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19.

Conclusions

COPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.
H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals
Authors: Piatek Paweł , Tarkowski Maciej , Namiecinska Magdalena , Riva Agostino , Wieczorek Marek , Michlewska Sylwia , Dulska Justyna , Domowicz Małgorzata , Kulińska-Michalska Małgorzata , Lewkowicz Natalia , Lewkowicz Przemysław
Published: July 2021

Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects. This dysregulation was accompanied by a deficient response of neutrophils to LPS, impaired cytokine/chemokine/growth factor synthesis, and increased apoptosis. Chromatin immunoprecipitation sequencing (ChIPseq) H3K4me3 histone analysis revealed that the most spectacular abnormalities were observed in the exons, introns, and promoter-TSS regions. Bioinformatic analysis of Gene Ontology, including biological processes, molecular function, and cellular components, demonstrated that the main changes were related to the genes responsible for cell activation, cytokine production, adhesive molecule expression, histone remodeling via upregulation of methyltransferase process, and downregulation of NF-κB transcription factor in canonical pathways. Abnormalities within H3K4me3 implicated LPS-mediated NF-κB canonical activation pathway that was a result of low amounts of κB DNA sites within histone H3K4me3, low NF-κB (p65 RelA) and TLR4 mRNA expression, and reduced free NF-κB (p65 RelA) accumulation in the nucleus. Genome-wide survey of H3K4me3 provided evidence that chromatin modifications lead to an impairment within the canonical NF-κB cell activation pathway causing the neutrophil dysfunction observed in HIV-infected individuals.