bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impacts and Decision of Community-friendly Corporate Social Responsibility Based on the Duopoly Model
Authors: CHEN Junlong , XU Bo , XIAO Yayun , SUN Chaoqun
Published: June 2021

There are multiple relationships between enterprises and communities, and the community-friendly corporate social responsibility (CSR) is unique. This paper constructs a duopoly model composed of two enterprises and a community, examines the impacts of community-friendly CSR on stakeholders, and analyzes the CSR decision. The results show that the level of community-friendly CSR, negative externalities, tax rate, and consumer sensitivity have multiple effects on profits, consumers, and social welfare, and the impacts of each factor are affected by the other factors; whether the competitors implement CSR affect the CSR decision of the other one; under certain circumstances, the implementation of CSR is conducive to achieving a win-win situation for the enterprises and the community.
The Socio-Cultural and Confessional Dimension of Delusional Ideas Content in the Spectrum of Non-Organic Psychotic Disorders
Authors: RADU Dania Andreea , SZALONTAY Andreea Silvana , CIOBANU Adela Magdalena , UNTU Ilinca , TEMELIE-OLINICI Doinita , BOLOS Alexandra , CHIRITA Roxana
Published: June 2021

In the last decade, population clinical trials support the disabling nature of most globally diagnosed psychotic disorders. As a defining integral part of this pathology, the delusional idea considered to be the result of the inaccurate and abnormal interpretation of an external reality is individualized, despite the contrary evidence. This ideation’s clinical expression variability is influenced by a heterogeneous spectrum of biological and psychosocial factors, predisposing and/or favouring. This review’s main objective is to identify a series of relational patterns of the content of delusional ideation with socio-familial and cultural/confessional parameters to obtain a holistic approach to patients. Careful decipherment of these conditions can be the basis for developing new interventions that are much more effective in establishing a long-term diagnostic and therapeutic strategy.
Florin Georgescu: A New Outlook on Romanian Capitalism
Authors: Stănescu Iulian
Published: June 2021

In 2021, the Romanian Sociological Association awarded economist Florin Georgescu its Award for Excellence. This essay covers the author’s magnum opus, titled Capital in Post-communist Romania, and focuses on the content most relevant to sociology. Unique in size and scope, the approximate 1,000 page three-volume book features three books in one: a 30-year economic history of Romania, a critical analysis of the way the Romanian capitalist economy developed in the second half of the 2010s, and a blueprint for structural reforms to foster development and reduce inequality. The essay includes a short author presentation and an overall review of the book’s contents, an appraisal of the work’s style and originality, and a review of the themes and subjects most salient for sociologists: capital ‒ labour relationship and the distribution and redistribution system, income and wealth inequality, precarious work, the transition and privatisation processes, structural problems of capitalism, and development policies.
Toward Smart Diagnostics in a Pandemic Scenario: COVID-19
Authors: Hosseinifard Mohammad , Naghdi Tina , Morales-Narváez Eden , Golmohammadi Hamed
Published: June 2021

The incredible spread rate of coronavirus disease 2019 (COVID-19) outbreak has shocked the world. More than ever before, this dramatic scenario proved the significance of diagnostics as a cornerstone to make life-saving decisions. In this context, novel diagnostics that generates smart data leading to superior strategies for treatment, control, surveillance, prediction, prevention, and management of pandemic diseases is vital. Herein, we discuss the characteristics that should be met by COVID-19 diagnostics to become smart diagnostics enabled by industry 4.0 especially Internet of Things (IoT). The challenges ahead and our recommendations for moving faster from pure diagnostics toward smart diagnostics of COVID-19 and other possible epidemic/pandemic diseases are also outlined. An IoT-Fog-Cloud model based on smartphones as IoT gateways for smart diagnostics with unified strategies for data collection/transmission/interpretation is also proposed to integrate new digital technologies into a single platform for smarter decisions. Last but not least, we believe that “smart diagnostics” is a perspective that should be realized sooner before we encounter a pandemic far worse than the present one.
20-Hydroxy-3-Oxolupan-28-Oic Acid, a Minor Component From Mahonia bealei (Fort.) Carr. Leaves Alleviates Lipopolysaccharide-Induced Inflammatory in Murine Macrophages
Authors: Yang Xiaojun , Zhou Jing , He Yang , Lv Lingyun , Cao Yufeng , Hu Weicheng
Published: June 2021

20-Hydroxyl-3-oxolupan-28-oic acid (HOA), a minor component from Mahonia bealei (Fort.) Carr. leaves, has been found to attenuate inflammatory responses. However, the underlying molecular mechanism is still unclear. In this study, we performed a comprehensive transcriptional study to investigate genetic changes. We used RNA sequencing technology to analyses the transcriptional changes in RAW 264.7 cells in a control group, lipopolysaccharide (LPS)-induced group, and HOA-treated group. We identified 1,313 and 388 differentially expressed genes (DEGs) in the control/LPS group and LPS/HOA group, respectively. Gene Ontology (GO) classification revealed that the DEGs were mainly enriched in a series of inflammatory and immune-related processes. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the DEGs were mainly enriched in inflammatory-related pathways such as the nuclear factor-kappa B (NF-κB) signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, mitogen-activated protein kinase (MAPK) pathway, and Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT) signaling pathway. The results of qPCR validation revealed that dynamic changes in immune-related mRNAs such as Saa3, Bcl2l1, Mapkapk2, Ccl9, Sdc4, Ddx3x, Socs3, Prdx5, Tlr4, Lif, IL15, Tnfaip3, Tet2, Tgf-β1, and Ccl20, which were significantly upregulated in the LPS group and downregulated in the HOA group. Taken together, these results suggest that HOA may be used as a source of anti-inflammatory agents as well as a dietary complement for health promotion.
Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression
Authors: Xu Bohan , Zhou Linbin , Chen Qishan , Zhang Jianing , Huang Lijuan , Wang Shasha , Ye Zhimin , Ren Xiangrong , Cai Yu , Jensen Lasse Dahl , Chen Weirong , Li Xuri , Ju Rong
Published: June 2021

Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression.
Anti-biofilm Approach in Infective Endocarditis Exposes New Treatment Strategies for Improved Outcome
Authors: Lerche Christian Johann , Schwartz Franziska , Theut Marie , Fosbøl Emil Loldrup , Iversen Kasper , Bundgaard Henning , Høiby Niels , Moser Claus
Published: June 2021

Infective endocarditis (IE) is a life-threatening infective disease with increasing incidence worldwide. From early on, in the antibiotic era, it was recognized that high-dose and long-term antibiotic therapy was correlated to improved outcome. In addition, for several of the common microbial IE etiologies, the use of combination antibiotic therapy further improves outcome. IE vegetations on affected heart valves from patients and experimental animal models resemble biofilm infections. Besides the recalcitrant nature of IE, the microorganisms often present in an aggregated form, and gradients of bacterial activity in the vegetations can be observed. Even after appropriate antibiotic therapy, such microbial formations can often be identified in surgically removed, infected heart valves. Therefore, persistent or recurrent cases of IE, after apparent initial infection control, can be related to biofilm formation in the heart valve vegetations. On this background, the present review will describe potentially novel non-antibiotic, antimicrobial approaches in IE, with special focus on anti-thrombotic strategies and hyperbaric oxygen therapy targeting the biofilm formation of the infected heart valves caused byStaphylococcus aureus. The format is translational from preclinical models to actual clinical treatment strategies.
Ligand–Receptor Interactions Elucidate Sex-Specific Pathways in the Trajectory From Primordial Germ Cells to Gonia During Human Development
Authors: Overeem Arend W. , Chang Yolanda W. , Spruit Jeroen , Roelse Celine M. , Chuva De Sousa Lopes Susana M.
Published: June 2021

The human germ cell lineage originates from primordial germ cells (PGCs), which are specified at approximately the third week of development. Our understanding of the signaling pathways that control this event has significantly increased in recent years and that has enabled the generation of PGC-like cells (PGCLCs) from pluripotent stem cells in vitro. However, the signaling pathways that drive the transition of PGCs into gonia (prospermatogonia in males or premeiotic oogonia in females) remain unclear, and we are presently unable to mimic this step in vitro in the absence of gonadal tissue. Therefore, we have analyzed single-cell transcriptomics data of human fetal gonads to map the molecular interactions during the sex-specific transition from PGCs to gonia. The CellPhoneDB algorithm was used to identify significant ligand–receptor interactions between germ cells and their sex-specific neighboring gonadal somatic cells, focusing on four major signaling pathways WNT, NOTCH, TGFβ/BMP, and receptor tyrosine kinases (RTK). Subsequently, the expression and intracellular localization of key effectors for these pathways were validated in human fetal gonads by immunostaining. This approach provided a systematic analysis of the signaling environment in developing human gonads and revealed sex-specific signaling pathways during human premeiotic germ cell development. This work serves as a foundation to understand the transition from PGCs to premeiotic oogonia or prospermatogonia and identifies sex-specific signaling pathways that are of interest in the step-by-step reconstitution of human gametogenesis in vitro.
Long Non-coding RNA MEG3 Promotes Pyroptosis in Testicular Ischemia-Reperfusion Injury by Targeting MiR-29a to Modulate PTEN Expression
Authors: Ning Jin-zhuo , He Kai-xiang , Cheng Fan , Li Wei , Yu Wei-min , Li Hao-yong , Rao Ting , Ruan Yuan
Published: June 2021

Increasing evidence shows that the abnormal long non-coding RNAs (lncRNAs) expression is closely related to ischemia-reperfusion injury (I/R) progression. Studies have previously described that lncRNA MEG3 regulates pyroptosis in various organs I/R. Nevertheless, the related mechanisms of MEG3 in testicular I/R has not been clarified. The aim of this research is to unravel underlying mechanisms of the regulation of pyroptosis mediated by MEG3 during testicular I/R. We have established a testicular torsion/detorsion (T/D) model and an oxygen-glucose deprivation/reperfusion (OGD/R)-treated spermatogenic cell model. Testicular ischemic injury was assessed by H&E staining. Western blotting, quantitative real-time PCR, MDA, and SOD tests and immunohistochemistry measured the expression of MEG3 and related proteins and the level of ROS production in testicular tissues. Quantitative real-time PCR and western blotting determined the relative expression of MEG3, miR-29a, and relevant proteins in GC-1. Cell viability and cytotoxicity were measured by CCK-8 and LDH assays. Secretion and expression levels of inflammatory proteins were determined by ELISA, immunofluorescence and western blotting. The interaction among MEG3, miR-29a, and PTEN was validated through a dual luciferase reporter assay and Ago2-RIP. In this research, we identified that MEG3 was upregulated in animal specimens and GC-1. In loss of function or gain of function assays, we verified that MEG3 could promote pyroptosis. Furthermore, we found that MEG3 negatively regulated miR-29a expression at the posttranscriptional level and promoted PTEN expression, and further promoted pyroptosis. Therefore, we explored the interaction among MEG3, miR-29a and PTEN and found that MEG3 directly targeted miR-29a, and miR-29a targeted PTEN. Overexpression of miR-29a effectively eliminated the upregulation of PTEN induced by MEG3, indicating that MEG3 regulates PTEN expression by targeting miR-29a. In summary, our research indicates that MEG3 contributes to pyroptosis by regulating miR-29a and PTEN during testicular I/R, indicating that MEG3 may be a potential therapeutic target in testicular torsion.
Antimicrobial Peptides and Proteins: From Nature’s Reservoir to the Laboratory and Beyond
Authors: Sarkar Tanumoy , Chetia Monikha , Chatterjee Sunanda
Published: June 2021

Rapid rise of antimicrobial resistance against conventional antimicrobials, resurgence of multidrug resistant microbes and the slowdown in the development of new classes of antimicrobials, necessitates the urgent development of alternate classes of therapeutic molecules. Antimicrobial peptides (AMPs) are small proteins present in different lifeforms in nature that provide defense against microbial infections. They have been effective components of the host defense system for a very long time. The fact that the development of resistance by the microbes against the AMPs is relatively slower or delayed compared to that against the conventional antibiotics, makes them prospective alternative therapeutics of the future. Several thousands of AMPs have been isolated from various natural sources like microorganisms, plants, insects, crustaceans, animals, humans, etc. to date. However, only a few of them have been translated commercially to the market so far. This is because of some inherent drawbacks of the naturally obtained AMPs like 1) short half-life owing to the susceptibility to protease degradation, 2) inactivity at physiological salt concentrations, 3) cytotoxicity to host cells, 4) lack of appropriate strategies for sustained and targeted delivery of the AMPs. This has led to a surge of interest in the development of synthetic AMPs which would retain or improve the antimicrobial potency along with circumventing the disadvantages of the natural analogs. The development of synthetic AMPs is inspired by natural designs and sequences and strengthened by the fusion with various synthetic elements. Generation of the synthetic designs are based on various strategies like sequence truncation, mutation, cyclization and introduction of unnatural amino acids and synthons. In this review, we have described some of the AMPs isolated from the vast repertoire of natural sources, and subsequently described the various synthetic designs that have been developed based on the templates of natural AMPs or fromde novodesign to make commercially viable therapeutics of the future. This review entails the journey of the AMPs from their natural sources to the laboratory.
SARS-CoV-2: Origin, Evolution, and Targeting Inhibition
Authors: Ning Shuo , Yu Beiming , Wang Yanfeng , Wang Feng
Published: June 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak in Wuhan city, China and quickly spread worldwide. Currently, there are no specific drugs or antibodies that claim to cure severe acute respiratory diseases. For SARS-CoV-2, the spike (S) protein recognizes and binds to the angiotensin converting enzyme 2 (ACE2) receptor, allowing viral RNA to enter the host cell. The main protease (Mpro) is involved in the proteolytic process for mature non-structural proteins, and RNA-dependent RNA polymerase (RdRp) is responsible for the viral genome replication and transcription processes. Owing to the pivotal physiological roles in viral invasion and replication, S protein, Mpro, RdRp are regarded as the main therapeutic targets for coronavirus disease 2019 (COVID-19). In this review, we carried out an evolutionary analysis of SARS-CoV-2 in comparison with other mammal-infecting coronaviruses that have sprung up in the past few decades and described the pathogenic mechanism of SARS-CoV-2. We displayed the structural details of S protein, Mpro, and RdRp, as well as their complex structures with different chemical inhibitors or antibodies. Structural comparisons showed that some neutralizing antibodies and small molecule inhibitors could inhibit S protein, Mpro, or RdRp. Moreover, we analyzed the structural differences between SARS-CoV-2 ancestral S protein and D614G mutant, which led to a second wave of infection during the recent pandemic. In this context, we outline the methods that might potentially help cure COVID-19 and provide a summary of effective chemical molecules and neutralizing antibodies.
Localized Provoked Vulvodynia-An Ignored Vulvar Pain Syndrome
Authors: Paavonen Jorma , Eschenbach David A.
Published: June 2021

Localized provoked vulvodynia (LPV) causes dyspareunia among reproductive aged women. We review the pathogenesis of LPV and suggest that LPV is an inflammatory pain syndrome of the vestibular mucosa triggered by microbial antigens in a susceptible host. Tissue inflammation and hyperinnervation are characteristic findings which explain symptoms and clinical signs. Education of health care providers of LPV is important since this condition is common, often unrecognized, and patients often become frustrated users of health care. Research is needed on the antigen triggers of the syndrome. Randomized clinical trials are needed to evaluate treatment modalities.
Bacteriophage Cocktails Protect Dairy Cows Against Mastitis Caused By Drug Resistant Escherichia coli Infection
Authors: Guo Mengting , Gao Ya , Xue Yibing , Liu Yuanping , Zeng Xiaoyan , Cheng Yuqiang , Ma Jingjiao , Wang Hengan , Sun Jianhe , Wang Zhaofei , Yan Yaxian
Published: June 2021

Mastitis caused by Escherichia coli (E. coli) remains a threat to dairy animals and impacts animal welfare and causes great economic loss. Furthermore, antibiotic resistance and the lagged development of novel antibacterial drugs greatly challenge the livestock industry. Phage therapy has regained attention. In this study, three lytic phages, termed vB_EcoM_SYGD1 (SYGD1), vB_EcoP_SYGE1 (SYGE1), and vB_EcoM_SYGMH1 (SYGMH1), were isolated from sewage of dairy farm. The three phages showed a broad host range and high bacteriolytic efficiency against E. coli from different sources. Genome sequence and transmission electron microscope analysis revealed that SYGD1 and SYGMH1 belong to the Myoviridae, and SYGE1 belong to the Autographiviridae of the order Caudovirales. All three phages remained stable under a wide range of temperatures or pH and were almost unaffected in chloroform. Specially, a mastitis infected cow model, which challenged by a drug resistant E. coli, was used to evaluate the efficacy of phages. The results showed that the cocktails consists of three phages significantly reduced the number of bacteria, somatic cells, and inflammatory factors, alleviated the symptoms of mastitis in cattle, and achieved the same effect as antibiotic treatment. Overall, our study demonstrated that phage cocktail may be a promising alternative therapy against mastitis caused by drug resistant E. coli.
Interpreting in Sexual and Reproductive Health Consults With Burma Born Refugees Post Settlement: Insights From an Australian Qualitative Study
Authors: Tuteja Amita , Riggs Elisha , Sanci Lena , Mascarenhas Lester , VanVliet Di , Sangster Katrina , McGuinness Kimberley , Temple-Smith Meredith
Published: June 2021

Interpreters work with health care professionals to overcome language challenges during sexual and reproductive (SRH) health discussions with people from refugee backgrounds. Disclosures of traumatic refugee journeys and sexual assault combined with refugees’ unfamiliarity with Western health concepts and service provision can increase the interpreting challenges. Published literature provides general guidance on working with interpreters in primary care but few studies focus on interpretation in refugee SRH consults. To address this, we explored the challenges faced by providers of refugee services (PRS) during interpreter mediated SRH consultations with Burma born refugees post settlement in Australia. We used qualitative methodology and interviewed 29 PRS involved with migrants from Burma including general practitioners, nurses, interpreters, bilingual social workers, and administrative staff. The interviews were audio-recorded, transcribed, and subjected to thematic analysis following independent coding by the members of the research team. Key themes were formulated after a consensus discussion. The theme of “interpretation related issues” was identified with six sub-themes including 1) privacy and confidentiality 2) influence of interpreter’s identity 3) gender matching of the interpreter 4) family member vs. professional interpreters 5) telephone vs. face-to-face interpreting 6) setting up the consultation room. When faced with these interpretation related challenges in providing SRH services to people from refugee backgrounds, health care providers combine best practice advice, experience-based knowledge and “mundane creativity” to adapt to the needs of the specific patients. The complexity of interpreted SRH consultations in refugee settings needs to be appreciated in making good judgments when choosing the best way to optimize communication. This paper identifies the critical elements which could be incorporated when making such a judgement. Future research should include the experiences of refugee patients to provide a more comprehensive perspective.
Alzheimer’s Dementia Recognition From Spontaneous Speech Using Disfluency and Interactional Features
Authors: Nasreen Shamila , Rohanian Morteza , Hough Julian , Purver Matthew
Published: June 2021

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder mainly characterized by memory loss with deficits in other cognitive domains, including language, visuospatial abilities, and changes in behavior. Detecting diagnostic biomarkers that are noninvasive and cost-effective is of great value not only for clinical assessments and diagnostics but also for research purposes. Several previous studies have investigated AD diagnosis via the acoustic, lexical, syntactic, and semantic aspects of speech and language. Other studies include approaches from conversation analysis that look at more interactional aspects, showing that disfluencies such as fillers and repairs, and purely nonverbal features such as inter-speaker silence, can be key features of AD conversations. These kinds of features, if useful for diagnosis, may have many advantages: They are simple to extract and relatively language-, topic-, and task-independent. This study aims to quantify the role and contribution of these features of interaction structure in predicting whether a dialogue participant has AD. We used a subset of the Carolinas Conversation Collection dataset of patients with AD at moderate stage within the age range 60–89 and similar-aged non-AD patients with other health conditions. Our feature analysis comprised two sets: disfluency features, including indicators such as self-repairs and fillers, and interactional features, including overlaps, turn-taking behavior, and distributions of different types of silence both within patient speech and between patient and interviewer speech. Statistical analysis showed significant differences between AD and non-AD groups for several disfluency features (edit terms, verbatim repeats, and substitutions) and interactional features (lapses, gaps, attributable silences, turn switches per minute, standardized phonation time, and turn length). For the classification of AD patient conversations vs. non-AD patient conversations, we achieved 83% accuracy with disfluency features, 83% accuracy with interactional features, and an overall accuracy of 90% when combining both feature sets using support vector machine classifiers. The discriminative power of these features, perhaps combined with more conventional linguistic features, therefore shows potential for integration into noninvasive clinical assessments for AD at advanced stages.
Non-invasive Imaging in the Evaluation of Cardiac Shunts for Interventional Closure
Authors: Pushparajah Kuberan
Published: June 2021

Multimodality imaging provides important information to guide patient selection and pre-procedural decision making for shunt lesions in CHD. While echocardiography, CT, and CMR are well-established, 3D printing and now virtual reality imaging are beginning to show promise.
Association of Total Bilirubin With All-Cause and Cardiovascular Mortality in the General Population
Authors: Chen Ziwei , He Jing , Chen Chu , Lu Qi
Published: June 2021

Objective: The study aims to investigate the association of total bilirubin with all-cause and cause-specific mortality in the general population.

Methods: A total of 37,234 adults from the United States National Health and Nutrition Examination Survey 1999–2014 were enrolled. Baseline levels of total bilirubin associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by quartile categories with Cox regression models.

Results: Higher levels of total bilirubin was positively associated with an increased risk of all-cause mortality [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.46–1.72; p < 0.001]. Compared with individuals with the lowest quartile of bilirubin, the multivariable adjusted hazard ratio for all-cause mortality was 1.25 (1.14–1.37) for individuals in the highest quartile. Restricted cubic splines indicated that the association was non-linear in cardiovascular mortality and cancer mortality while linear in all-cause mortality.

Conclusions: Total bilirubin was associated with all-cause and cause-specific mortality in the general population.
Long-Term Effect of a Vaccine Targeting Endothelin-1 Receptor Type A in Pulmonary Arterial Hypertension
Authors: Dai Yong , Qiu Zhihua , Ma Wenrui , Li Chang , Chen Xiao , Song Xiaoxiao , Bai Zeyang , Shi Dingyang , Zheng Jiayu , Pan Guangwei , Liao Yuhua , Liao Mengyang , Zhou Zihua
Published: June 2021

Background: Previously, we invented a therapeutic vaccine targeting the endothelin-A receptor (termed ETRQβ-002). ETRQβ-002 successfully prevented the remodeling of pulmonary arterioles (PAs) and right ventricle (RV) without significant immune-mediated damage in experimental pulmonary arterial hypertension (PAH) mice models.

Objective: Here, we aim to further evaluate the long-term effects of ETRQβ-002.

Methods: PAH mice model was induced by a combination of subcutaneous injection with Sugen5416 and chronic hypoxic conditions (10% O2). PAH mice were immunized with ETRQβ-002 at different time points, and the experiment lasted for 21 weeks. Hemodynamic, histological, and biochemical analyses were conducted to evaluate the long-term effects of ETRQβ-002.

Results: We demonstrated that the titer of the specific antibody against ETR-002 could be maintained chronically after periodic booster immunization in PAH mice. Long-term reduction of right ventricular systolic pressure and amelioration of PA remodeling by ETRQβ-002 were confirmed. Moreover, we found that ETRQβ-002 also exerted antiproliferation, anti-inflammation, and antifibrosis effects in PA remodeling. Besides, ETRQβ-002 durably limited pathological RV hypertrophy and fibrosis. Finally, no immune-mediated damage was observed in hepatic or renal function or by pathology in liver and kidney during the long-term administration of ETRQβ-002.

Conclusion: Our findings indicate that ETRQβ-002 provides long-term therapeutic effects in Sugen/hypoxia-induced PAH animals and offers a promising clinical prospect for PAH treatment.
Myocardial Work Assessment for the Prediction of Prognosis in Advanced Heart Failure
Authors: Hedwig Felix , Nemchyna Olena , Stein Julia , Knosalla Christoph , Merke Nicolas , Knebel Fabian , Hagendorff Andreas , Schoenrath Felix , Falk Volkmar , Knierim Jan
Published: June 2021

Objectives: The aim of this study was to investigate whether echocardiographic assessment of myocardial work is a predictor of outcome in advanced heart failure.

Background: Global work index (GWI) and global constructive work (GCW) are calculated by means of speckle tracking, blood pressure measurement, and a normalized reference curve. Their prognostic value in advanced heart failure is unknown.

Methods: Cardiopulmonary exercise testing and echocardiography with assessment of GWI and GCW was performed in patients with advanced heart failure caused by ischemic heart disease or dilated cardiomyopathy (n = 105). They were then followed up repeatedly. The combined endpoint was all-cause death, implantation of a left ventricular assist device, or heart transplantation.

Results: The median patient age was 54 years (interquartile range [IQR]: 48–59.9). The mean left ventricular ejection fraction was 27.8 ± 8.2%, the median NT-proBNP was 1,210 pg/ml (IQR: 435–3,696). The mean GWI was 603 ± 329 mmHg% and the mean GCW was 742 ± 363 mmHg%. The correlation between peak oxygen uptake and GWI as well as GCW was strongest in patients with ischemic cardiomyopathy (r = 0.56, p = 0.001 and r = 0.53, p = 0.001, respectively). The median follow-up was 16 months (IQR: 12–18.5). Thirty one patients met the combined endpoint: Four patients died, eight underwent transplantation, and 19 underwent implantation of a left ventricular assist device. In the multivariate Cox regression analysis, only NYHA class, NT-proBNP and GWI (hazard ratio [HR] for every 50 mmHg%: 0.85; 95% CI: 0.77–0.94; p = 0.002) as well as GCW (HR for every 50 mmHg%: 0.86; 95% CI: 0.79–0.94; p = 0.001) were identified as independent predictors of the endpoint. The cut-off value for predicting the outcome was 455 mmHg% for GWI (AUC: 0.80; p < 0.0001; sensitivity 77.4%; specificity 71.6%) and 530 mmHg% for GCW (AUC: 0.80; p < 0.0001; sensitivity 74.2%; specificity 78.4%).

Conclusions: GWI and GCW are powerful predictors of outcome in patients with advanced heart failure.
Travel Time Tomography to Delineate 3-D Regional Seismic Velocity Structure in the Banyumas Basin, Central Java, Indonesia, Using Dense Borehole Seismographic Stations
Authors: Hidayat Hidayat , Nugraha Andri Dian , Priyono Awali , Marjiyono Marjiyono , Setiawan Januar H. , Sahara David P. , Winardhi Sonny , Zulfakriza Zulfakriza , Rosalia Shindy , Lelono Eko B. , Permana Asep K. , Setiawan Ahmad
Published: June 2021

The Banyumas Basin is a tertiary sedimentary basin located in southern Central Java, Indonesia. Due to the presence of volcanic deposits, 2-D seismic reflection methods cannot provide a good estimation of the sediment thickness and the subsurface geology structure in this area. In this study, the passive seismic tomography (PST) method was applied to image the 3-D subsurface Vp, Vs, and Vp/Vs ratio. We used 70 seismograph borehole stations with a recording duration of 177 days. A total of 354 events with 9, 370 P and 9, 368 S phases were used as input for tomographic inversion. The checkshot data of a 4, 400-meter deep exploration well (Jati-1) located within the seismic network were used to constrain the shallow crustal layer of the initial 1-D velocity model. The model resolution of the tomographic inversions was assessed using the checkerboard resolution test (CRT), the diagonal resolution element (DRE), and the derivative weight sum (DWS). Using the obtained Vp, Vs, and Vp/Vs ratio, we were able to sharpen details of the geological structures within the basin from previous geological studies, and a fault could be well-imaged at a depth of 4 km. We interpreted this as the main dextral strike-slip fault that controls the pull apart process of the Banyumas Basin. The thickness of the sediment layers, as well as its layering, were also could be well determined. We found prominent features of the velocity contrast that aligned very well with the boundary between the Halang and Rambatan formations as observed in the Jati-1 well data. Furthermore, an anticline structure, which is a potential structural trap for the petroleum system in the Banyumas Basin, was also well imaged. This was made possible due to the dense borehole seismographic stations which were deployed in the study area.
Botryoidal and Spherulitic Aragonite in Carbonates Associated with Microbial Mats: Precipitation or Diagenetic Replacement Product?
Authors: Ge Yuzhu , Della Porta Giovanna , Pederson Chelsea L. , Lokier Stephen W. , Hoffmann René , Immenhauser Adrian
Published: June 2021

Similar carbonate fabrics may result from different pathways of precipitation and diagenetic replacement. Distinguishing the underlying mechanisms leading to a given carbonate fabric is relevant, both in terms of an environmental and diagenetic interpretation. Prominent among carbonate fabrics are aragonite botryoids and spherulites, typically interpreted as direct seawater precipitates and used as proxies for fluid properties and depositional environments. This study investigated μm to mm-scale Holocene botryoidal and spherulitic aragonite from marine and non-marine carbonate settings associated with microbial mats, and reports two distinct formation mechanisms: 1) early diagenetic replacement, and 2) primary precipitation via nanocrystal aggregation. In the intertidal microbial mats of Khawr Qantur (Abu Dhabi), botryoidal and spherulitic aragonite are replacement products of heavily micritized bioclasts. To form the botryoidal and spherulitic aragonite, skeletal rods and needles, resulting from disintegration of micritized bioclasts, recrystallize into nanocrystals during early marine diagenesis. These nanocrystals then grow into fibrous crystals, forming botryoidal and spherulitic aragonite. In the lacustrine microbial bioherms of the hypersaline Great Salt Lake (United States) and in the hydrothermal travertines of Bagni San Filippo (Italy), botryoidal and spherulitic aragonite evolve from nanocrystals via precipitation. The nanocrystals are closely associated with extracellular polymeric substances in microbial biofilms and aggregate to form fibrous crystals of botryoidal and spherulitic aragonite. The studied fabrics form a portion of the bulk sediment and show differences in terms of their formation processes and petrological features compared to the often larger (few mm to over 1 m) botryoidal and spherulitic aragonite described from open-marine reefal cavities. Features shown here may represent modern analogues for ancient examples of carbonate depositional environments associated with microbialites. The implication of this research is that botryoidal and spherulitic aragonite associated with microbial mats are relevant in paleoenvironmental interpretations, but must be combined with a detailed evaluation of their formation process. Care must be taken as the term “botryoidal and spherulitic aragonite” may in fact include, from the viewpoint of their nucleation and formation mechanism, similar fabrics originated from different pathways. At present, it seems unclear to which degree the μm to mm-scale botryoids and spherulites described here are comparable to their cm-to dm-size counterparts precipitated as cements in the open pore space of reefal environments. However, it is clear that the investigation of ancient botryoidal and spherulitic aragonite must consider the possibility of an early diagenetic replacement origin of these precipitates.
Prognostic Significance of Altered ATRX/DAXX Gene in Pancreatic Neuroendocrine Tumors: A Meta-Analysis
Authors: Wang Fei , Xu Xiaowu , Ye Zeng , Qin Yi , Yu Xianjun , Ji Shunrong
Published: June 2021

Background

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing recently has shown very frequent somatic mutations in the alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes in PanNETs. And the prognostic significance of altered ATRX/DAXX genes in PanNETs patients have been revealed in several reports. However, many of these include small sample size and hold controversial opinions. To increase statistical power, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of altered ATRX/DAXX genes mainly on overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) in PanNETs.

Methods

Eligible studies were identified and quality was assessed using multiple search strategies (last search May 2021). Data were collected from studies about prognostic significance of altered ATRX/DAXX in PanNETs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.

Results

Fourteen studies involving 2313 patients treated for PanNETs were included. After evaluating for publication bias, disease-free survival and relapse-free survival was significantly shortened in patients with altered ATRX/DAXX gene, with combined HR 5.05 (95% confidence interval (CI): 1.58-16.20, P = 0.01) and 3.21 (95% confidence interval (CI): 1.44-7.16, P < 0.01) respectively. However, the combined data showed there were no difference between patients with altered ATRX/DAXX gene or not in overall survival, with a combined HR 0.71 (95% confidence interval (CI): 0.44-1.15, P = 0.23). We also performed a subgroup analysis with metastatic patients in overall survival, showing a combined HR 0.22 (95% confidence interval (CI): 0.11-0.48, P = 0.96). The small number of studies and paucity of multivariate analyses are the limitations of our study.

Conclusions

This is the first rigorous pooled analysis assessing ATRX/DAXX mutation as prognostic biomarkers in PanNETs. Patients with altered ATRX/DAXX gene would have poor DFS according to the combined data. And altered ATRX/DAXX genes in metastatic patients showed a trend towards improved overall survival, although the difference did not reach statistical significance.
Evidence of Range Shifts in Riparian Plant Assemblages in Response to Multidecadal Streamflow Declines
Authors: White Helen A. , Scott John K. , Didham Raphael K.
Published: June 2021

Riparian corridors are thought to form hydrological refugia that may buffer species and communities against regional climate changes. In regions facing a warming and drying climate, however, the hydrological regime driving riparian communities is also under threat. We examined recruitment in response to streamflow declines for species inhabiting the riparian zone in southwest Western Australia, testing the extent to which the riparian system has buffered riparian communities from the drying climate. We stratified 49 vegetation transects across the >600 mm per annum regional rainfall gradient encompassed by the Warren River Catchment. Local hydrological conditions were estimated over two 10-year periods; 1980–1989, and 2001–2010, to quantify changes in the flood regime. Mixed effects models tested the relationship between rainfall and flooding on the relative frequency of immature to mature individuals of 17 species of trees and shrubs common to the riparian zones. At the low-rainfall extent of their geographic range, the relative frequency of immature riparian species decreased with declining flow, whereas at the high-rainfall extent of their geographic range the relative frequency of immature individuals increased with declining flow. These results suggest that the geographic ranges of riparian species may be contracting at the low-rainfall margin of their range, while at the high-rainfall margin of their geographic range, reduced flooding regimes appear to be opening up new habitat suitable for recruitment and narrowing the river corridor. No such patterns were observed in upland species, suggesting the river may be buffering upland species. We discuss these findings and their implications for ongoing management and species conservation in a region projected to face further, significant rainfall declines.
A Novel Immune-Related Prognostic Signature in Head and Neck Squamous Cell Carcinoma
Authors: Zhang Yi , Chen Ping , Zhou Qiang , Wang Hongyan , Hua Qingquan , Wang Jie , Zhong Hongliang
Published: June 2021

The immune response within the tumor microenvironment plays a key role in tumorigenesis and determines the clinical outcomes of head and neck squamous cell carcinoma (HNSCC). However, to date, very limited robust and reliable immunological biomarkers have been developed that are capable of estimating prognosis in HNSCC patients. In this study, we aimed to identify the effects of novel immune-related gene signatures (IRGs) that can predict HNSCC prognosis. Based on gene expression profiles and clinical data of HNSCC patient cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, a total of 439 highly variable expressed immune-related genes (including 239 upregulated and 200 downregulated genes) were identified by using differential gene expression analysis. Pathway enrichment analysis indicated that these immune-related differentially expressed genes were enriched in inflammatory functions. After process screening in the training TCGA cohort, six immune-related genes (PLAU,STC2,TNFRSF4,PDGFA,DKK1, andCHGB) were significantly associated with overall survival (OS) based on the LASSO Cox regression model. Integrating these genes with clinicopathological features, a multivariable model was built and suggested better performance in determining patients’ OS in the testing cohort, and the independent validation cohort. In conclusion, a well-established model encompassing both immune-related gene signatures and clinicopathological factors would serve as a promising tool for the prognostic prediction of HNSCC.
Comprehensive Analysis of lncRNA and miRNA Regulatory Network Reveals Potential Prognostic Non-coding RNA Involved in Breast Cancer Progression
Authors: Gao Sheng , Lu Xun , Ma Jingjing , Zhou Qian , Tang RanRan , Fu Ziyi , Wang Fengliang , Lv Mingming , Lu Cheng
Published: June 2021

Breast cancer is one of the most common malignant tumors in women and is the second leading cause of cancer deaths among women. The tumorigenesis and progression of breast cancer are not well understood. The existing researches have indicated that non-coding RNAs, which mainly include long non-coding RNA (lncRNA) and microRNA (miRNA), have gradually become important regulators of breast cancer. We aimed to screen the differential expression of miRNA and lncRNA in the different breast cancer stages and identify the key non-coding RNA using TCGA data. Based on series test of cluster (STC) analysis, bioinformatics analysis, and negatively correlated relationships, 122 lncRNAs, 67 miRNAs, and 119 mRNAs were selected to construct the regulatory network of lncRNA and miRNA. It was shown that the miR-93/20b/106a/106b family was at the center of the regulatory network. Furthermore, 6 miRNAs, 10 lncRNAs, and 15 mRNAs were significantly associated with the overall survival (OS, log-rank P < 0.05) of patients with breast cancer. Overexpressed miR-93 in MCF-7 breast cancer cells was associated with suppressed expression of multiple lncRNAs, and these downregulated lncRNAs (MESTIT1, LOC100128164, and DNMBP-AS1) were significantly associated with poor overall survival in breast cancer patients. Therefore, the miR-93/20b/106a/106b family at the core of the regulatory network discovered by our analysis above may be extremely important for the regulation of lncRNA expression and the progression of breast cancer. The identified key miRNA and lncRNA will enhance the understanding of molecular mechanisms of breast cancer progression. Targeting these key non-coding RNA may provide new therapeutic strategies for breast cancer treatment and may prevent the progression of breast cancer from an early stage to an advanced stage.
Insights Into Forensic Features and Genetic Structures of Guangdong Maoming Han Based on 27 Y-STRs
Authors: Fan Haoliang , Xie Qiqian , Li Yanning , Wang Lingxiang , Wen Shao-Qing , Qiu Pingming
Published: June 2021

Maoming is located in the southwest region of Guangdong Province and is the cradle of Gaoliang culture, which is the representative branch of Lingnan cultures. Historical records showed that the amalgamations between Gaoliang aborigines and distinct ethnic minorities had some influences on the shaping of Gaoliang culture, especially for the local Tai-kadai language-speaking Baiyue and Han Chinese from Central China. However, there is still no exact genetic evidence for the influences on the genetic pool of Maoming Han, and the genetic relationships between Maoming Han and other Chinese populations are still unclear. Hence, in order to get a better understanding of the paternal genetic structures and characterize the forensic features of 27 Y-chromosomal short tandem repeats (Y-STRs) in Han Chinese from Guangdong Maoming, we firstly applied the AmpFLSTR® Yfiler® Plus PCR Amplification Kit (Thermo Fisher Scientific, Waltham, MA, United States) to genotype the haplotypes in 431 Han males residing in Maoming. A total of 263 different alleles were determined across all 27 Y-STRs with the corresponding allelic frequencies from 0.0004 to 0.7401, and the range of genetic diversity (GD) was 0.4027 (DYS391) to 0.9596 (DYS385a/b). In the first batch of 27 Yfiler data in Maoming Han, 417 distinct haplotypes were discovered, and nine off-ladder alleles were identified at six Y-STRs; in addition, no copy number variant or null allele was detected. The overall haplotype diversity (HD) and discrimination capacity (DC) of 27 Yfiler were 0.9997 and 0.9675, respectively, which demonstrated that the 6-dye and 27-plex system has sufficient system effectiveness for forensic applications in Maoming Han. What is more, the phylogenetic analyses indicated that Maoming Han, which is a Southern Han Chinese population, has a close relationship with Meizhou Kejia, which uncovered that the role of the gene flows from surrounding Han populations in shaping the genetic pool of Maoming Han cannot be ignored. From the perspectives of genetics, linguistics, and geographies, the genetic structures of Han populations correspond to the patterns of the geographical-scale spatial distributions and the relationships of language families. Nevertheless, no exact genetic evidence supports the intimate relationships between Maoming Han and Tai-Kadai language-speaking populations and Han populations of Central Plains in the present study.