bluuebunny/crossref_metadata_2025 huggingface dataset:
The design of nonlinear damped building isolation systems by using mobility analysis
Authors: Zhu Yun-Peng , Lang Z. Q. , Fujita Kohei , Takewaki Izuru
Published: September 2022

Additional power law nonlinear damping has shown advantages in seismic isolation of buildings. The design of nonlinear damped building isolation systems can be conducted in the frequency domain based on the output frequency response function (OFRF) of the building’s frequency output responses. But this often requires many runs of simulations of nonlinear building systems, which will spend a long time when the finite element (FE) model or differential equation model of the building system is complex. In this study, the issue will be resolved by an integrated mobility analysis and equivalent linearization approach. In this approach, the complex linear building system without additional nonlinear damping is represented by several data-driven autoregressive with exogenous input (ARX) models. Mobilities of the building system can be evaluated from these ARX models, so that a mobility-based frequency domain representation of the linear building system can be achieved. After that, an equivalent linearization approach is applied to simulate the building system with additional nonlinear damping. Finally, the OFRF-based design can be conducted based on the proposed mobility analysis and equivalent linearization approach. A 4-degree of freedom (DoF) building system is discussed to demonstrate the advantages of the proposed method. The results indicate that the new approach can significantly increase the efficiency of the design and be effectively applied to the design of complex nonlinear building isolation systems.
A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells
Authors: Taiber Shahar , Gozlan Oren , Cohen Roie , Andrade Leonardo R. , Gregory Ellen F. , Starr Daniel A. , Moran Yehu , Hipp Rebecca , Kelley Matthew W. , Manor Uri , Sprinzak David , Avraham Karen B.
Published: September 2022

Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, Nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how Nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of Nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between Nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.
Serengeti’s futures: Exploring land use and land cover change scenarios to craft pathways for meeting conservation and development goals
Authors: Kariuki Rebecca W. , Capitani Claudia , Munishi Linus K. , Shoemaker Anna , Courtney Mustaphi Colin J. , William Njonga , Lane Paul J. , Marchant Rob
Published: September 2022

Rapid land use transformations and increased climatic uncertainties challenge potential sustainable development pathways for communities and wildlife in regions with strong economic reliance on natural resources. In response to the complex causes and consequences of land use change, participatory scenario development approaches have emerged as key tools for analyzing drivers of change to help chart the future of socio-ecological systems. We assess stakeholder perspectives of land use and land cover change (LULCC) and integrate co-produced scenarios of future land cover change with spatial modeling to evaluate how future LULCC in the wider Serengeti ecosystem might align or diverge with the United Nations’ Sustainable Development Goals and the African Union’s Agenda 2063. Across the wider Serengeti ecosystem, population growth, infrastructural development, agricultural economy, and political will in support of climate change management strategies were perceived to be the key drivers of future LULCC. Under eight scenarios, declines in forest area as a proportion of total land area ranged from 0.1% to 4% in 2030 and from 0.1% to 6% in 2063, with the preservation of forest cover linked to the level of protection provided. Futures with well-demarcated protected areas, sound land use plans, and stable governance were highly desired. In contrast, futures with severe climate change impacts and encroached and degazetted protected areas were considered undesirable. Insights gained from our study are important for guiding pathways toward achieving sustainability goals while recognizing societies’ relationship with nature. The results highlight the usefulness of multi-stakeholder engagement, perspective sharing, and consensus building toward shared socio-ecological goals.
The novel bio-SYNTAX scoring system for predicting the prognosis of patients undergoing percutaneous coronary intervention with left main coronary artery disease
Authors: Yoon Jae Yong , Lee Jang Hoon , Kim Hong Nyun , Kim Namkyun , Jang Se Yong , Bae Myung Hwan , Yang Dong Heon , Park Hun Sik , Cho Yongkeun
Published: September 2022

Background

Simple and effective risk models incorporating biomarkers associated with left main coronary artery (LMCA) stenosis are limited. This study aimed to validate the novel Bio-Clinical SYNTAX score (Bio-CSS) incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with LMCA stenosis.

Methods

Patients who underwent percutaneous coronary intervention (PCI) for LMCA stenosis using a drug-eluting stent (n = 275) were included in the study. We developed the Bio-CSS incorporating NT-proBNP and validated the ability of the Bio-CSS to predict major adverse cardiac events (MACEs) and compared its performance to that of the SYNTAX score (SS) and SS II. The MACEs were defined as death, non-fatal myocardial infarction (MI), and repeat revascularizations.

Results

The Bio-CSS (34.7 ± 18.3 vs. 51.9 ± 28.4, p < 0.001), as well as SS (23.6 ± 7.3 vs. 26.7 ± 8.1, p = 0.003) and SS II (29.4 ± 9.9 vs. 36.1 ± 12.8, p < 0.001), was significantly higher in patients with MACEs. In the Cox proportional hazards model, the log Bio-CSS (hazard ratio 8.31, 95% CI 1.84–37.55) was an independent prognostic factor for MACEs after adjusting for confounding variables. In the receiver operating characteristic curves, the area under the curve of the Bio-CSS was significantly higher compared to those of SS (0.608 vs. 0.706, p = 0.001) and SS II (0.655 vs. 0.706, p = 0.026). Patients were categorized into the three groups based on the tertiles of the Bio-CSS. Patients in the highest tertile of the Bio-CSS had significantly higher MACEs compared to those in the lower two tertiles (log-rank p < 0.001).

Conclusion

In patients who underwent PCI for LMCA stenosis, the novel Bio-CSS improved the discrimination accuracy of established combined scores, such as SS and SS II. The addition of NT-proBNP to the clinical and angiographic findings in the Bio-CSS could potentially provide useful long-term prognostic information in these patients.
Research on the propagation mechanism of hydraulic fractures in infill horizontal wells
Authors: Liu Erhu , Yao Tingwei , Qiao Lianlian , Li Jing , Wang Haiyang , Gao Qian
Published: September 2022

In recent years, infill horizontal well technology has been used to develop oil and gas in the remaining oil areas of unconventional low-permeability reservoirs. However, the initial fractures in parent wells will affect the hydraulic fractures formed by fracturing infilling horizontal wells. The interaction mechanisms between initial fractures and artificial fractures in infill horizontal wells are still unclear. Combined with the boundary element method and the maximum circumferential tensile stress criterion, a numerical model of hydraulic fracturing that can simulate the evolution of fracture trajectory and stress field was established. The analytical solution of the hydraulic fracture-induced stress field was used to verify the accuracy of the model. Using this model, propagation of hydraulic fractures in infill horizontal wells under different conditions was analyzed. Simulation results show that both the fracture spacing and well spacing have a significant impact on the propagation trajectory of hydraulic fractures in infill horizontal wells. The shorter the fracture spacing and well spacing is, the stronger the inter-fracture stress interference between the initial fractures and hydraulic fractures is. Reasonable fracture spacing and well spacing can enhance the induced stress field and form a complex fracture network in the reservoir. Too small well spacing may cause artificial fractures to communicate with initial fractures, thereby reducing hydraulic fracturing efficiency and limiting the stimulation volume of the reservoir.
Reimagining the broader impacts criterion in the NSF graduate research fellowship
Authors: Estien Cesar O. , Quintana Brandon , Olivares-Zambrano Daniel
Published: September 2022

For graduate students, securing prestigious fellowships provides incredible benefits such as increased job opportunities and likelihood of receiving awards. These benefits can be particularly life-changing for a graduate student who may come from a marginalized background. However, the inequity in fellowship distribution hinders the success of graduate students, especially those who are marginalized. The majority of the National Science Foundation’s Graduate Research Fellowship Program (GRFP) is white and attend top-ranked institutions. Within the GRFP, there is a clear disconnect between the grantee’s proposed broader impacts and follow-through. To value and support communities, and graduate students of color in the process, the GRFP must be reimagined. In this article, we provide a brief background on the relationship between STEM and marginalized communities, and how broader impacts currently function as a band-aid to the issues of justice, equity, diversity, and inclusion (JEDI) in STEM. We then conclude by providing recommendations to improve the broader impacts section and the awardee selection process.
A novel FGF23 mutation in hyperphosphatemic familial tumoral calcinosis and its deleterious effect on protein O-glycosylation
Authors: Zuo Qingyao , Yang Weili , Liu Baoyue , Yan Dong , Wang Zhixin , Wang Hong , Deng Wei , Cao Xi , Yang Jinkui
Published: September 2022

Background

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disease characterized by hyperphosphatemia and ectopic calcification, predominantly at periarticular locations. This study was performed to characterize the clinical profile of tumoral calcinosis and to identify gene mutations associated with HFTC and elucidated its pathogenic role.

Methods

The three subjects (two male and one female) were aged 30, 25 and 15 years, respectively. The clinical features, histopathological findings, and outcomes of three subjects with HFTC were retrospectively reviewed. The three subjects were analyzed for FGF23, GALNT3 and KL mutations. Function of mutant gene was analyzed by western blotting and wheat germ agglutinin affinity chromatography.

Results

All subjects had hyperphosphatemia and elevated calcium-phosphorus product. Calcinosis positions included the left shoulder, left index finger, and right hip. Bone and joint damage were present in two cases and multiple foci influenced body growth in one case. The histopathological features were firm, rubbery masses comprising multiple nodules of calcified material bordered by the proliferation of mononuclear or multinuclear macrophages, osteoclastic-like giant cells, fibroblasts, and chronic inflammatory cells. The novel mutation c.484A>G (p.N162D) in exon 3 of FGF23 was identified in one subject and his family members. Measurement of circulating FGF23 in the subject confirmed low intact FGF23 and increased C-terminal fragment. In vitro experiments showed that the mutant FGF23 proteins had defective O-glycosylation and impaired protein proteolysis protection.

Conclusion

We identified a novel FGF23 missense mutation, and confirmed its damaging role in FGF23 protein O-glycosylation. Our findings expand the current spectrum of FGF23 variations that influence phosphorus metabolism.
New insights into thyroid dysfunction in patients with inactivating parathyroid hormone/parathyroid hormone-related protein signalling disorder (the hormonal and ultrasound aspects): One-centre preliminary results
Authors: Januś Dominika , Roztoczyńska Dorota , Janeczko Magdalena , Starzyk Jerzy B.
Published: September 2022

Objective

This study aimed to present the spectrum of thyroid dysfunction, including hormonal and ultrasound aspects, in a cohort of paediatric and adult patients diagnosed with inactivating parathyroid hormone (PTH)/PTH-related protein signalling disorders 2 and 3 (iPPSD).

Methods

The medical records of 31 patients from 14 families diagnosed with iPPSD between 1980 and 2021 in a single tertiary unit were retrospectively analysed. Biochemical, hormonal, molecular, and ultrasonographic parameters were assessed.

Results

In total, 28 patients from 13 families were diagnosed with iPPSD2 (previously pseudohypoparathyroidism [PHP], PHP1A, and pseudo-PHP) at a mean age of 12.2 years (ranging from infancy to 48 years), and three patients from one family were diagnosed with iPPSD3 (PHP1B). Thyroid dysfunction was diagnosed in 21 of the 28 (75%) patients with iPPSD2. Neonatal screening detected congenital hypothyroidism (CH) in 4 of the 20 (20%) newborns. The spectrum of thyroid dysfunction included: CH, 3/21 (14.2%); CH and autoimmune thyroiditis with nodular goitre, 1/21 (4.8%); subclinical hypothyroidism, 10/21 (47.6%); subclinical hypothyroidism and nodular goitre, 1/21 (4.8%); primary hypothyroidism, 4/21 (19%); and autoimmune thyroiditis (Hashimoto and Graves’ disease), 2/21 (9.6%). Thyroid function was normal in 7 of the 28 (25%) patients with iPPSD2 and in all patients with iPPSD3. Ultrasound evaluation of the thyroid gland revealed markedly inhomogeneous echogenicity and structure in all patients with thyroid dysfunction. Goitre was found in three patients.

Conclusion

The spectrum of thyroid dysfunction in iPPSD ranges from CH to autoimmune thyroiditis and nodular goitre. Ultrasonography of the thyroid gland may reveal an abnormal thyroid parenchyma.
Outcomes of hyperlactatemia on admission in critically ill patients with acute myocardial infarction: A retrospective study from MIMIC-IV
Authors: Lu Ting , Tan Liao , Xu Kai , Liu Jia , Liu Chong , Zhang Guogang , Shi Ruizheng , Huang Zheng
Published: September 2022

Background

It has not been verified whether there is a correlation between admission hyperlactatemia and outcomes in critically ill patients with acute myocardial infarction (AMI), especially in large data studies, which we aimed to do in this study.

Methods

For this retrospective study, we extracted analysis data from a famous online intensive care unit database, the Medical Information Mart for Intensive Care (MIMIC)-IV. Included patients were divided into four groups according to the serum lactate level on admission. Hospital mortality and mortality over time were the main outcomes. To explore the relationship between admission hyperlactatemia and outcomes in critically ill patients with AMI, logistic regression, Cox regression, Kaplan-Meier curves, and subgroup analyses were used.

Results

2171 patients matching the selection criteria were enrolled in this study. After adjusting for potential confounding factors, hyperlactatemia on admission contributed to increased short-term mortality in critically ill patients with AMI. The adjusted odds ratio for hospital mortality were 1.62, 3.46 and 5.28 in the mild, moderate, and severe hyperlactatemia groups (95% CI: 1.20-2.18, 2.15-5.58, and 2.20-12.70, respectively). The adjusted hazard ratio for 7-day and 30-day mortality were 1.99 and 1.35 (95% CI: 1.45-2.73 and 1.09-1.67) in the mild hyperlactatemia group, 3.33 and 2.31 (95% CI: 2.22-4.99 and 1.72-3.10) in the moderate hyperlactatemia group, 4.81 and 2.91 (95% CI: 2.86-8.08 and 1.88-4.50) in the severe hyperlactatemia group. The adjusted hazard ratio for 1-year and 5-year mortality were 2.03 and 1.93 (95% CI: 1.58-2.62 and 1.52-2.47) in the moderate hyperlactatemia group, 1.92 and 1.74 (95% CI: 1.28-2.89 and 1.17-2.59) in the severe hyperlactatemia group. Subgroup analyses indicated that the positive correlation between serum lactate level on admission and short-term mortality of critically ill patients with AMI was similar in the subgroups of cardiogenic shock and acute heart failure (P for interaction > 0.05).

Conclusion

Hyperlactatemia, especially moderate and severe hyperlactatemia, on admission is closely related to higher short-term mortality incidence in critically ill patients with AMI. The relationship between serum lactate level on admission and short-term mortality of critical AMI patients is stable in subgroups of cardiogenic shock and acute heart failure.
Construction of China’s automobile financial market network and its sustainability evaluation
Authors: Liang Hongzhen , Yao Hongxing
Published: September 2022

“Made in China” has spread all over the world, and China has the status of “world factory”. However, the weak ability of independent innovation has affected the sustainable development of China’s manufacturing industry. The industrial revolution with digital and intelligent manufacturing as the core is coming. In the future, our development is not fast, and the key is how to be sustainable and healthy. The development of zero carbon vehicles such as intelligent transportation and electric vehicles is one of the highlands of technological competition in the transportation field, and it is also the core measure to achieve carbon peak and carbon neutralization. Identifying important firms in the automobile industry has always been a topical issue. This study used the transaction data of listed companies in China’s automobile manufacturing industry to build a complex network based on the quantitative data of enterprise development status using network modeling and the multi-attribute decision evaluation method. The relationship between the network structure of the financial market and the multi-index sustainability evaluation of enterprises were also studied. By extracting the financial information of environmental protection investment from the social responsibility reports of listed companies and analyzing the current status of target investment in the automobile manufacturing industry, the research shows that the current environmental protection investment in the automobile manufacturing industry is not strong and the government needs to increase supervision. The finding reveals three dynamic relationships for practical impact. The empirical result verifies that our method is effective and reliable. This approach can effectively overcome the effect of subjective factors on evaluation and provide sustainable evaluation strategy suggestions for investors in the automobile manufacturing industry.
Pumped storage power station using abandoned mine in the Yellow River basin: A feasibility analysis under the perspective of carbon neutrality
Authors: Xi Furui , Yan Ruiwen , Shi Jusong , Zhang Jinde , Wang Runping
Published: September 2022

Greenhouse gas emissions, mainly CO2, lead to global climate change, and the resulting ecological environment problems bring severe challenges to human survival and development. As the world’s largest developing country and carbon emitter, China is facing the dual pressure of socio-economic development and carbon emission reduction. In order to cope with global climate change and achieve the goal of carbon neutrality and carbon peak as soon as possible, China needs to accelerate the optimization of energy structure, gradually increase the proportion of renewable energy utilization, and accelerate the solution of the bottleneck problem of renewable energy storage. As an energy basin, the Yellow River basin is a key demonstration area to promote energy system reform in China. There are a large number of abandoned mines in the Yellow River basin, which provide a new idea to build pumped storage power stations using abandoned mines (PSPSuM) for renewable energy storage. From the perspective of multidisciplinary integration, this study deeply discusses the relevant evaluation principles and technical key points of constructing PSPSuM in the region, and preliminarily carries out the feasibility assessment. The results show that 91 PSPSuM can be built in the Yellow River basin, with a total installed capacity of 15,830 MW, comprehensively considering the aspects of spatial size, spatial structure and space stability.
Alcohol consumption and colorectal cancer risk: A mendelian randomization study
Authors: Li Yuwei , Ye Ding , Zhou Wenkai , Liu Bin , Mao Yingying , Sun Xiaohui
Published: September 2022

Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis.

Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption.

Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05–1.12, p = 1.51 × 10–5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27–1.52, p = 5.29 × 10–13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99–1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98–1.05, p = 0.545 by IVW).

Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.
Cuproptosis-related lncRNAs predict the clinical outcome and immune characteristics of hepatocellular carcinoma
Authors: Zhu Hongfei , Mao Feifei , Wang Kang , Feng Jinkai , Cheng Shuqun
Published: September 2022

Cuproptosis, as a novel copper-dependent and non-apoptotic form of cell death, is induced by aggregation of lipoylated mitochondrial proteins and the instability of Fe-S cluster proteins. However, the role of cuproptosis-related long noncoding RNAs (CRLncRNAs) in hepatocellular carcinoma (HCC) has not been clearly elucidated. In this study, we identified and characterized cuproptosis-related lncRNAs in HCC. 343 HCC cases from The Cancer Genome Atlas (TCGA) with gene transcriptome data and clinical data were obtained for analysis after the screening. Univariate and multivariate Cox proportional hazards analyses were performed to establish a prognostic cuproptosis-related lncRNA signature (CRlncSig). We established a prognosis-related model consisting of nine cuproptosis-related lncRNAs: GSEC, AL158166.1, AC005479.2, AL365361.1, AC026412.3, AL031985.3, LINC00426, AC009974.2, AC245060.7, which was validated in the internal cohort. High-risk group stratified by the CRlncSig was significantly related to poor prognosis (p < 0.001). The area under the receiver operating characteristic curve (AUC) of 1 year, 3 years, and 5 years of survival were 0.813, 0.789, and 0.752, respectively. Furthermore, a prognostic nomogram including CRlncSig with clinicopathologic factors was built with favorable predictive power. In addition, GO and KEGG enrichment analysis suggested that CRlncSig was involved in many carcinogenesis and immune-related pathways. Additionally, we found that tumor microenvironment, immune infiltration, immune function, and drug response were significantly different between the high-risk and low-risk groups based on the risk model. These results highlight the value of cuproptosis-related lncRNAs on prognosis for HCC patients and provide insight into molecular and immune features underlying cuproptosis-related lncRNAs, which might play an important role in patient management and immunotherapy.
MTHFR C677T polymorphism and cerebrovascular lesions in elderly patients with CSVD: A correlation analysis
Authors: Li Zhuoran , Wu Xiaoyan , Huang Haowei , Xu Fan , Liang Guangtie , Lin Chuying , Qin Qinbao , Lei Xiuxia , Zeng Xuwen , Jiang Xinqing , Wei Xinhua
Published: September 2022

Plasma homocysteine (Hcy) has been identified as a potential risk factor for cerebral small vessel disease. Cerebral small vessel disease (CSVD) leads to cognitive impairment, depression, and other symptoms and is a common disease in middle-aged and elderly people. To investigate the relationship between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and CSVD in elderly patients, plasma levels of homocysteine (Hcy) and MTHFR genotyping were assessed. MRI and MRA were performed at the same time to analyze the relationship between different genotypes and cerebrovascular lesions. We showed that Hcy plasma levels in the TT group were significantly higher than those in the CC and CT groups. Moreover, we observed that the severity of white matter lesions was associated with women and positively correlated with age, previous coronary heart disease, luminal infarction, and MTHFR polymorphism. The multivariate logistic regression analysis showed that age, TT genotype, and lacunar infarction were independent risk factors for white matter hyperintensity (WMH). Importantly, we showed that there was a significant correlation between Hcy plasma levels and MTHFR gene polymorphism, with the TT genotype constituting an independent risk factor for WMH. Therefore, we recommended early detection of MTHFR gene polymorphisms with concomitant early intervention concerning risk factors to delay the occurrence of cognitive impairment in CSVD elderly patients.
miR-1306 induces cell apoptosis by targeting BMPR1B gene in the ovine granulosa cells
Authors: Abdurahman Anwar , Aierken Wusimanjiang , Zhang Fei , Obulkasim Rahmantay , Aniwashi Jueken , Sulayman Ablat
Published: September 2022

Bone morphogenetic protein receptor type-1B (BMPR1B) is one of the major gene for sheep prolificacy. However, few studies investigated its regulatory region. In this study, we reported that miR-1306 is a direct inhibitor of BMPR1B gene in the ovine granulosa cells (ovine GCs). We detected a miRNA response element of miR-1306 in the 3’ untranslated region of the ovine BMPR1B gene. Luciferase assay showed that the ovine BMPR1B gene is a direct target of miR-1306. qPCR and western blotting revealed that miR-1306 reduces the expression of BMPR1B mRNA and protein in the ovine granulosa cells. Furthermore, miR-1306 promoted cell apoptosis by suppressing BMPR1B expression in the ovine granulosa cells. Overall, our results suggest that miR-1306 is an epigenetic regulator of BMPR1B, and may serve as a potential target to improve the fecundity of sheep.
Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics
Authors: Bizjak Daniel Alexander , Stangl Manfred , Börner Nikolaus , Bösch Florian , Durner Joachim , Drunin Gergana , Buhl Jasmine-Leonike , Abendroth Dietmar
Published: September 2022

Introduction

In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples.

Material and methods

The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels.

Results

Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range.

Conclusion

Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.
Membrane attack complexes, endothelial cell activation, and direct allorecognition
Authors: Song Guiyu , Wang Shaoxun , Barkestani Mahsa Nouri , Mullan Clancy , Fan Matthew , Jiang Bo , Jiang Quan , Li Xue , Jane-wit Dan
Published: September 2022

Endothelial cells (ECs) form a critical immune interface regulating both the activation and trafficking of alloreactive T cells. In the setting of solid organ transplantation, donor-derived ECs represent sites where alloreactive T cells encounter major and minor tissue-derived alloantigens. During this initial encounter, ECs may formatively modulate effector responses of these T cells through expression of inflammatory mediators. Direct allorecognition is a process whereby recipient T cells recognize alloantigen in the context of donor EC-derived HLA molecules. Direct alloresponses are strongly modulated by human ECs and are galvanized by EC-derived inflammatory mediators.

Complement are immune proteins that mark damaged or foreign surfaces for immune cell activation. Following labeling by natural IgM during ischemia reperfusion injury (IRI) or IgG during antibody-mediated rejection (ABMR), the complement cascade is terminally activated in the vicinity of donor-derived ECs to locally generate the solid-phase inflammatory mediator, the membrane attack complex (MAC). Via upregulation of leukocyte adhesion molecules, costimulatory molecules, and cytokine trans-presentation, MAC strengthen EC:T cell direct alloresponses and qualitatively shape the alloimmune T cell response. These processes together promote T cell-mediated inflammation during solid organ transplant rejection.

In this review we describe molecular pathways downstream of IgM- and IgG-mediated MAC assembly on ECs in the setting of IRI and ABMR of tissue allografts, respectively. We describe work demonstrating that MAC deposition on ECs generates ‘signaling endosomes’ that sequester and post-translationally enhance the stability of inflammatory signaling molecules to promote EC activation, a process potentiating EC-mediated direct allorecognition. Additionally, with consideration to first-in-human xenotransplantation procedures, we describe clinical therapeutics based on inhibition of the complement pathway. The complement cascade critically mediates EC activation and improved understanding of relevant effector pathways will uncover druggable targets to obviate dysregulated alloimmune T cell infiltration into tissue allografts.
Long Intergenic Noncoding RNA MIAT as a Regulator of Human Th17 Cell Differentiation
Authors: Khan Mohd Moin , Khan Meraj Hasan , Kalim Ubaid Ullah , Khan Sofia , Junttila Sini , Paulin Niklas , Kong Lingjia , Rasool Omid , Elo Laura L. , Lahesmaa Riitta
Published: September 2022

T helper 17 (Th17) cells protect against fungal and bacterial infections and are implicated in autoimmunity. Several long intergenic noncoding RNAs (lincRNA) are induced during Th17 differentiation, however, their contribution to Th17 differentiation is poorly understood. We aimed to characterize the function of the lincRNA Myocardial Infarction Associated Transcript (MIAT) during early human Th17 cell differentiation. We found MIAT to be upregulated early after induction of human Th17 cell differentiation along with an increase in the chromatin accessibility at the gene locus. STAT3, a key regulator of Th17 differentiation, directly bound to the MIAT promoter and induced its expression during the early stages of Th17 cell differentiation. MIAT resides in the nucleus and regulates the expression of several key Th17 genes, including IL17A, IL17F, CCR6 and CXCL13, possibly by altering the chromatin accessibility of key loci, including IL17A locus. Further, MIAT regulates the expression of protein kinase C alpha (PKCα), an upstream regulator of IL17A. A reanalysis of published single-cell RNA-seq data showed that MIAT was expressed in T cells from the synovium of RA patients. Our results demonstrate that MIAT contributes to human Th17 differentiation by upregulating several genes implicated in Th17 differentiation. High MIAT expression in T cells of RA patient synovia suggests a possible role of MIAT in Th17 mediated autoimmune pathologies.
Unique profile of predominant CCR5-tropic in CRF07_BC HIV-1 infections and discovery of an unusual CXCR4-tropic strain
Authors: Hu Xiaoyan , Feng Yi , Li Kang , Yu Yueyang , Rashid Abdur , Xing Hui , Ruan Yuhua , Lu Lingling , Wei Min , Shao Yiming
Published: September 2022

CRF07_BC is one of the most prevalent HIV-1 strains in China, which contributes over one-third of the virus transmissions in the country. In general, CRF07_BC is associated with slower disease progression, while the underlying mechanisms remain unclear. Our study focused on envelope proteins (Env) and its V3 loop which determine viral binding to co-receptors during infection of cells. We studied a large dataset of 3,937 env sequences in China and found that CRF07_BC had a unique profile of predominantly single CCR5 tropism compared with CCR5 and CXCR4 dual tropisms in other HIV-1 subtypes. The percentages of the CXCR4-tropic virus in B (3.7%) and CRF01_AE (10.4%) infection are much higher than that of CRF07_BC (0.1%), which is supported by median false-positive rates (FPRs) of 69.8%, 25.5%, and 13.4% for CRF07_BC, B, and CRF01_AE respectively, with a cutoff FPR for CXCR4-tropic at 2%. In this study, we identified the first pure CXCR4-tropic virus from one CRF07_BC-infected patient with an extremely low CD4+T cell count (7 cells/mm3). Structural analysis found that the V3 region of this virus has the characteristic 7T and 25R and a substitution of conserved “GPGQ” crown motif for “GPGH”. This study provided compelling evidence that CRF07_BC has the ability to evolve into CXCR4 strains. Our study also lay down the groundwork for studies on tropism switch, which were commonly done for other HIV-1 subtypes, for the long-delayed CRF07_BC.
Immunogenicity of two COVID-19 vaccines used in India: An observational cohort study in health care workers from a tertiary care hospital
Authors: Arankalle Vidya , Kulkarni-Munje Archana , Kulkarni Ruta , Palkar Sonali , Patil Rahul , Oswal Jitendra , Lalwani Sanjay , Mishra Akhilesh Chandra
Published: September 2022

COVID-19 pandemic witnessed rapid development and use of several vaccines. In India, a country-wide immunization was initiated in January 2021. COVISHIELD, the chimpanzee adenoviral-vectored vaccine with full-length SARS-COV-2 spike insert and COVAXIN, the whole virus-inactivated vaccines were used. To assess and compare immune response of health-care-workers to COVISHIELD (n=187) and COVAXIN (n=21), blood samples were collected pre-vaccination, 1month post-1/post-2 doses and 6months post-dose-2 and tested for IgG-anti-SARS-CoV-2 (ELISA) and neutralizing (Nab,PRNT50) antibodies. Spike-protein-specific T cells were quantitated by IFN-γ-ELISPOT. In pre-vaccination-antibody-negative COVISHIELD recipients (pre-negatives, n=120), %Nab seroconversion (median, IQR Nab titers) increased from 55.1% (16, 2.5-36.3) post-dose-1 to 95.6% (64.5, 4.5-154.2, p<0.001) post-dose-2 that were independent of age/gender/BMI. Nab response was higher among pre-positives with hybrid immunity at all-time points (p<0.01-0.0001) and independent of age/gender/BMI/Comorbidities. Post-dose-2-seroconversion (50%, p<0.001) and Nab titers (6.75, 2.5-24.8, p<0.001) in COVAXIN-recipients were lower than COVISHIELD. COVAXIN elicited a superior IFN-γ-T cell response as measured by ELISPOT (100%; 1226, 811-1532 spot forming units, SFU/million PBMCs v/s 57.8%; 21.7,1.6-169.2; p<0.001). At 6months, 28.3% (15/53) COVISHIELD and 3/3COVAXIN recipients were Nab-negative. T cell response remained unchanged. During immunization, COVID-19 cases were detected among COVISHIELD (n=4) and COVAXIN (n=2) recipients. At 6months, 9cases were recorded in COVISHIELD-recipients. This first-time, systematic, real-world assessment and long-term follow up revealed generation of higher neutralizing antibody titers by COVISHIELD and stronger T-cell response by COVAXIN. Diminished Nab titers at 6months emphasize early booster. Immunogenicity/efficacy of vaccines will change with the progression of the pandemic needing careful evaluations in the field-settings.
Identification of immune cell infiltration and diagnostic biomarkers in unstable atherosclerotic plaques by integrated bioinformatics analysis and machine learning
Authors: Wang Jing , Kang Zijian , Liu Yandong , Li Zifu , Liu Yang , Liu Jianmin
Published: September 2022

Objective

The decreased stability of atherosclerotic plaques increases the risk of ischemic stroke. However, the specific characteristics of dysregulated immune cells and effective diagnostic biomarkers associated with stability in atherosclerotic plaques are poorly characterized. This research aims to investigate the role of immune cells and explore diagnostic biomarkers in the formation of unstable plaques for the sake of gaining new insights into the underlying molecular mechanisms and providing new perspectives for disease detection and therapy.

Method

Using the CIBERSORT method, 22 types of immune cells between stable and unstable carotid atherosclerotic plaques from RNA-sequencing and microarray data in the public GEO database were quantitated. Differentially expressed genes (DEGs) were further calculated and were analyzed for enrichment of GO Biological Process and KEGG pathways. Important cell types and hub genes were screened using machine learning methods including least absolute shrinkage and selection operator (LASSO) regression and random forest. Single-cell RNA sequencing and clinical samples were further used to validate critical cell types and hub genes. Finally, the DGIdb database of gene–drug interaction data was utilized to find possible therapeutic medicines and show how pharmaceuticals, genes, and immune cells interacted.

Results

A significant difference in immune cell infiltration was observed between unstable and stable plaques. The proportions of M0, M1, and M2 macrophages were significantly higher and that of CD8+ T cells and NK cells were significantly lower in unstable plaques than that in stable plaques. With respect to DEGs, antigen presentation genes (CD74, B2M, and HLA-DRA), inflammation-related genes (MMP9, CTSL, and IFI30), and fatty acid-binding proteins (CD36 and APOE) were elevated in unstable plaques, while the expression of smooth muscle contraction genes (TAGLN, ACAT2, MYH10, and MYH11) was decreased in unstable plaques. M1 macrophages had the highest instability score and contributed to atherosclerotic plaque instability. CD68, PAM, and IGFBP6 genes were identified as the effective diagnostic markers of unstable plaques, which were validated by validation datasets and clinical samples. In addition, insulin, nivolumab, indomethacin, and α-mangostin were predicted to be potential therapeutic agents for unstable plaques.

Conclusion

M1 macrophages is an important cause of unstable plaque formation, and CD68, PAM, and IGFBP6 could be used as diagnostic markers to identify unstable plaques effectively.
Role of cross-reactivity in cellular immune targeting of influenza A M158-66 variant peptide epitopes
Authors: Petrova Galina V. , Naumov Yuri N. , Naumova Elena N. , Gorski Jack
Published: September 2022

The immunologic significance of cross-reactivity of TCR recognition of peptide:MHC complexes is still poorly understood. We have described TCR cross-reactivity in a system involving polyclonal CD8 T cell recognition of the well characterized influenza viral M158-66epitope. While M158-66is generally conserved between influenza A isolates, error-prone transcription generates stable variant RNA during infection which could act as novel epitopes. If packaged and viable, variant genomic RNA generates an influenza quasispecies. The stable RNA variants would generate a new transmissible epitope that can select a specific repertoire, which itself should have cross-reactive properties. We tested two candidate peptides in which Thr65 is changed to Ala (A65) or Ser (S65) using recall responses to identify responding T cell clonotypes. Both peptides generated large polyclonal T cell repertoires of their own with repertoire characteristics and cross-reactivity patterns like that observed for the M158-66repertoire. Both substitutions could be present in viral genomes or mRNA at sufficient frequency during an infection to drive immunity. Peptides from the resulting protein would be a target for CD8 cells irrespective of virus viability or transmissibility. These data support the hypothesis that cross-reactivity is important for immunity against RNA virus infections.
Genetic analysis of CFH and MCP in Egyptian patients with immune-complex proliferative glomerulonephritis
Authors: Gouda Heba R. , Talaat Iman M. , Bouzid Amal , El-Assi Hoda , Nabil Amira , Venkatachalam Thenmozhi , Manasa Bhamidimarri Poorna , Wohlers Inken , Mahdami Amena , EL-Gendi Saba , ElKoraie Ahmed , Busch Hauke , Saber-Ayad Maha , Hamoudi Rifat , Baddour Nahed
Published: September 2022

Glomerulonephritis (GN) is a complex disease with intricate underlying pathogenic mechanisms. The possible role of underlying complement dysregulation is not fully elucidated in some GN subsets, especially in the setting of autoimmunity or infection. In the current study, diagnosed cases of lupus nephritis (LN) and post-infectious GN (PIGN) were recruited for molecular genetic analysis and targeted next-generation DNA sequencing was performed for two main complement regulating genes: in the fluid phase; CFH, and on tissue surfaces; MCP. Three heterozygous pathogenic variants in CFH (Q172*, W701*, and W1096*) and one likely pathogenic heterozygous variant in MCP (C223R) have been identified in four of the studied LN cases. Additionally, among the several detected variants of uncertain significance, one novel variant (CFH:F614S) was identified in 74% of the studied LN cases and in 65% of the studied PIGN cases. This variant was detected for the first time in the Egyptian population. These findings suggest that subtle mutations may be present in complement regulating genes in patients with immune-complex mediated category of GN that may add to the disease pathogenesis. These findings also call for further studies to delineate the impact of these gene variants on the protein function, the disease course, and outcome.
PD-1 inhibitors plus anti-angiogenic therapy with or without intensity-modulated radiotherapy for advanced hepatocellular carcinoma: A propensity score matching study
Authors: Su Ke , Guo Lu , Ma Wenqiong , Wang Jing , Xie Yunchuan , Rao Mingyue , Zhang Jianwen , Li Xueting , Wen Lianbin , Li Bo , Yang Xiaoli , Song Yanqiong , Huang Weihong , Chi Hao , Gu Tao , Xu Ke , Liu Yanlin , Chen Jiali , Wu Zhenying , Jiang Yi , Li Han , Zeng Hao , Wang Pan , Feng Xunjie , Chen Siyu , Yang Binbin , Jin Hongping , He Kun , Han Yunwei
Published: September 2022

Background

Whether intensity-modulated radiotherapy (IMRT) can enhance the efficacy of the programmed death (PD)-1 inhibitors combined with anti-angiogenic therapy for hepatocellular carcinoma (HCC) is unclear. Therefore, we conducted this multicenter retrospective study to investigate the efficacy of the combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT.

Methods

From April 2019 to March 2022, a total of 197 patients with HCC [combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT (triple therapy group), 54; PD-1 inhibitors plus anti-angiogenic therapy (control group), 143] were included in our study. Propensity score matching (PSM) was applied to identify two groups with similar baselines. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) of the two groups were compared before and after matching.

Results

Prior to PSM, the triple therapy group had higher ORR (42.6% vs 24.5%, P = 0.013) and more superior median OS (mOS) (20.1 vs 13.3 months, P = 0.009) and median PFS (mPFS) (8.7 vs 5.4 months, P = 0.001) than the control group. Following PSM, the triple therapy group still exhibited better mPFS (8.7 vs 5.4 months, P = 0.013) and mOS (18.5 vs 12.6 months, P = 0.043) than the control group. However, the ORR of the two groups was similar (40% vs 25%, P = 0.152). No significant difference was observed in the treatment-related adverse events between the two groups (P < 0.05 for all).

Conclusions

The combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT for HCC is a promising regimen.