bluuebunny/crossref_metadata_2025 huggingface dataset:
Adipokine Signaling Pathways in Osteoarthritis
Authors: Zhang Chaofan , Lin Yunzhi , Yan Chun Hoi , Zhang Wenming
Published: April 2022

Osteoarthritis (OA) is a debilitating joint disease that affects millions of individuals. The pathogenesis of OA has not been fully elucidated. Obesity is a well-recognized risk factor for OA. Multiple studies have demonstrated adipokines play a key role in obesity-induced OA. Increasing evidence show that various adipokines may significantly affect the development or clinical course of OA by regulating the pro/anti-inflammatory and anabolic/catabolic balance, matrix remodeling, chondrocyte apoptosis and autophagy, and subchondral bone sclerosis. Several signaling pathways are involved but still have not been systematically investigated. In this article, we review the cellular and molecular mechanisms of adipokines in OA, and highlight the possible signaling pathways. The review suggested adipokines play important roles in obesity-induced OA, and exert downstream function via the activation of various signaling pathways. In addition, some pharmaceuticals targeting these pathways have been applied into ongoing clinical trials and showed encouraging results. However, these signaling pathways are complex and converge into a common network with each other. In the future work, more research is warranted to further investigate how this network works. Moreover, more high quality randomised controlled trials are needed in order to investigate the therapeutic effects of pharmaceuticals against these pathways for the treatment of OA. This review may help researchers to better understand the pathogenesis of OA, so as to provide new insight for future clinical practices and translational research.
Community Impact on a Cryptocurrency: Twitter Comparison Example Between Dogecoin and Litecoin
Authors: Lansiaux Edouard , Tchagaspanian Noé , Forget Joachim
Published: April 2022

Context: The third generation of cryptocurrencies gathers cryptocurrencies that are as diverse as the market is big (e.g., Dogecoin or Litecoin). While Dogecoin is seen as a memecoin, the other gathers a very different category of investors. To our knowledge, no study has independently assessed the crypto community’s economical impact on these cryptocurrencies. Furthermore, various methodological possibilities exist to forecast cryptocurrency price—mainly coming from online communities.

Method: Our study has retrospectively studied (from 01/01/2015 to 03/11/2021)—using open access data—the association strength (using normalized mutual information) and the linear correlation (using Pearson’s correlation) between Twitter activity and cryptocurrency economical attributes. In addition, we have computed different models (ADF, ARIMA, and Interpretable MultiVvariable Long Short-Term Memory recurrent neural network) that forecast past price values and assessed their precision.

Findings and conclusions: While the average Dogecoin transaction value is impacted by tweets, tweets are impacted by Litecoin transactions number and average Litecoin transaction value. Tweet number is impacted by Dogecoin whale behavior, but no significant relationship was found between Litecoin whales and tweets. The forecasting error resulting from our ARIMA (0,0,0) models was 0.08% (with Litecoin) and 0.22% (with Dogecoin). Therefore, those are just the beginning of scientific findings that may lead to building a trading robot based on these results. However, in itself, this study is only for academic discussion, and conclusions need to be drawn by further research. The authors cannot be liable if any financial investment is made based on its conclusions.
Maternal Protein Restriction Alters the Expression of Proteins Related to the Structure and Functioning of the Rat Offspring Epididymis in an Age-Dependent Manner
Authors: Cavariani Marilia Martins , de Mello Santos Talita , Chuffa Luiz Gustavo de Almeida , Pinheiro Patrícia Fernanda Felipe , Scarano Wellerson Rodrigo , Domeniconi Raquel Fantin
Published: April 2022

Nutrition is an environmental factor able to activate physiological interactions between fetus and mother. Maternal protein restriction is able to alter sperm parameters associated with epididymal functions. Since correct development and functioning of the epididymides are fundamental for mammalian reproductive success, this study investigated the effects of maternal protein restriction on epididymal morphology and morphometry in rat offspring as well as on the expression of Src, Cldn-1, AR, ER, aromatase p450, and 5α-reductase in different stages of postnatal epididymal development. For this purpose, pregnant females were allocated to normal-protein (NP—17% protein) and low-protein (LP—6% protein) groups that received specific diets during gestation and lactation. After weaning, male offspring was provided only normal-protein diet until the ages of 21, 44, and 120 days, when they were euthanized and their epididymides collected. Maternal protein restriction decreased genital organs weight as well as crown-rump length and anogenital distance at all ages. Although the low-protein diet did not change the integrity of the epididymal epithelium, we observed decreases in tubular diameter, epithelial height and luminal diameter of the epididymal duct in 21-day-old LP animals. The maternal low-protein diet changed AR, ERα, ERβ, Src 416, and Src 527 expression in offspring epididymides in an age-dependent manner. Finally, maternal protein restriction increased Cldn-1 expression throughout the epididymides at all analyzed ages. Although some of these changes did not remain until adulthood, the insufficient supply of proteins in early life altered the structure and functioning of the epididymis in important periods of postnatal development.
Extensive Chromatin Structure-Function Associations Revealed by Accurate 3D Compartmentalization Characterization
Authors: Wen Zi , Zhang Weihan , Zhong Quan , Xu Jinsheng , Hou Chunhui , Qin Zhaohui Steve , Li Li
Published: April 2022

A/B compartments are observed in Hi-C data and coincide with eu/hetero-chromatin. However, many genomic regions are ambiguous under A/B compartment scheme. We develop MOSAIC (MOdularity and Singular vAlue decomposition-based Identification of Compartments), an accurate compartmental state detection scheme. MOSAIC reveals that those ambiguous regions segregate into two additional compartmental states, which typically correspond to short genomic regions flanked by long canonical A/B compartments with opposite activities. They are denoted as micro-compartments accordingly. In contrast to the canonical A/B compartments, micro-compartments cover ∼30% of the genome and are highly dynamic across cell types. More importantly, distinguishing the micro-compartments underpins accurate characterization of chromatin structure-function relationship. By applying MOSAIC to GM12878 and K562 cells, we identify CD86, ILDR1 and GATA2 which show concordance between gene expression and compartmental states beyond the scheme of A/B compartments. Taken together, MOSAIC uncovers fine-scale and dynamic compartmental states underlying transcriptional regulation and disease.
Regulation of Peroxisome Homeostasis by Post-Translational Modification in the Methylotrophic Yeast Komagataella phaffii
Authors: Ohsawa Shin , Oku Masahide , Yurimoto Hiroya , Sakai Yasuyoshi
Published: April 2022

The methylotrophic yeast Komagataella phaffii (synoym Pichia pastoris) can grow on methanol with an associated proliferation of peroxisomes, which are subsequently degraded by pexophagy upon depletion of methanol. Two cell wall integrity and stress response component (WSC) family proteins (Wsc1 and Wsc3) sense the extracellular methanol concentration and transmit the methanol signal to Rom2. This stimulates the activation of transcription factors (Mxr1, Trm1, and Mit1 etc.), leading to the induction of methanol-metabolizing enzymes (methanol-induced gene expression) and synthesis of huge peroxisomes. Methanol-induced gene expression is repressed by the addition of ethanol (ethanol repression). This repression is not conducted directly by ethanol but rather by acetyl-CoA synthesized from ethanol by sequential reactions, including alcohol and aldehyde dehydrogenases, and acetyl-CoA synthetase. During ethanol repression, Mxr1 is inactivated by phosphorylation. Peroxisomes are degraded by pexophagy on depletion of methanol and this event is triggered by phosphorylation of Atg30 located at the peroxisome membrane. In the presence of methanol, Wsc1 and Wsc3 repress pexophagy by transmitting the methanol signal via the MAPK cascade to the transcription factor Rlm1, which induces phosphatases involved in dephosphorylation of Atg30. Upon methanol consumption, repression of Atg30 phosphorylation is released, resulting in initiation of pexophagy. Physiological significance of these machineries involved in peroxisome homeostasis and their post-translational modification is also discussed in association with the lifestyle of methylotrophic yeast in the phyllosphere.
Asymptomatic Transmissibility Calls for Implementing a Zero-COVID Strategy to End the Current Global Crisis
Authors: Zhang Chaobao , Wang Hongzhi , Wen Zilu , Gu Mingjun , Liu Lianyong , Li Xiangqi
Published: April 2022

The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented global challenges. A zero-COVID strategy is needed to end the crisis, but there is a lack of biological evidence. In the present study, we collected available data on SARS, MERS, and COVID-19 to perform a comprehensive comparative analysis and visualization. The study results revealed that the fatality rate of COVID-19 is low, whereas its death toll is high compared to SARS and MERS. Moreover, COVID-19 had a higher asymptomatic rate. In particular, COVID-19 exhibited unique asymptomatic transmissibility. Further, we developed a foolproof operating software in Python language to simulate COVID-19 spread in Wuhan, showing that the cumulative cases of existing asymptomatic spread would be over 100 times higher than that of only symptomatic spread. This confirmed the essential role of asymptomatic transmissibility in the uncontrolled global spread of COVID-19, which enables the necessity of implementing the zero-COVID policy. In conclusion, we revealed the triggering role of the asymptomatic transmissibility of COVID-19 in this unprecedented global crisis, which offers support to the zero-COVID strategy against the recurring COVID-19 spread.
Statistical Analysis and Machine Learning Prediction of Disease Outcomes for COVID-19 and Pneumonia Patients
Authors: Zhao Yu , Zhang Rusen , Zhong Yi , Wang Jingjing , Weng Zuquan , Luo Heng , Chen Cunrong
Published: April 2022

The Coronavirus Disease 2019 (COVID-19) has spread all over the world and impacted many people’s lives. The characteristics of COVID-19 and other types of pneumonia have both similarities and differences, which confused doctors initially to separate and understand them. Here we presented a retrospective analysis for both COVID-19 and other types of pneumonia by combining the COVID-19 clinical data, eICU and MIMIC-III databases. Machine learning models, including logistic regression, random forest, XGBoost and deep learning neural networks, were developed to predict the severity of COVID-19 infections as well as the mortality of pneumonia patients in intensive care units (ICU). Statistical analysis and feature interpretation, including the analysis of two-level attention mechanisms on both temporal and non-temporal features, were utilized to understand the associations between different clinical variables and disease outcomes. For the COVID-19 data, the XGBoost model obtained the best performance on the test set (AUROC = 1.000 and AUPRC = 0.833). On the MIMIC-III and eICU pneumonia datasets, our deep learning model (Bi-LSTM_Attn) was able to identify clinical variables associated with death of pneumonia patients (AUROC = 0.924 and AUPRC = 0.802 for 24-hour observation window and 12-hour prediction window). The results highlighted clinical indicators, such as the lymphocyte counts, that may help the doctors to predict the disease progression and outcomes for both COVID-19 and other types of pneumonia.
The Potential Role of Hypochlorhydria in the Development of Duodenal Dysbiosis: A Preliminary Report
Authors: Filardo Simone , Scalese Giulia , Virili Camilla , Pontone Stefano , Di Pietro Marisa , Covelli Antonio , Bedetti Giorgio , Marinelli Paride , Bruno Giovanni , Stramazzo Ilaria , Centanni Marco , Sessa Rosa , Severi Carola
Published: April 2022

In recent years, the role of gastric and duodenal microbiota has acquired increasing importance in the homeostasis of the host, although, to date, most evidence concern the faecal microbiota. Indeed, the gastric, and duodenal microbiota are challenging to study, due to gastric acid, bile, digestive enzymes, and rapid transit time. Specifically, the gastric acid environment may influence their bacterial composition since the acid barrier protects against orally ingested microorganisms and leads to their inactivation before reaching the intestine. The aim of this study was to assess a correlation between intragastric pH and gastric as well as intestinal microbiota of patients with histologic gastric alterations. pH was measured in the gastric juice and the bacterial composition in gastric and duodenal biopsies and faecal samples, was investigated via 16s rRNA gene sequencing. The main result is the direct correlation of duodenal microbiota biodiversity, via alpha diversity measures, with intragastric pH values. In particular, patients with hypochlorhydria showed increased duodenal microbiota biodiversity, higher intragastric pH values being prevalent in patients with chronic atrophic gastritis. Lastly, the latter was also strongly associated to the presence of oral bacteria, like Rothia mucilaginosa, Streptococcus salivarius and Granulicatella adiacens, in the duodenal microbiota. In conclusions, our results suggest a low-acid gastric environment as a contributive factor for duodenal dysbiosis, potentially leading to the development of pathological conditions of the gastrointestinal tract.
Hemodynamic Changes During Physiological and Pharmacological Stress Testing in Patients With Heart Failure: A Systematic Review and Meta-Analysis
Authors: Bingel Anne , Messroghli Daniel , Weimar Andreas , Runte Kilian , Salcher-Konrad Maximilian , Kelle Sebastian , Pieske Burkert , Berger Felix , Kuehne Titus , Goubergrits Leonid , Fuerstenau Daniel , Kelm Marcus
Published: April 2022

Although disease etiologies differ, heart failure patients with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) both present with clinical symptoms when under stress and impaired exercise capacity. The extent to which the adaptation of heart rate (HR), stroke volume (SV), and cardiac output (CO) under stress conditions is altered can be quantified by stress testing in conjunction with imaging methods and may help to detect the diminishment in a patient’s condition early. The aim of this meta-analysis was to quantify hemodynamic changes during physiological and pharmacological stress testing in patients with HF. A systematic literature search (PROSPERO 2020:CRD42020161212) in MEDLINE was conducted to assess hemodynamic changes under dynamic and pharmacological stress testing at different stress intensities in HFpEF and HFrEF patients. Pooled mean changes were estimated using a random effects model. Altogether, 140 study arms with 7,248 exercise tests were analyzed. High-intensity dynamic stress testing represented 73% of these data (70 study arms with 5,318 exercise tests), where: HR increased by 45.69 bpm (95% CI 44.51–46.88; I2 = 98.4%), SV by 13.49 ml (95% CI 6.87–20.10; I2 = 68.5%), and CO by 3.41 L/min (95% CI 2.86–3.95; I2 = 86.3%). No significant differences between HFrEF and HFpEF groups were found. Despite the limited availability of comparative studies, these reference values can help to estimate the expected hemodynamic responses in patients with HF. No differences in chronotropic reactions, changes in SV, or CO were found between HFrEF and HFpEF. When compared to healthy individuals, exercise tolerance, as well as associated HR and CO changes under moderate-high dynamic stress, was substantially impaired in both HF groups. This may contribute to a better disease understanding, future study planning, and patient-specific predictive models.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020161212].
Correlation Between Plasma Proteomics and Adverse Outcomes Among Older Men With Chronic Coronary Syndrome
Authors: Cai Yu-Lun , Hao Ben-Chuan , Chen Jian-Qiao , Li Yue-Rui , Liu Hong-Bin
Published: April 2022

Background

Chronic coronary syndrome (CCS) is a newly proposed concept and is hallmarked by more long-term major adverse cardiovascular events (MACEs), calling for accurate prognostic biomarkers for initial risk stratification.

Methods

Data-independent acquisition liquid chromatography tandem mass spectrometry (DIA LC-MS/MS) quantitative proteomics was performed on 38 patients with CCS; 19 in the CCS events group and 19 in the non-events group as the controls. We also developed a machine-learning-based pipeline to identify proteins as potential biomarkers and validated the target proteins by enzyme-linked immunosorbent assay in an independent prospective cohort.

Results

Fifty-seven differentially expressed proteins were identified by quantitative proteomics and three final biomarkers were preliminarily selected from the machine-learning-based pipeline. Further validation with the prospective cohort showed that endothelial protein C receptor (EPCR) and cholesteryl ester transfer protein (CETP) levels at admission were significantly higher in the CCS events group than they were in the non-events group, whereas the carboxypeptidase B2 (CPB2) level was similar in the two groups. In the Cox survival analysis, EPCR and CETP were independent risk factors for MACEs. We constructed a new prognostic model by combining the Framingham coronary heart disease (CHD) risk model with EPCR and CETP levels. This new model significantly improved the C-statistics for MACE prediction compared with that of the Framingham CHD risk model alone.

Conclusion

Plasma proteomics was used to find biomarkers of predicting MACEs in patients with CCS. EPCR and CETP were identified as promising prognostic biomarkers for CCS.
Seasonal Impact on 3D GPR Performance for Surveying Yedoma Ice Complex Deposits
Authors: Schennen Stephan , Wetterich Sebastian , Schirrmeister Lutz , Schwamborn Georg , Tronicke Jens
Published: April 2022

Ground-penetrating radar (GPR) is a popular geophysical method for imaging subsurface structures with a resolution at decimeter scale, which is based on the emission, propagation, and reflection of electromagnetic waves. GPR surveys for imaging the cryosphere benefit from the typically highly resistive conditions in frozen ground, resulting in low electromagnetic attenuation and, thus, an increased penetration depth. In permafrost environments, seasonal changes might affect not only GPR performance in terms of vertical resolution, attenuation, and penetration depth, but also regarding the general complexity of data (e.g., due to multiple reflections at thaw boundaries). The experimental setup of our study comparing seasonal differences of summertime thawed and winter- and springtime frozen active layer conditions above ice-rich permafrost allows for estimating advantages and disadvantages of both scenarios. Our results demonstrate major differences in the data and the final GPR image and, thus, will help in future studies to decide about particular survey seasons based on the GPR potential for non-invasive and high-resolution investigations of permafrost properties.
Performance Practice in a Pandemic: Training Ensemble Skills Using E-Tivities in Music Teacher Education
Authors: Karkina Svetlana , Faizrakhmanova Lyalya , Kamalova Ilmira , Akbarova Gulnaz , Kaur Balwinder
Published: April 2022

The emergency situation due to the spread of COVID-19 has brought new requirements to Higher Education to continue the learning process. In musical ensemble class, performance practice is mandatory and plays a crucial role in musical education. The pandemic has forced all classes online, but for performance practice, it was mandatory to implement a new type of student-teacher interaction, such as e-tivity. It is a dynamic and interactive learning process led by a teacher online. The investigation of the efficiency of e-tivity for training musical ensemble skills was carried out in this paper. The research was tested through experimental work that took place at Kazan Federal University (Russian Federation). Due to a complete shift in the education process to distanced learning, all disciplines were studied online, including the specific musical courses that required collective work with face-to-face interaction. The curriculum of future music teachers includes an ensemble basic course to train students‘ musical performance skills in groups. For the study, 114 students from classes with instrumental and vocal ensembles were gathered and were organized by means of e-tivity based on several online tools, including Aiseesoft Video Converter Ultimate. This tool creates a video with a split-screen effect. By using such a tool, students created the video by following the teacher‘s instructions separately, and afterward they united their musical records in one video with a split-screen effect. At the end of the research work, musical artworks belonging to certain art styles, namely classical, Tatar and Russian folk music, and jazz, were collected. The analysis of the obtained data exhibited a high level of results in each criterion scale and effectiveness of the online work with musical ensembles. Students saw improvement in self-education by the means of creativity and critical self-assessment. The increasing frequency of students‘ listening of their own performance during the ensemble music-making by e-tivity brought advantages for the involuntary repetition process.
Restoring Impaired Fertility Through Diet: Observations of Switching From High-Fat Diet During Puberty to Normal Diet in Adulthood Among Obese Male Mice
Authors: Qi Xiangyu , Zhang Meijie , Sun Mingqi , Luo Dandan , Guan Qingbo , Yu Chunxiao
Published: April 2022

Background

Obesity is associated with a decrease in testicular function, yet the effects and mechanisms relative to different stages of sexual development remain unclear. The aim of this study is to determine whether high-fat diet-induced obesity impairs male fertility during puberty and in adulthood, and to ascertain its underlying mechanisms. This study aims to further reveal whether restoring to a normal diet can improve impaired fertility.

Methods

Male mice were divided into 6 groups: the group N and H exposed to a normal diet or high-fat diet during puberty. The group NN or NH were further maintained a normal diet or exposed to high-fat diet in adulthood, the group HH or HN were further maintained high-fat diet or switched to normal diet in adulthood. Metabolic parameters, fertility parameters, testicular function parameters, TUNEL staining and testicular function-related proteins were evaluated, respectively.

Results

The fertility of the mice in the high-fat diet group was impaired, which validated by declines in pregnancy rates and litter weight loss. Further analysis demonstrated the increased level of oxidative stress, the increased number of spermatogenic cell apoptosis and decreased number of sperm and decreased acrosome integrity. The expression of steroidogenic acute regulatory (StAR) and spermatogenesis related proteins (WT-1) decreased. Fertility among the HN group recovered, accompanied by the recovery of metabolism, fertility and testicular function parameters, StAR and WT-1 expression.

Conclusions

The findings suggest that high-fat diet-induced obesity impairs male fertility during puberty and in adulthood. The loss of acrosome integrity, the increase of oxidative stress, the increase of cells apoptosis and the down-regulation of StAR and WT-1 may be the underlying mechanisms. Switching from high-fat diets during puberty to normal diets in adulthood can improve male fertility.
Pasireotide for Refractory Hypoglycemia in Malignant Insulinoma- Case Report and Review of the Literature
Authors: Oziel-Taieb Sandrine , Maniry-Quellier Jemima , Chanez Brice , Poizat Flora , Ewald Jacques , Niccoli Patricia
Published: April 2022

Malignant insulinomas are functional neuroendocrine tumors of the pancreas and the primary cause of tumor-related hypoglycemia. Malignant insulinoma is rare and has a poor prognosis. We report a case of metastatic malignant insulinoma in a 64-year-old female patient with severe and refractory hypoglycemia. After several ineffective locoregional and systemic therapeutic lines for the secretory disease, the introduction of pasireotide, a second-generation somatostatin analog, provided an improved clinical and secretory evolution both quickly and sustainably, with an excellent safety profile. Pasireotide is an effective and well-tolerated therapy in the treatment of refractory hypoglycemia in metastatic insulinoma.
A Predictive–Proactive Approach for Slot Management of a Loading Facility With Truck ETA Information
Authors: Prakoso Emanuel Febrianto , Maknoon Yousef , Pel Adam , Tavasszy Lóránt A. , Vanga Ratnaji
Published: April 2022

Due to the uncertain and dynamic environment around scheduling systems, timely revisions or reschedules of the master plans are essential for achieving optimal utilization. With the recent development of Industry 4.0 technologies, many researchers perceive the creation of cyber-physical systems as a solution for managing systems under uncertainty. This article focuses on a loading facility under uncertain truck arrivals due to road congestion and proposes utilizing real-time truck location information to improve performance. We do this by developing an integrated system consisting of a predictive model using machine learning (MC) classifiers and a mathematical model for real-time slot rescheduling. The ML classifier is used to predict the presence probabilities of all the incoming trucks at a particular slot based on the historical traffic data and the real-time truck location. Subsequently, a Mixed-Integer Quadratic Programming (MIQP) model is developed to solve a Probabilistic Slot Rescheduling Problem (P-SRP), which uses the estimated truck presence probabilities and minimizes the total expected cost of rescheduling. We implemented this by first testing multiple ML classifiers and selected the ANN classifier for prediction as it outperformed others. Our limited experiments showed that the proposed method reduced the total rescheduling cost by 42%. Furthermore, our sensitivity analysis with different congestion levels, complexity, and rescheduling strategy also showed the practicality of the proposed approach.
Patterns of Recurrent Thrombosis in Primary Antiphospholipid Syndrome—Multicenter, Real-Life Long-Term Follow-Up
Authors: Niznik Stanley , Rapoport Micha J. , Avnery Orly , Lubetsky Aharon , Haj Yahia Soad , Ellis Martin H. , Agmon-Levin Nancy
Published: April 2022

Background

Antiphospholipid syndrome (APS) is an acquired hypercoagulable condition associated with antiphospholipid antibody (aPL) presence. Data on re-thrombosis following APS-diagnosis are limited.

Methods

This is a retrospective analysis of new thrombotic events among primary APS (pAPS) patients followed for up to 15 years in three medical centers in Israel.

Results

Among 312 primary-APS patients, 143 (46%) had new thrombotic event classified to three patterns: (1)Arterial—associated with heart valve disease (OR 7.24, 95% C.I. 2.26–24.6), hypertension (OR 3, 95% C.I. 1.44–6.25), elevated anti-B2-GPI IgM (OR 1.04, 95% C.I. 0.996–1.08), arterial thrombosis at presentation (OR 1.74 95% C.I. 0.992–3.26), and older age (41 vs. 34 years, p < 0.001). (2)Venous—linked with venous thrombosis at presentation (OR 12.9, 95% C.I. 5.27–31.6, p < 0.001), heart valve disease (OR 9.81 95% C.I. 1.82–52.9, p = 0.018), aGAPSS (OR 1.15 95% C.I. 1.02–1.29), and younger age (31 vs. 36.5 years, p = 0.001); and (3)Combined pattern—associated with heart valve disease (OR 40.5 95% C.I. 7.7–212) and pulmonary embolism (OR 7.47 95% C.I. 1.96–28.5). A 4th variant “the Breakthrough pattern” defined by re-thrombosis despite prophylactic therapy was observed in 100/143 (70%) patients and linked with heart valve disease (OR 8. 95% C.I. 2.43–26.3), venous thrombosis at presentation (OR 2.61 95% C.I. 1.47–4.66), leg ulcers (OR 12.2, 95% C.I. 1.4–107), hypertension (OR 1.99, 95% C.I. 0.92–4.34), and higher aGAPSS (OR 1.08, 95% C.I. 0.99–1.18).

Conclusion

In this real-life observation, re-thrombosis was common among pAPS patients including in those recommended to receive prophylactic therapy. Different patterns of recurrence were identified and linked with presenting symptoms, specific serological markers, APS manifestations, and comorbidities. Studies that will address interventions to prevent recurrences of APS-related events are needed.
Comparison Between Nr4a Transcription Factor Regulation and Function in Lymphoid and Tumor Treg Cells
Authors: Sekiya Takashi
Published: April 2022

Although the “lymphoid” function of regulatory T (Treg) cells is crucial for organismal homeostasis, these cells are also known to suppress the antitumor immune response in the tumor microenvironments. Thus, a detailed understanding of Treg cell maintenance and function in both lymphoid organs and tumor environments may help to establish novel methods for the reactivating antitumor immunity, while retaining necessary immune tolerance towards self and non-hazardous antigens. Previous studies have hypothesized that Treg cells behave similarly in lymphoid organs and in tumor environments; however, few studies have been conducted specifically researching Treg cell activity in tumor environments. In addition, several recent studies identified a novel mechanism regulating Treg cell function in tumor environments. Our group has previously described the critical roles of the Nr4a family of nuclear orphan receptors, comprising Nr4a1, Nr4a2, and Nr4a3, in the differentiation and maintenance of Treg cells in lymphoid organs. Subsequently, it was found that Nr4a factors help to maintain Treg cell function in tumor environments, thereby playing a suppressive role against T cell antitumor immunity. Importantly, there were some differences between the activities of these Nr4a factors under these conditions, including the specific function of the COX/PGE2 axis in tumor environments. This review was designed to investigate the role of Nr4a factors in the regulation of Treg cell activities both in the lymphoid organs and tumor environments, highlighting the commonalities and differences in their behaviors between Treg cells in these two different environments.
Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells
Authors: Li Shuang , Zou Dawei , Chen Wenhao , Cheng Yating , Britz Gavin W. , Weng Yi-Lan , Liu Zhaoqian
Published: April 2022

Allogeneic CD8+ T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8+ T cells. We found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8+ T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8+ T cell response, BATF–/– and wild-type (WT) CD8+ T cells were mixed in a 1:1 ratio and adoptively transferred into B6.Rag1–/– mice 1 day prior to skin transplantation. Compared with WT CD8+ T cells at the peak of rejection response, BATF–/– CD8+ T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127–KLRG1+ terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF–/– CD8+ T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8+ T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8+ T cells in the transplantation setting. Targeting BATF in CD8+ T cells may be an attractive therapeutic approach to promote transplant acceptance.
Case Report and Literature Review: Behçet’s Disease With a Novel TFPI Gene Mutation
Authors: Ma Jiewen , Sun Wengang , Tang Liang , Yang Di
Published: April 2022

We report a case of Behçet’s disease (BD) with a newly identified tissue factor pathway inhibitor (TFPI) gene mutation. The patient suffered from recurrent deep vein thrombosis and dural sinus thrombosis which could not be relieved by constant anticoagulation therapy. Slight relapsing oral lesion was the initial manifestation of BD but was neglected. Genital ulcers and ocular symptoms were manifest 8-month later than vascular involvement. The patient was diagnosed with BD at last and a novel mutation in TFPI was identified simultaneously. After administration with azathioprine and dexamethasone, the clinical symptoms were quickly gone and no relapse was found during 7-month follow-up.
Understanding Individual Barriers to HIV Testing Among Undergraduate University Students: Results From a Cross-Sectional Study in Italy
Authors: Licata Francesca , Angelillo Silvia , Nobile Carmelo Giuseppe Angelo , Di Gennaro Gianfranco , Bianco Aida
Published: April 2022

Background

In Europe during 2019, just over half of those with HIV were diagnosed at a late stage of infection. Even though HIV testing is crucial for all strategies related to care, prevention and treatment of HIV/AIDS, we hypothesized that it is less practiced among university students, and, therefore, this study aimed to assess the uptake and factors associated with HIV testing in southern part of Italy.

Methods

A cross-sectional study was conducted from 1st to 31st July 2020 among undergraduate university students aged 18–29 years. Data were collected through an anonymous online questionnaire and included questions on socio-demographic and sexual history characteristics, knowledge and attitudes toward HIV infection, sexual and testing behaviors, and sources of information about HIV.

Findings

Among 1007 students, 41.5 and 54.7% knew that in Italy the test for early detection of HIV infection has not to be prescribed by a physician and that it is provided to anyone free of charge, respectively. Only 16.2% of the eligible students reported having ever tested for HIV and a very similar proportion (17.8%) was displayed among those who reported risky sexual behaviors. The multiple logistic regression analysis results indicated that the strongest predictor of HIV testing was attending medical or life sciences majors.

Interpretation

The uptake of HIV testing was low among Italian university students. Effective strategies to increase HIV testing and diagnoses have to aim at overarching individual barriers, such as lack of knowledge about information around the test itself.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Dehydroquinate Synthase Directly Binds to Streptomycin and Regulates Susceptibility of Mycobacterium bovis to Streptomycin in a Non-canonical Mode
Authors: Wei Wenping , Qiao Junjie , Jiang Xiaofang , Cai Luxia , Hu Xiaomin , He Jin , Chen Min , Yang Min , Cui Tao
Published: April 2022

Antimicrobial resistance (AMR) represents one of the main challenges in Tuberculosis (TB) treatment. Investigating the genes involved in AMR and the underlying mechanisms holds promise for developing alternative treatment strategies. The results indicate that dehydroquinate synthase (DHQS) regulates the susceptibility of Mycobacterium bovis BCG to first-line anti-TB drug streptomycin. Perturbation of the expression of aroB encoding DHQS affects the susceptibility of M. bovis BCG to streptomycin. Purified DHQS impairs in vitro antibacterial activity of streptomycin, but did not hydrolyze or modify streptomycin. DHQS directly binds to streptomycin while retaining its own catalytic activity. Computationally modeled structure analysis of DHQS–streptomycin complex reveals that DHQS binds to streptomycin without disturbing native substrate binding. In addition, streptomycin treatment significantly induces the expression of DHQS, thus resulting in DHQS-mediated susceptibility. Our findings uncover the additional function of DHQS in AMR and provide an insight into a non-canonical resistance mechanism by which protein hijacks antibiotic to reduce the interaction between antibiotic and its target with normal protein function retained.
Ginsenoside Rb1 Improves Metabolic Disorder in High-Fat Diet-Induced Obese Mice Associated With Modulation of Gut Microbiota
Authors: Zou Hong , Zhang Man , Zhu Xiaoting , Zhu Liyan , Chen Shuo , Luo Mingjing , Xie Qinglian , Chen Yue , Zhang Kangxi , Bu Qingyun , Wei Yuchen , Ye Tao , Li Qiang , Yan Xing , Zhou Zhihua , Yang Chen , Li Yu , Zhou Haokui , Zhang Chenhong , You Xiaoyan , Zheng Guangyong , Zhao Guoping
Published: April 2022

Gut microbiota plays an important role in metabolic homeostasis. Previous studies demonstrated that ginsenoside Rb1 might improve obesity-induced metabolic disorders through regulating glucose and lipid metabolism in the liver and adipose tissues. Due to low bioavailability and enrichment in the intestinal tract of Rb1, we hypothesized that modulation of the gut microbiota might account for its pharmacological effects as well. Here, we show that oral administration of Rb1 significantly decreased serum LDL-c, TG, insulin, and insulin resistance index (HOMA-IR) in mice with a high-fat diet (HFD). Dynamic profiling of the gut microbiota showed that this metabolic improvement was accompanied by restoring of relative abundance of some key bacterial genera. In addition, the free fatty acids profiles in feces were significantly different between the HFD-fed mice with or without Rb1. The content of eight long-chain fatty acids (LCFAs) was significantly increased in mice with Rb1, which was positively correlated with the increase of Akkermansia and Parasuttereller, and negatively correlated with the decrease of Oscillibacter and Intestinimonas. Among these eight increased LCFAs, eicosapentaenoic acid (EPA), octadecenoic acids, and myristic acid were positively correlated with metabolic improvement. Furthermore, the colonic expression of the free fatty acid receptors 4 (Ffar4) gene was significantly upregulated after Rb1 treatment, in response to a notable increase of LCFA in feces. These findings suggested that Rb1 likely modulated the gut microbiota and intestinal free fatty acids profiles, which should be beneficial for the improvement of metabolic disorders in HFD-fed mice. This study provides a novel mechanism of Rb1 for the treatment of metabolic disorders induced by obesity, which may provide a therapeutic avenue for the development of new nutraceutical-based remedies for treating metabolic diseases, such as hyperlipidemia, insulin resistance, and type 2 diabetes.
The Game for Three: Salmonella–Host–Microbiota Interaction Models
Authors: Grzymajlo Krzysztof
Published: April 2022

Colonization of the gastrointestinal (GI) tract by enteric pathogens occurs in a context strongly determined by host-specific gut microbiota, which can significantly affect the outcome of infection. The complex gameplay between the trillions of microbes that inhabit the GI tract, the host, and the infecting pathogen defines a specific triangle of interaction; therefore, a complete model of infection should consider all of these elements. Many different infection models have been developed to explain the complexity of these interactions. This review sheds light on current knowledge, along with the strengths and limitations of in vitro and in vivo models utilized in the study of Salmonella–host–microbiome interactions. These models range from the simplest experiment simulating environmental conditions using dedicated growth media through in vitro interaction with cell lines and 3-D organoid structure, and sophisticated “gut on a chip” systems, ending in various animal models. Finally, the challenges facing this field of research and the important future directions are outlined.
Analysis and Comparison of Gut Microbiome in Young Detection Dogs
Authors: Li Zongjie , Sun Qing , Li Yuhao , Guan Zhixin , Wei Jianchao , Li Beibei , Liu Ke , Shao Donghua , Mi Rongsheng , Liu Haixia , Qiu Yafeng , Ma Zhiyong
Published: April 2022

The detection dogs are well-known for their excellent capabilities to sense different kinds of smells, which can play an important role in completing various searching and rescuing missions. The recent studies have demonstrated that the excellent olfactory function of detection dogs might be related with the gut microbes via the bidirectional communications between the gastrointestinal tract and the brain. In this study, the gut microbial communities of three types of breeds of detection dogs (Springer Spaniel, Labrador Retriever, and German Shepherd) were studied and compared. The results revealed that the richness and the diversity of gut microbiome German Shepherd dogs were significantly higher than the Labrador Retriever dogs and the Springer Spaniel dogs. At the phylum level, the most predominant gut microbial communities of the detection dogs were comprised of Fusobacteriota, Bacteroidetes, Firmicutes, Proteobacteria, Campilobacterota, and Actinobacteriota. At the genus level the most predominant gut microbial communities were comprised of Fusobacterium, Megamonas, Prevotella, Alloprevotella, Bacteroides, Haemophilus, Anaerobiospirillum, Helicobacter, Megasphaera, Peptoclostridium, Phascolarctobacterium, and Streptococcus. However, the gut microbial communities of the three dogs group were also obviously different. The mean relative abundance of Fusobacterium, Prevotella, Alloprevotella, Megamonas, Bacteroides, and Phascolarctobacterium presented significant differences in the three groups. According to the portraits and characteristics of the gut microbiome in young detection dogs, multiple kinds of nutritional interventions could be applied to manipulate the gut microbiota, with the aim of improving the health states and the olfactory performances.
Identification of the Biosynthetic Pathway of Glycine Betaine That Is Responsible for Salinity Tolerance in Halophilic Thioalkalivibrio versutus D301
Authors: Liu Mengshuang , Liu Hui , Mei Fangtong , Yang Niping , Zhao Dahe , Ai Guomin , Xiang Hua , Zheng Yanning
Published: April 2022

Thioalkalivibrio versutus D301 has been widely used in the biodesulfurization process, as it is capable of oxidizing hydrogen sulfide to elemental sulfur under strongly halo-alkaline conditions. Glycine betaine contributes to the increased tolerance to extreme environments in some of Thioalkalivibrio species. However, the biosynthetic pathway of glycine betaine in Thioalkalivibrio remained unknown. Here, we found that genes associated with nitrogen metabolism of T. versutus D301 were significantly upregulated under high-salt conditions, causing the enhanced production of glycine betaine that functions as a main compatible solute in response to the salinity stress. Glycine betaine was synthesized by glycine methylation pathway in T. versutus D301, with glycine N-methyltransferase (GMT) and sarcosine dimethylglycine N-methyltransferase (SDMT) as key enzymes in this pathway. Moreover, substrate specificities of GMT and SDMT were quite different from the well characterized enzymes for glycine methylation in halophilic Halorhodospira halochloris. Our results illustrate the glycine betaine biosynthetic pathway in the genus of Thioalkalivibrio for the first time, providing us with a better understanding of the biosynthesis of glycine betaine in haloalkaliphilic Thioalkalivibrio.
The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity
Authors: Caefer Danielle M. , Phan Nhat Q. , Liddle Jennifer C. , Balsbaugh Jeremy L. , O’Shea Joseph P. , Tzingounis Anastasios V. , Schwartz Daniel
Published: April 2022

Okur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by heterozygous mutations to the CSNK2A1 gene, which encodes the alpha subunit of protein kinase CK2. The most frequently occurring mutation is lysine 198 to arginine (K198R). To investigate the impact of this mutation, we first generated a high-resolution phosphorylation motif of CK2WT, including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2K198R substrate specificity was also generated. Here we report the impact of the OCNDS associated CK2K198R mutation. Contrary to prior speculation, the mutation does not result in a complete loss of function, but rather shifts the substrate specificity of the kinase. Broadly speaking the mutation leads to 1) a decreased preference for acidic residues in the +1 position, 2) a decreased preference for threonine phosphorylation, 3) an increased preference for tyrosine phosphorylation, and 4) an alteration of the tyrosine phosphorylation specificity motif. To further investigate the result of this mutation we have developed a probability-based scoring method, allowing us to predict shifts in phosphorylation in the K198R mutant relative to the wild type kinase. As an initial step we have applied the methodology to the set of axonally localized ion channels in an effort to uncover potential alterations of the phosphoproteome associated with the OCNDS disease condition.
Functional Neural Alterations in Pathological Internet Use: A Meta-Analysis of Neuroimaging Studies
Authors: Peng Wei , Hao Qinghong , Gao Heng , Wang Yang , Wang Jun , Tu Yang , Yu Siyi , Li Hui , Zhu Tianmin
Published: April 2022

Previous resting-state functional MRI (fMRI) studies found spontaneous neural activity in the brains of Pathological Internet Use (PIU) subjects. However, the findings were inconsistent in studies using different neuroimaging analyses. This meta-analytic study aimed to identify a common pattern of altered brain activity from different studies. Resting-state fMRI studies, based on whole-brain analysis methods published before July 1, 2021, were searched in multiple databases (PubMed, EMBASE, MEDLINE, and Web of Science). A voxel-based signed differential mapping (SDM) method was used to clarify brain regions, which showed anomalous activity in PIU subjects compared with healthy controls (HCs). Ten eligible publications consisting of 306 PIU subjects and 314 HCs were included in the SDM meta-analysis. Compared with HCs, subjects with PIU showed increased spontaneous neural functional activity in the left temporal pole of the superior temporal cortex, left amygdala, bilateral median cingulate cortex, and right insula. Meanwhile, a decreased spontaneous neural activity was identified in the left dorsolateral superior frontal gyrus and right middle frontal gyrus in the subjects with PIU. These abnormal brain regions are associated with cognitive executive control and emotional regulation. The consistent changes under different functional brain imaging indicators found in our study may provide important targets for the future diagnosis and intervention of PIU.

Systematic Review Registration:www.crd.york.ac.uk/PROSPERO, identifier: CRD42021258119.