bluuebunny/crossref_metadata_2025 huggingface dataset:
Tail-flick latency and self-mutilation following unilateral deafferentation in rats
Authors: Kříž N , Yamamotová A , Tobiáš J , Rokyta R
Published: March 2022

Unilateral deafferentation induced by transection of the C(4)-C(8) dorsal roots of spinal cord, followed by a complex of abnormal self-mutilating behavior, is interpreted as an animal model of chronic nociception. The objective of our study was to test the differences in tail-flick latency between intact control and unilaterally deafferented animals and to assess the changes in their acute nociceptive sensation. The initial hypothesis was that deafferentation-induced painful sensation might cause stress-induced analgesia that should be manifested as prolonged tail-flick latency. The experiment was carried out on 11 male and 10 female adult Wistar rats. The tail-flick latency was repeatedly measured over a period of 10 consecutive weeks both in the preoperative baseline period and following multiple cervical dorsal rhizotomy. Contrary to our hypothesis, unilateral deafferentation was followed by a significant shortening of the tail-flick latency both in males and females. In deafferented animals, compared to the controls, variations of tail-flick latency were reduced. In individual animals after deafferentation, concurrent dynamic changes were observed in self-mutilating behavior, in a loss and regaining of body weight, and in tail-flick latency. Our data suggest that changes in tail-flick latency may be interpreted in terms of central sensitization and that tail-flick latency might be considered as a useful marker of chronic nociception.
DEVELOPMENT CAPACITY AND SYNERGY OF REGIONAL AUTHORITIES IN EARLY DETECTION OF TERRORISM ACTIONS
Authors: Rusfiana Yudi , Hanifah Abu
Published: March 2022

Terorisme yang terjadi di Indonesia tidak terlepas dari rangkaian terorisme global, deteksi dini harus dilakukan melalui peningkatan kapasitas dan sinergitas pejabat daerah yang memiliki fungsi intelijen baik di lingkungan TNI, Poliri maupun pemerintah daerah. Optimalisasi kapasitas dan sinergi para pejabat tersebut dapat dilakukan melalui Pemerintah, termasuk pemerintah daerah, dengan mensinergikan deteksi dini melalui berbagai cara, terutama dengan melakukan tindakan sesuai prosedur hukum yang berlaku. Pemerintah melalui pejabat terkait telah melakukan pendekatan melalui tokoh masyarakat, tokoh agama moderat dan mereka yang cenderung radikal dalam rangka mengubah pemikiran radikal menjadi moderat, yaitu dengan memberikan pemahaman yang benar tentang istilah jihad. Dari peningkatan kapasitas dan sinergi tersebut, diharapkan aksi terorisme dapat selalu diantisipasi.

Kata kunci: Deteksi dini, Aparatur Teritorial, Terorisme
World Class Sub District Model
Authors: Batubara Yusi Eva , Wasistiono Sadu
Published: March 2022

Konsep pemerintahan kelas dunia selama ini berlaku pada tingkatan negara. Secara eksplisit kebijakan politik yang ditetapkan melalui Perpres Nomor 81 Tahun 2010 belum ada roadmap terinci untuk setiap susunan pemerintahan, apalagi sampai tingkat kecamatan. Mengingat belum adanya parameter tentang kecamatan berkelas dunia, maka perlu disusun konsep awal dengan memadukan antara berbagai kebijakan dengan teori. Hal ini sejalan dengan tekad Pemerintah Kabupaten Sumedang yang ingin unggul di tingkat nasional. Penelitian ini menggunakan metode SWAR, memadukan konsep SWOT dan SOAR. Konsep baru yang dihasilkan dalam penelitian ini meliputi 11 aspek diantaranta: penentuan model dan kecamatan; penentuan kewenangan kecamatan terpilih; penentuan core business kecamatan terpilih; penentuan besarnya anggaran kecamatan terpilih; penentuan bentuk dan susunan organisasi kecamatan terpilih; penentuan banyaknya ASN kecamatan terpilih; pengukuran kinerja kecamatan kecamatan terpilih; pengembangan IT di kecamatan; kepemimpinan camat di kecamatan terpilih; evaluasi pada kecamatan terpilih; peta jalan menuju pemerintahan kecamatan kelas dunia.
Structural Remodeling and Rotational Activity in Persistent/Long-Lasting Atrial Fibrillation: Gender-Effect Differences and Impact on Post-ablation Outcome
Authors: Ríos-Muñoz Gonzalo R. , Soto Nina , Ávila Pablo , Carta Alejandro , Atienza Felipe , Datino Tomás , González-Torrecilla Esteban , Fernández-Avilés Francisco , Arenal Ángel
Published: March 2022

Background

Structural and post-ablation gender differences are reported in atrial fibrillation (AF). We analyzed the gender differences in structural remodeling and AF mechanisms in patients with persistent/long-lasting AF who underwent wide area circumferential pulmonary vein isolation (WACPVI).

Materials and Methods

Ultra-high-density mapping was used to study atrial remodeling and AF drivers in 85 consecutive patients. Focal and rotational activity (RAc) were identified with the CartoFinder system and activation sequence analysis. The impact of RAc location on post-ablation outcomes was analyzed.

Results

This study included 64 men and 21 women. RAc was detected in 73.4% of men and 38.1% of women (p = 0.003). RAc patients had higher left atrium (LA) voltage (0.64 ± 0.3 vs. 0.50 ± 0.2 mV; p = 0.01), RAc sites had higher voltage than non-RAc sites 0.77 ± 0.46 vs. 0.53 ± 0.37 mV (p < 0.001). Women had lower LA voltage than men (0.42 vs. 0.64 mV; p < 0.001), including pulmonary vein (PV) antra (0.16 vs. 0.30 mV; p < 0.001) and posterior wall (0.34 vs. 0.51 mV; p < 0.001). RAc in the posterior atrium was recorded in few women (23.8 vs. 54.7% in men; p = 0.014). AF recurrence rate was higher in patients with RAc outside WACPVI than those with all RAc inside WACPVI or no RAc (63.4 vs. 11.1 and 31.0%; p = 0.008 and p = 0.01). Comparison of selected patients using propensity score matching confirmed lower atrial voltage (0.4 ± 0.2 vs. 0.7 ± 0.3 mV; p = 0.007) and less RAc (38 vs. 75%; p = 0.02) in women.

Conclusion

Women have shown more advanced structural remodeling at ablation, which is associated with a lower incidence of RAc (usually located outside the WACPVI). These findings could explain post-ablation gender differences.
Diagnostic Accuracy of Subtraction Coronary CT Angiography in Severely Calcified Segments: Comparison Between Readers With Different Levels of Experience
Authors: Li Fang , He Qing , Xu Lixue , Zhou Yan , Sun Yufei , Wang Zhenchang , Xu Yinghao , Yang Zhenghan , He Yi
Published: March 2022

Purpose

Subtraction coronary CT angiography (CCTA) may reduce blooming and beam-hardening artifacts. This study aimed to assess its value in improving the diagnostic accuracy of readers with different experience levels.

Method

We prospectively enrolled patients with target segment who underwent CCTA and invasive coronary angiography (ICA). Target segment images were independently evaluated by three groups of radiologists with different experience levels with CCTA using ICA as the standard reference. Diagnostic accuracy was measured by the area under the curve (AUC), using ≥50% stenosis as the cut-off value.

Results

In total, 134 target segments with severe calcification from 47 patients were analyzed. The mean specificity of conventional CCTA for each group ranged from 22.4 to 42.2%, which significantly improved with subtraction CCTA, ranging from 81.3 to 85.7% (all p < 0.001). The mean sensitivity of conventional CCTA for each group ranged from 83.3 to 88.0%. Following calcification subtraction, the mean sensitivity decreased for the novice (p < 0.001) and junior (p = 0.017) radiologists but was unchanged for the senior radiologists (p = 0.690). With subtraction CCTA, the mean AUCs of CCTA significantly increased: values ranged from 0.53, 0.54, and 0.61 to 0.70, 0.74, and 0.85 for the novice, junior, and senior groups (all p < 0.001).

Conclusion

Subtraction CCTA could improve the diagnostic accuracy of radiologists at all experience levels of CCTA interpretation.
Prognostic Value of Coronary Angiography-Derived Fractional Flow Reserve Immediately After Stenting
Authors: Zhou Zuoyi , Zhu Baozhen , Fan Fangfang , Yang Fan , Fang Shu , Wang Zhi , Qiu Lin , Gong Yanjun , Huo Yong
Published: March 2022

Objectives

The aim of this study was to investigate the potential prognostic value of post-percutaneous coronary intervention (PCI) angiography-derived fractional flow reserve (FFR) and its gradient across the stent.

Background

Post-PCI FFR and its gradient across the stent have been proved to be associated with clinical outcomes. However, little is known about the prognostic value of post-PCI coronary angiography-derived FFR and its gradient across the stent.

Methods

Patients diagnosed with coronary heart disease and participated in drug-eluting stent (DES) clinical trials for stent implantation in a single center were included for this retrospective analysis. A novel coronary angiography-derived FFR (caFFR) and its gradient across the stent were calculated offline using two projections from coronary angiography performed after PCI. Clinical follow-up was completed at 9 months after the index procedure and the primary outcome was target vessel failure (TVF), defined as a composite of target vessel-related myocardial infarction (MI), target vessel-related revascularization (TVR), and cardiac death. Coronary angiography was also performed at the 9 months follow-up time to get data of late lumen loss (LLL) and percent diameter stenosis (%DS).

Results

A total of 159 vessels in 136 patients were analyzed. The mean value of post-PCI caFFR was 0.90 ± 0.06. The median value of trans-stent caFFR gradient (ΔcaFFRstent) was 0.04 (interquartile range 0.02–0.08). ΔcaFFRstent>0 was demonstrated in 147 vessels (92.45%). The TVF rate was significantly higher in patients with post-PCI caFFR < 0.90 (4 [8.16%] vs. 1 [1.15%], P = 0.037), which was mainly achieved by the difference between the TVR rate. In the subgroup with lesions located in the left anterior descending coronary artery (LAD), post-PCI caFFR was an independent predictor of LLL (β = −1.07, 95% CI: −1.74 to −0.39, P = 0.002) and %DS at follow-up (β = −30.24, 95% CI: −56.44 to −4.04, P = 0.025), ΔcaFFRstent was an independent predictor of LLL (β=0.98, 95% CI:0.13–1.83, P = 0.026).

Conclusion

Suboptimal post-PCI caFFR and trans-stent caFFR gradient were common among vessels immediately after stenting. Lower post-PCI caFFR was associated with a higher rate of 9-month TVF. After LAD PCI, both post-PCI caFFR and its gradient across stent were independent predictors of the neointimal proliferation of the target vessel evaluated by LLL and %DS at follow-up.
Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics
Authors: Soukarieh Omar , Meguerditchian Caroline , Proust Carole , Aïssi Dylan , Eyries Mélanie , Goyenvalle Aurélie , Trégouët David-Alexandre
Published: March 2022

High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in the identification of genetic variations contributing to the risk of rare (Mendelian) and common (multifactorial) human diseases. So far, they have led to numerous successes in identifying rare disease-causing mutations in coding regions, but few in non-coding regions that include introns, untranslated (UTR), and intergenic regions. One class of neglected non-coding variations is that of 5′UTR variants that alter upstream open reading frames (upORFs) of the coding sequence (CDS) of a natural protein coding transcript. Following a brief summary of the molecular bases of the origin and functions of upORFs, we will first review known 5′UTR variations altering upORFs and causing rare cardiovascular disorders (CVDs). We will then investigate whether upORF-affecting single nucleotide polymorphisms could be good candidates for explaining association signals detected in the context of genome-wide association studies for common complex CVDs.
Case Report: Cardiac Tamponade in Association With Cytokine Release Syndrome Following CAR-T Cell Therapy
Authors: Moriyama Shohei , Fukata Mitsuhiro , Yokoyama Taku , Ueno Shohei , Nunomura Takuya , Mori Yasuo , Kato Koji , Miyamoto Toshihiro , Akashi Koichi
Published: March 2022

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy.

Case Summary

A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion.

Conclusion

Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.
Predicting Soil Organic Carbon Dynamics of Integrated Crop-Livestock System in Brazil Using the CQESTR Model
Authors: Oliveira Janaina M. , Gollany Hero T. , Polumsky Robert Wayne , Madari Beata E. , Leite Luiz F. C. , Machado Pedro L. O. A. , Carvalho Márcia T. M.
Published: March 2022

Land degradation and reduction in productivity have resulted in losses of soil organic carbon (SOC) in agricultural areas in Brazil. Our objectives were to 1) evaluate the predictive performance of CQESTR model for a tropical savannah; and 2) examine the effect of integrated management systems, including Integrated Crop-Livestock System (ICLS) scenarios on SOC stocks. Two long-term paddocks, under similar edaphic and climate conditions were used in this study. In Paddock 4 (P4) the rotation was corn (Zea mays L.) and 3.5/4.5 years pasture (Urochloa ruziziensis), while rotations in Paddock 5 (P5) included 2.5 years of soybean (Glycine max L.), dryland rice (Oryza sativa L.), and corn followed by 2.5/3.5 years pasture (U. brizantha). Measured and CQESTR simulated values were significantly (0.0001) correlated (r = 0.94) with a mean square deviation (MSD) of 7.55, indicating that the model captured spatial-temporal dynamics of SOC. Predicted SOC increased by 18.0 and 12.04 Mg ha−1 at the rate of 0.90 and 0.60 Mg ha−1 year−1 under current ICLS management for P4 and P5, respectively, by 2039. ICLS increased soil C sequestration compared to simple grain cropping systems under both NT and CT due to high biomass input into the production system.
Identification of lncRNA/circRNA-miRNA-mRNA ceRNA Network as Biomarkers for Hepatocellular Carcinoma
Authors: Chen Shanshan , Zhang Yongchao , Ding Xiaoyan , Li Wei
Published: March 2022

Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer, with the incidence and mortality rates increasing every year. Despite the improvement of clinical management, substantial challenges remain due to its high recurrence rates and short survival period. This study aimed to identify potential diagnostic and prognostic biomarkers in HCC through bioinformatic analysis.

Methods: Datasets from GEO and TCGA databases were used for the bioinformatic analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out by WebGestalt website and clusterProfiler package of R. The STRING database and Cytoscape software were used to establish the protein-protein interaction (PPI) network. The GEPIA website was used to perform expression analyses of the genes. The miRDB, miRWalk, and TargetScan were employed to predict miRNAs and the expression levels of the predicted miRNAs were explored via OncomiR database. LncRNAs were predicted in the StarBase and LncBase while circRNA prediction was performed by the circBank. ROC curve analysis and Kaplan-Meier (KM) survival analysis were performed to evaluate the diagnostic and prognostic value of the gene expression, respectively.

Results: A total of 327 upregulated and 422 downregulated overlapping DEGs were identified between HCC tissues and noncancerous liver tissues. The PPI network was constructed with 89 nodes and 178 edges and eight hub genes were selected to predict upstream miRNAs and ceRNAs. A lncRNA/circRNA-miRNA-mRNA network was successfully constructed based on the ceRNA hypothesis, including five lncRNAs (DLGAP1-AS1, GAS5, LINC00665, TYMSOS, and ZFAS1), six circRNAs (hsa_circ_0003209, hsa_circ_0008128, hsa_circ_0020396, hsa_circ_0030051, hsa_circ_0034049, and hsa_circ_0082333), eight miRNAs (hsa-miR-150-5p, hsa-miR-19b-3p, hsa-miR-23b-3p, hsa-miR-26a-5p, hsa-miR-651-5p, hsa-miR-10a-5p, hsa-miR-214-5p and hsa-miR-486-5p), and five mRNAs (CDC6, GINS1, MCM4, MCM6, and MCM7). The ceRNA network can promote HCC progression via cell cycle, DNA replication, and other pathways. Clinical diagnostic and survival analyses demonstrated that the ZFAS1/hsa-miR-150-5p/GINS1 ceRNA regulatory axis had a high diagnostic and prognostic value.

Conclusion: These results revealed that cell cycle and DNA replication pathway could be potential pathways to participate in HCC development. The ceRNA network is expected to provide potential biomarkers and therapeutic targets for HCC management, especially the ZFAS1/hsa-miR-150-5p/GINS1 regulatory axis.
Causal Association and Shared Genetics Between Asthma and COVID-19
Authors: Baranova Ancha , Cao Hongbao , Chen Jiu , Zhang Fuquan
Published: March 2022

Objectives

Recent studies suggest that asthma may have a protective effect on COVID-19.We aimed to investigate the causality between asthma and two COVID-19 outcomes and explore the mechanisms underlining this connection.

Methods

Summary results of GWAS were used for the analyses, including asthma (88,486 cases and 447,859 controls), COVID-19 hospitalization (6,406 hospitalized COVID-19 cases and 902,088 controls), and COVID-19 infection (14,134 COVID-19 cases and 1,284,876 controls). The Mendelian randomization (MR) analysis was performed to evaluate the causal effects of asthma on the two COVID-19 outcomes. A cross-trait meta-analysis was conducted to analyze genetic variants within two loci shared by COVID-19 hospitalization and asthma.

Results

Asthma is associated with decreased risk both for COVID-19 hospitalization (odds ratio (OR): 0.70, 95% confidence interval (CI): 0.70-0.99) and for COVID-19 infection (OR: 0.83, 95%CI: 0.51-0.95). Asthma and COVID-19 share two genome-wide significant genes, including ABO at the 9q34.2 region and OAS2 at the 12q24.13 region. The meta-analysis revealed that ABO and ATXN2 contain variants with pleiotropic effects on both COVID-19 and asthma.

Conclusion

In conclusion, our results suggest that genetic liability to asthma is associated with decreased susceptibility to SARS-CoV-2 and to severe COVID-19 disease, which may be due to the protective effects of ongoing inflammation and, possibly, related compensatory responses against COVID-19 in its early stage.
Whole-Transcriptome Profiling and circRNA-miRNA-mRNA Regulatory Networks in B-Cell Development
Authors: Pan Jie , Hu Saineng , Ren Xuanyao , Hu Hao , Deng Xiaoying , Yu Bo , Cobos Inma , Chen Xiaofan , Zhang Wei
Published: March 2022

The generation and differentiation of B lymphocytes (B cells) is a flexible process with many critical regulatory factors. Previous studies indicated that non-coding RNAs play multiple roles in the development of lymphocytes. However, little has been known about the circular RNA (circRNA) profiles and their competing endogenous RNA (ceRNA) networks in B-cell development and differentiation. Here, four B-cell subsets were purified from single-cell suspensions of mouse bone marrow. Then RNA sequencing (RNA-Seq) was used to display expression profiles of circRNAs, miRNAs and mRNAs during B-cell differentiation. 175, 203, 219 and 207 circRNAs were specifically expressed in pro-B cells, pre-B cells, immature B cells and mature B cells, respectively. The circRNA-associated ceRNA networks constructed in two sequential stages of B-cell differentiation revealed the potential mechanism of circRNAs in these processes. This study is the first to explore circRNA profiles and circRNA-miRNA-mRNA networks in different B-cell developmental stages of mouse bone marrow, which contribute to further research on their mechanism in B-cell development and differentiation.
Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology
Authors: Fernández-Velasco José I. , Monreal Enric , Kuhle Jens , Meca-Lallana Virginia , Meca-Lallana José , Izquierdo Guillermo , Oreja-Guevara Celia , Gascón-Giménez Francisco , Sainz de la Maza Susana , Walo-Delgado Paulette E. , Lapuente-Suanzes Paloma , Maceski Aleksandra , Rodríguez-Martín Eulalia , Roldán Ernesto , Villarrubia Noelia , Saiz Albert , Blanco Yolanda , Diaz-Pérez Carolina , Valero-López Gabriel , Diaz-Diaz Judit , Aladro Yolanda , Brieva Luis , Íñiguez Cristina , González-Suárez Inés , Rodríguez de Antonio Luis A , García-Domínguez José M. , Sabin Julia , Llufriu Sara , Masjuan Jaime , Costa-Frossard Lucienne , Villar Luisa M.
Published: March 2022

Objective

To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS).

Methods

Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula.

Results

More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels.

Conclusion

Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.
Soluble C-Type Lectin-Receptor Ligands Stimulate ROS Production in Dendritic Cells and Potentiate Killing of MRSA as Well as the MRSA Induced IL-12 Production
Authors: Eld Helene M. S. , Johnsen Peter R. , Nielsen Emilie M. , Jørgensen Frederikke Z. , Lindstrøm-Svendsen Marie , Baldry Mara , Ingmer Hanne , Frøkiær Hanne
Published: March 2022

Methicillin resistant Staphylococcus aureus (MRSA) has developed resistance to most β-lactam antibiotics leaving few treatment options against infections with MRSA. Through mannose receptors, mannan potentiates IL-12 production induced by Gram-positive bacteria, a cytokine crucial in the clearance of S. aureus infection. We investigated the IL-12 potentiating effect of mannan pre-treatment of bone marrow-derived dendritic cells prior to stimulation with clinical MRSA strains. Mannan almost doubled IL-12 as well as IFN-β production in response to USA300, also when USA300 was treated with the β-lactam cefoxitin. The MRSA-induced IL-12 production was dependent on bacterial uptake and reactive oxygen species (ROS). Mannan alone induced ROS production, and in combination with USA300, the ROS produced corresponded to the sum induced by mannan and USA300. Addition of a monoclonal antibody against the mannose receptor likewise enhanced USA300-induced IL-12 and induced ROS production. Mannan addition further increased the endocytosis as well as the rate of endosomal killing of bacteria. Pre-treatment with soluble β-glucans also induced ROS and potentiated the USA300-induced IL-12 indicating that other C-type receptors may play a similar role. In the presence of the pro-inflammatory mediators, GM-CSF or IFN-γ, the mannan-enhanced IL-12 production increased further. The USA300-induced and the mannan-facilitated enhanced IFN-β and IL-12 showed same dependency on MAPK c-Jun N-terminal kinase signaling, suggesting that mannan enhances the signals already induced by the bacteria, rather than changing them. We suggest that the C-type lectin-induced ROS production is a key factor in the IFN-β and IL-12 potentiation.
High Levels of CD244 Rather Than CD160 Associate With CD8+ T-Cell Aging
Authors: Wang Xinyue , Wang Di , Du Juan , Wei Yuqing , Song Rui , Wang Beibei , Qiu Shuang , Li Bei , Zhang Leidan , Zeng Yongqin , Zhao Hongxin , Kong Yaxian
Published: March 2022

Aging leads to functional dysregulation of the immune system, especially T cell defects. Previous studies have shown that the accumulation of co-inhibitory molecules plays an essential role in both T cell exhaustion and aging. In the present study, we showed that CD244 and CD160 were both up-regulated on CD8+T cells of elderly individuals. CD244+CD160-CD8+T cells displayed the increased activity of β-GAL, higher production of cytokines, and severe metabolic disorders, which were characteristics of immune aging. Notably, the functional dysregulation associated with aging was reversed by blocking CD244 instead of CD160. Meanwhile, CD244+CD160+CD8+T cells exhibited features of exhaustion, including lower levels of cytokine, impaired proliferation, and intrinsic transcriptional regulation, compared to CD244+CD160-population. Collectively, our findings demonstrated that CD244 rather than CD160 acts as a prominent regulator involved in T cell aging, providing a solid therapeutic target to improve disorders and comorbidities correlated to immune system aging.
Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis
Authors: Thomas Charles , Leleu Damien , Masson David
Published: March 2022

HIF-1α exerts both detrimental and beneficial actions in atherosclerosis. While there is evidence that HIF-1α could be pro-atherogenic within the atheromatous plaque, experimental models of atherosclerosis suggest a more complex role that depends on the cell type expressing HIF-1α. In atheroma plaques, HIF-1α is stabilized by local hypoxic conditions and by the lipid microenvironment. Macrophage exposure to oxidized LDLs (oxLDLs) or to necrotic plaque debris enriched with oxysterols induces HIF-1α -dependent pathways. Moreover, HIF-1α is involved in many oxLDL-induced effects in macrophages including inflammatory response, angiogenesis and metabolic reprogramming. OxLDLs activate toll-like receptor signaling pathways to promote HIF-1α stabilization. OxLDLs and oxysterols also induce NADPH oxidases and reactive oxygen species production, which subsequently leads to HIF-1α stabilization. Finally, recent investigations revealed that the activation of liver X receptor, an oxysterol nuclear receptor, results in an increase in HIF-1α transcriptional activity. Reciprocally, HIF-1α signaling promotes triglycerides and cholesterol accumulation in macrophages. Hypoxia and HIF-1α increase the uptake of oxLDLs, promote cholesterol and triglyceride synthesis and decrease cholesterol efflux. In conclusion, the impact of HIF-1α on cholesterol homeostasis within macrophages and the feedback activation of the inflammatory response by oxysterols via HIF-1α could play a deleterious role in atherosclerosis. In this context, studies aimed at understanding the specific mechanisms leading to HIF-1α activation within the plaque represents a promising field for research investigations and a path toward development of novel therapies.
Cytochrome P450 and Glutathione S-Transferase Confer Metabolic Resistance to SYP-14288 and Multi-Drug Resistance in Rhizoctonia solani
Authors: Cheng Xingkai , Dai Tan , Hu Zhihong , Cui Tongshan , Wang Weizhen , Han Ping , Hu Maolin , Hao Jianjun , Liu Pengfei , Liu Xili
Published: March 2022

SYP-14288 is a fungicide as an uncoupler of oxidative phosphorylation, which is effective in controlling fungal pathogens like Rhizoctonia solani. To determine whether R. solani can develop SYP-14288 resistance and possibly multi-drug resistance (MDR), an SYP-14288-resistant mutant of R. solani X19-7 was generated from wild-type strain X19, and the mechanism of resistance was studied through metabolic and genetic assays. From metabolites of R. solani treated with SYP-14288, three compounds including M1, M2, and M3 were identified according to UPLC-MS/MS analysis, and M1 accumulated faster than M2 and M3 in X19-7. When X19-7 was treated by glutathione-S-transferase (GST) inhibitor diethyl maleate (DEM) and SYP-14288 together, or by DEM plus one of tested fungicides that have different modes of action, a synergistic activity of resistance occurred, implying that GSTs promoted metabolic resistance against SYP-14288 and therefore led to MDR. By comparing RNA sequences between X19-7 and X19, six cytochrome P450s (P450s) and two GST genes were selected as a target, which showed a higher expression in X19-7 than X19 both before and after the exposure to SYP-14288. Furthermore, heterologous expression of P450 and GST genes in yeast was conducted to confirm genes involved in metabolic resistance. In results, the P450 gene AG1IA_05136 and GST gene AG1IA_07383 were related to fungal resistance to multiple fungicides including SYP-14288, fluazinam, chlorothalonil, and difenoconazole. It was the first report that metabolic resistance of R. solani to uncouplers was associated with P450 and GST genes.
Whole Genome Sequencing and RNA-seq-Driven Discovery of New Targets That Affect Carotenoid Synthesis in Phaffia rhodozyma
Authors: Shi Zhihui , He Xiaoxian , Zhang Hailiang , Guo Xuena , Cheng Yanfei , Liu Xuelian , Wang Zhaoyue , He Xiuping
Published: March 2022

Carotenoids are unsaturated compounds with terpene groups. Among them, astaxanthin has strong antioxidant properties. It is widely used in aquaculture, food, medicine, and cosmetics with a broad market prospect. Phaffia rhodozyma is an important microorganism that synthesizes astaxanthin, but its wild strains have low pigment content, long growth cycle, and low fermentation temperature. Therefore, it is important to research the genetic improvement of the physiological and biochemical properties of P. rhodozyma. In this study, the atmospheric and room temperature plasma mutagenesis technology was adopted, through the functional evolution of the carotenoid production performance; then, through the comparative analysis of the genomics and transcriptomics of the wild strain and evolved strain, the key factor GST1 gene that affects carotenoid synthesis was discovered.
Advantages of Using Extremophilic Bacteria for the Biosynthesis of Metallic Nanoparticles and Its Potential for Rare Earth Element Recovery
Authors: Atalah Joaquín , Espina Giannina , Blamey Lotsé , Muñoz-Ibacache Sebastián A. , Blamey Jenny M.
Published: March 2022

The exceptional potential for application that metallic nanoparticles (MeNPs) have shown, has steadily increased their demand in many different scientific and technological areas, including the biomedical and pharmaceutical industry, bioremediation, chemical synthesis, among others. To face the current challenge for transitioning toward more sustainable and ecological production methods, bacterial biosynthesis of MeNPs, especially from extremophilic microorganisms, emerges as a suitable alternative with intrinsic added benefits like improved stability and biocompatibility. Currently, biogenic nanoparticles of different relevant metals have been successfully achieved using different bacterial strains. However, information about biogenic nanoparticles from rare earth elements (REEs) is very scarce, in spite of their great importance and potential. This mini review discusses the current understanding of metallic nanoparticle biosynthesis by extremophilic bacteria, highlighting the relevance of searching for bacterial species that are able to biosynthesize RRE nanoparticles.
Novel Secreted Peptides From Rhizopus arrhizus var. delemar With Immunomodulatory Effects That Enhance Fungal Pathogenesis
Authors: Soliman Sameh S. M. , El-Labbad Eman M. , Abu-Qiyas Ameera , Fayed Bahgat , Hamoda Alshaimaa M. , Al-Rawi Ahmed M. , Dakalbab Salam , El-Shorbagi Abdel-Nasser A. , Hamad Mawieh , Ibrahim Ashraf S. , Mohammad Mohammad G.
Published: March 2022

Secreted fungal peptides are known to influence the interactions between the pathogen and host innate immunity. The aim of this study is to screen and evaluate secreted peptides from the fungus Rhizopus arrhizus var. delemar for their immunomodulatory activity. By using mass spectrometry and immuno-informatics analysis, we identified three secreted peptides CesT (S16), Colicin (S17), and Ca2+/calmodulin-dependent protein kinase/ligand (CAMK/CAMKL; S27). Culturing peripheral blood-derived monocytic macrophages (PBMMs) in the presence of S16 or S17 caused cell clumping, while culturing them with S27 resulted in the formation of spindle-shaped cells. S27-treated PBMMs showed cell cycle arrest at G0 phase and exhibited alternatively activated macrophage phenotype with pronounced reduction in scavenger receptors CD163 and CD206. Homology prediction indicated that IL-4/IL-13 is the immunomodulatory target of S27. Confirming this prediction, S27 initiated macrophage activation through phosphorylation of STAT-6; STAT-6 inhibition reversed the activity of S27 and reduced the formation of spindle-shaped PBMMs. Lastly, S27 treatment of PBMMs was associated with altered expression of key iron regulatory genes including hepcidin, ferroportin, transferrin receptor 1, and ferritin in a pattern consistent with increased cellular iron release; a condition known to enhance Rhizopus infection. Collectively, R. arrhizus var. delemar secretes peptides with immunomodulatory activities that support fungal pathogenesis. Targeting the IL-4/IL-13R/STAT-6 axis is a potential therapeutic approach to enhance the PBMM-mediated fungal phagocytosis. This represents a potential new approach to overcome lethal mucormycosis.
Social Determinants of Inter-Individual Variability and Vulnerability: The Role of Dopamine
Authors: Faure Philippe , Fayad Sophie L. , Solié Clément , Reynolds Lauren M.
Published: March 2022

Individuals differ in their traits and preferences, which shape their interactions, their prospects for survival and their susceptibility to diseases. These correlations are well documented, yet the neurophysiological mechanisms underlying the emergence of distinct personalities and their relation to vulnerability to diseases are poorly understood. Social ties, in particular, are thought to be major modulators of personality traits and psychiatric vulnerability, yet the majority of neuroscience studies are performed on rodents in socially impoverished conditions. Rodent micro-society paradigms are therefore key experimental paradigms to understand how social life generates diversity by shaping individual traits. Dopamine circuitry is implicated at the interface between social life experiences, the expression of essential traits, and the emergence of pathologies, thus proving a possible mechanism to link these three concepts at a neuromodulatory level. Evaluating inter-individual variability in automated social testing environments shows great promise for improving our understanding of the link between social life, personality, and precision psychiatry – as well as elucidating the underlying neurophysiological mechanisms.
Plasma Calprotectin Is Predictive for Short-Term Functional Outcomes of Acute Ischemic Stroke
Authors: Hu Zicheng , Li Haihua , Zhu Yongping , Zhang Jun , Yang Xiao , Huang Rongzhong , Li Yongyong , Ran Haitao , Shang Tingting
Published: March 2022

Background

Blood-based prognostic biomarkers of acute ischemic stroke (AIS) are limiting. Calprotectin is suggested to be involved in directing post-stroke inflammatory conditions. However, the pathological alteration of circulating calprotectin in AIS is yet to be thoroughly elucidated. Therefore, this study aimed to investigate the levels and clinical relevance of calprotectin in AIS.

Methods

This study recruited 271 patients with AIS within 24 h since symptom onset and 145 non-stroke healthy controls (HC) from February 1, 2018, to Dec 31, 2020. Patients were followed up for 2 weeks for observation of functional outcomes, as determined by the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Plasma calprotectin concentrations were determined by ELISA.

Results

Plasma calprotectin concentrations were significantly higher in patients with AIS compared with controls [patients vs. control: median (IQR) 54.2 (39.01–99.04) vs. 50.04 (35.42–61.22), p < 0.001]. Besides, patients with poor prognosis, as defined by mRS ≥ 3, had significantly higher calprotectin levels than patients with good prognosis [poor prognosis patients vs. good prognosis patients: median (IQR) 61.99 (47.52–108) vs. 43.36 (33.39–60.2), p < 0.001]. Plasma calprotectin levels were positively associated with the disease severity of AIS, as reflected by infarction volume and NIHSS score at baseline. Furthermore, baseline calprotectin was found to be independently associated with poor prognosis [odds ratio (OR): 1.02, 95% CI: 1.01–1.03] and disease progression (OR: 1.03, 95% CI: 1.02–1.04) of AIS during a 2-week follow-up, with adjustment of possible confounding factors.

Conclusion

Plasma calprotectin is associated with short-term functional outcomes of AIS.
A Novel SACS Variant Identified in a Chinese Patient: Case Report and Review of the Literature
Authors: Chen Yuchao , Lu Xiaodong , Jin Yi , Li Dan , Ye Xiaojun , Tao Chenjuan , Zhou Menglu , Jiang Haibo , Yu Hao
Published: March 2022

Mutations in the SACS gene have been linked to autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS). It is a clinically and genetically heterogeneous disease characterized by slow progressive ataxia, spasticity, sensorimotor neuropathy, and a combination of other manifestations, such as lack of spasticity, hearing loss, and epileptic seizures. Currently, there have been very few case reports regarding the SACS gene mutation in Chinese patients. Here, we describe a 35-year-old Chinese patient carrying a novel variant in SACS (c.11486C>T) presenting with progressive ataxia and demyelinating peripheral neuropathy. We then reviewed 22 Chinese cases carrying SACS gene mutations, including our patient. All of them had a cerebellar ataxia gait and showed cerebellar atrophy on brain magnetic resonance imaging (MRI). A total of 28 SACS mutations were identified in these patients. Our study further expands the mutation spectrum of the SACS gene and contributes to the evaluation of genotype-phenotype correlations.
Identification and Classification of Parkinsonian and Essential Tremors for Diagnosis Using Machine Learning Algorithms
Authors: Xing Xupo , Luo Ningdi , Li Shun , Zhou Liche , Song Chengli , Liu Jun
Published: March 2022

Due to overlapping tremor features, the medical diagnosis of Parkinson’s disease (PD) and essential tremor (ET) mainly relies on the clinical experience of doctors, which often leads to misdiagnosis. Seven predictive models using machine learning algorithms including random forest (RF), eXtreme Gradient Boosting (XGBoost), support vector machine (SVM), logistic regression (LR), ridge classification (Ridge), backpropagation neural network (BP), and convolutional neural network (CNN) were evaluated and compared aiming to better differentiate between PD and ET by using accessible demographics and tremor information of the upper limbs. The tremor information including tremor acceleration and surface electromyogram (sEMG) signals were collected from 398 patients (PD = 257, ET = 141) and then were used to train the established models to separate PD and ET. The performance of the models was evaluated by indices of accuracy and area under the curve (AUC), which indicated the ensemble learning models including RF and XGBoost showed the best overall predictive ability with accuracy above 0.84 and AUC above 0.90. Furthermore, the relative importance of sex, age, four postures, and five tremor features was analyzed and ranked showing that the dominant frequency of sEMG of flexors, the average amplitude of sEMG of flexors, resting posture, and winging posture had a greater impact on the diagnosis of PD, whereas sex and age were less important. These results provide a reference for the intelligent diagnosis of PD and show promise for use in wearable tremor suppression devices.
Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling
Authors: Zhu Xue , Zou Wenjun , Meng Xinmin , Ji Jiali , Wang Xun , Shu Hong , Chen Yuan , Pan Donghui , Wang Ke , Zhou Fanfan
Published: March 2022

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burden. Therefore, new drug therapies are highly desired for UM. Our in vitro studies showed that Elaiophylin, a late-stage autophagy inhibitor, exhibited an outstanding anticancer activity in human UM cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress and leading to autophagic cell death. Our mechanistic study revealed that Elaiophylin exerted its effect by down-regulating SIRT1 and thus influencing deacetylation and mitochondrial localization of FoxO3a. In our confirmatory experiments, SRT1720, a SIRT1 specific activator, could attenuate Elaiophylin-induced inhibition of mitophagy and elevation of oxidative stress, and such effects was partly reversed by FoxO3a knockdown. Our further in vivo studies showed that Elaiophylin dramatically inhibited tumor growth in the human UM xenograft mouse model, which was accompanied with a decreased SIRT1 expression. Thus, the current study is the first to demonstrate that Elaiophylin has a potent anti-cancer effect against UM, which activity is possibly mediated through regulating SIRT1-FoxO3a signaling axis. And Elaiophylin may be a new and promising drug candidate to treat human UM.
Medication Regimen Complexity and Medication Burden Among Patients With Type 2 Diabetes Mellitus: A Retrospective Analysis
Authors: Ab Rahman Norazida , Lim Ming Tsuey , Thevendran Shantini , Ahmad Hamdi Najwa , Sivasampu Sheamini
Published: March 2022

Introduction: Most type 2 diabetes mellitus (T2DM) patients with chronic conditions require multiple medications to achieve and maintain good glycemic control.

Objective: This study assessed medication burden, regimen complexity, and adherence among T2DM patients and evaluate its association with glycemic control.

Method: We analyzed data of 2,696 T2DM patients at public health clinics in Malaysia from January 2018 until May 2019. Medication burden was based on medication count, regimen complexity was measured using the validated Medication Regimen Complexity Index (MRCI) tool, and adherence was measured using proportion of days covered (PDC) formula. Logistic regression models were used to compute unadjusted and adjusted odds ratio (aOR) with 95% confidence interval (CI) for association between the medication parameters and glycemic control (HbA1c ≤ 7.0%) over a 90-day period.

Results: The cohort mean age was 60.4 years old (±10.8) and 62.9% were female. Overall, the average medication count was 4.8 with MRCI score of 15.1. Mean adherence score (PDC) was 90%. High medication count and MRCI scores were associated with lower odds of achieving good glycemic control (aOR 0.88; 95% CI 0.82, 0.94 and aOR 0.89; 95% CI 0.87, 0.92, respectively) while inverse association was observed between adherence and HbA1c level (aOR 2.7, 95% CI 1.66, 5.19). Similar findings were observed for diabetes-specific measures.

Conclusions: High medication count, high regimen complexity, and low medication adherence were associated with poor glycemic control over the 3-month follow-up period. These parameters could be used to identify patients with complex pharmacotherapy regimens so that targets for intervention can be taken to achieve optimum outcomes and ease of self-care.