bluuebunny/crossref_metadata_2025 huggingface dataset:
Stressor-Induced “Inflammaging” of Vascular Smooth Muscle Cells via Nlrp3-Mediated Pro-inflammatory Auto-Loop
Authors: Herrmann Jaqueline , Xia Mengdi , Gummi Manasa Reddy , Greco Anna , Schacke Annika , van der Giet Markus , Tölle Markus , Schuchardt Mirjam
Published: December 2021

Calcification of the vessel wall as one structural pathology of aged vessels is associated with high cardiovascular mortality of elderly patients. Aging is linked to chronic sterile inflammation and high burden of reactive oxygen species (ROS), leading to activation of pattern recognition receptors (PRRs) such as Nlrp3 in vascular cells. The current study investigates the role of PRR activation in the calcification of vascular smooth muscle cells (VSMCs). Therefore, in vitro cell culture of primary rat VSMCs and ex vivo aortic stimulations were used to analyze osteogenic, senescence and inflammatory markers via real-time PCR, in situ RNA hybridization, Western Blot, photometric assays and histological staining. Induction of ROS and DNA-damage by doxorubicin induces a shift of VSMC phenotype toward the expression of osteogenic, senescence and inflammatory proteins. Induction of calcification is dependent on Nlrp3 activity. Il-1β as a downstream target of Nlrp3 induces the synthetic, pro-calcifying VSMC phenotype. Inhibition of PRR with subsequent reduction of chronic inflammation might be an interesting target for reduction of calcification of VSMCs, with subsequent reduction of cardiovascular mortality of patients suffering from vessel stiffness.
Inflammation in the Pathogenesis of Arrhythmogenic Cardiomyopathy: Secondary Event or Active Driver?
Authors: Meraviglia Viviana , Alcalde Mireia , Campuzano Oscar , Bellin Milena
Published: December 2021

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiac disease characterized by arrhythmia and progressive fibro-fatty replacement of the myocardium, which leads to heart failure and sudden cardiac death. Inflammation contributes to disease progression, and it is characterized by inflammatory cell infiltrates in the damaged myocardium and inflammatory mediators in the blood of ACM patients. However, the molecular basis of inflammatory process in ACM remains under investigated and it is unclear whether inflammation is a primary event leading to arrhythmia and myocardial damage or it is a secondary response triggered by cardiomyocyte death. Here, we provide an overview of the proposed players and triggers involved in inflammation in ACM, focusing on those studied using in vivo and in vitro models. Deepening current knowledge of inflammation-related mechanisms in ACM could help identifying novel therapeutic perspectives, such as anti-inflammatory therapy.
Exercise-Induced Cardiac Fatigue in Soldiers Assessed by Echocardiography
Authors: Charton Marion , Kervio Gäelle , Matelot David , Lachard Thibault , Galli Elena , Donal Erwan , Carré François , Le Douairon Lahaye Solène , Schnell Frédéric
Published: December 2021

Background: Echocardiographic signs of exercise-induced cardiac fatigue (EICF) have been described after strenuous endurance exercise. Nevertheless, few data are available on the effects of repeated strenuous exercise, especially when associated with other constraints as sleep deprivation or mental stress which occur during military selection boot camps. Furthermore, we aimed to study the influence of experience and training level on potential EICF signs.

Methods: Two groups of trained soldiers were included, elite soldiers from the French Navy Special Forces (elite; n = 20) and non-elite officer cadets from a French military academy (non-elite; n = 38). All underwent echocardiography before and immediately after exposure to several days of uninterrupted intense exercise during their selection boot camps. Changes in myocardial morphology and function of the 4 cardiac chambers were assessed.

Results: Exercise-induced decrease in right and left atrial and ventricular functions were demonstrated with 2D-strain parameters in both groups. Indeed, both atrial reservoir strain, RV and LV longitudinal strain and LV global constructive work were altered. Increase in LV mechanical dispersion assessed by 2D-strain and alteration of conventional parameters of diastolic function (increase in E/e' and decrease in e') were solely observed in the non-elite group. Conventional parameters of LV and RV systolic function (LVEF, RVFAC, TAPSE, s mitral, and tricuspid waves) were not modified.

Conclusions: Alterations of myocardial functions are observed in soldiers after uninterrupted prolonged intense exercise performed during selection boot camps. These alterations occur both in elite and non-elite soldiers. 2D-strain is more sensitive to detect EICF than conventional echocardiographic parameters.
Associations Between Healthy Lifestyle Trajectories and the Incidence of Cardiovascular Disease With All-Cause Mortality: A Large, Prospective, Chinese Cohort Study
Authors: Ding Xiong , Fang Wei , Yuan Xiaojie , Seery Samuel , Wu Ying , Chen Shuohua , Zhou Hui , Wang Guodong , Li Yun , Yuan Xiaodong , Wu Shouling
Published: December 2021

Background: Lifestyles generally change across the life course yet no prospective study has examined direct associations between healthy lifestyle trajectories and subsequent cardiovascular disease (CVD) or all-cause mortality risk.

Methods: Healthy lifestyle score trajectories during 2006–2007, 2008–2009, and 2010–2011 were collated through latent mixture modeling. An age-scale based Cox proportional hazard regression model was implemented to calculate hazard ratios (HR) with corresponding 95% confidence intervals (CI) for developing CVD or all-cause mortality across healthy lifestyle trajectories.

Results: 52,248 participants were included with four distinct trajectories identified according to healthy lifestyle scores over 6 years i.e., low-stable (n = 11,248), high-decreasing (n = 7,374), low-increasing (n = 7,828), and high-stable (n = 25,799). Compared with the low-stable trajectory, the high-stable trajectory negatively correlated with lower subsequent risk of developing CVD (HR, 0.73; 95% CI, 0.65–0.81), especially stroke (HR, 0.70; 95% CI, 0.62–0.79), and all-cause mortality (HR, 0.89; 95% CI, 0.80–0.99) under a multivariable-adjusted model. A protective effect for CVD events was observed only in men and in those without diabetes, while a reduced risk of all-cause mortality was observed only in those older than 60 years, though interactions were not statistically significant. Marginally significant interactions were observed between the changing body mass index (BMI) group, healthy lifestyle score trajectories and stratified analysis. This highlighted an inverse correlation between the high-stable trajectory and CVD in BMI decreased and stable participants as well as all-cause mortality in the stable BMI group. The low-increasing trajectory also had reduced risk of CVD only when BMI decreased and in all-cause mortality only when BMI was stable.

Conclusions: Maintaining a healthy lifestyle over 6 years corresponds with a 27% lower risk of CVD and an 11% lower risk in all-cause mortality, compared with those engaging in a consistently unhealthy lifestyle. The benefit of improving lifestyle could be gained only after BMI change is considered further. This study provides further evidence from China around maintaining/improving healthy lifestyles to prevent CVD and early death.
Benefit and Risk of Prolonged Dual Antiplatelet Therapy After Percutaneous Coronary Intervention With Drug-Eluting Stents in Patients With Elevated Lipoprotein(a) Concentrations
Authors: Cui Kongyong , Wang Hao-Yu , Yin Dong , Zhu Chenggang , Song Weihua , Wang Hongjian , Jia Lei , Zhang Dong , Song Chenxi , Feng Lei , Dou Kefei
Published: December 2021

Background: Lipoprotein(a) is positively related to cardiovascular events in patients with coronary artery disease (CAD). Given that lipoprotein(a) has a prothrombotic effect, prolonged dual antiplatelet therapy (DAPT) might have a beneficial effect on reducing ischemic events in patients with elevated lipoprotein(a) levels after percutaneous coronary intervention (PCI). We performed this study to assess the efficacy and safety of prolonged DAPT (>1 year) in this population.

Methods: We evaluated a total of 3,025 CAD patients with elevated lipoprotein(a) levels who were event-free at 1 year after PCI from the prospective Fuwai PCI Registry, of which 913 received DAPT ≤ 1 year and 2,112 received DAPT>1 year. The primary endpoint was major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction or stroke.

Results: After a median follow-up of 2.4 years, patients who received DAPT>1 year were associated with lower risks of MACCE compared with DAPT ≤ 1 year (1.6 vs. 3.8%; hazard ratio [HR] 0.383, 95% confidence interval [CI] 0.238–0.616), which was primarily driven by the lower all-cause mortality (0.2 vs. 2.3%; HR 0.078, 95% CI 0.027–0.227). In addition, DAPT>1 year was also associated with lower risks of cardiac death, and definite/probable stent thrombosis than those who received DAPT ≤ 1 year (P < 0.05). Conversely, no difference was found between the two groups in terms of clinically relevant bleeding. Similar results were observed in multivariate Cox regression analysis and inverse probability of treatment weighting analysis.

Conclusions: In patients with elevated lipoprotein(a) concentrations after PCI, prolonged DAPT (>1 year) reduced ischemic cardiovascular events, including MACCE, all-cause mortality, cardiac mortality, and definite/probable stent thrombosis, without increase in clinically relevant bleeding risk compared with ≤ 1-year DAPT. Lipoprotein(a) levels might be a new important consideration when deciding the duration of DAPT after PCI.
Improving Carbonate Equilibria-Based Estimation of pCO2 in Anthropogenically Impacted River Systems
Authors: Nayna Omme K. , Begum Most Shirina , Ran Lishan , Park Ji-Hyung
Published: December 2021

Estimating riverine carbon dioxide (CO2) emissions has been constrained by lacking field measurements of the partial pressure of CO2 (pCO2) and inaccuracies in calculating pCO2 using carbonate equilibria-based models such as CO2SYS. To evaluate potential errors in applying the carbonate equilibria-based pCO2 calculation to river systems affected by monsoon rainfall and water pollution, we compared pCO2 values calculated using CO2SYS and those measured by headspace equilibration in five Asian rivers (Ganges, Mekong, Yangtze, Yellow, and Han rivers) undergoing various water pollution stages. Across the five rivers, calculated and measured pCO2 values exhibited larger discrepancies during the monsoon season, particularly in the low pH range, while in the Han River mismatches were also noticeable during the dry season. In the Han River, pH was negatively correlated with dissolved organic carbon (DOC) during the monsoon, indicating organic acids flushed from soils during rainfalls as a key factor for overestimated pCO2 at sites with low pH and alkalinity, whereas dry-season overestimation of pCO2 may be ascribed to non-carbonate alkalinity including organic acids and inorganic anions delivered by wastewater effluents or sporadic rainfalls. The four large rivers exhibited a positive correlation between pH and DOC in tributaries during the monsoon season, indicating that DOC flushed from soils may be diluted by monsoonal floods to such a degree as to exert little influence on pH and hence pCO2. Therefore, the monsoonal overestimation of pCO2 at sites with low pH and alkalinity warrants further investigation of other factors than non-carbonate alkalinity to explain the increased sensitivity of pCO2 to subtle changes in acidity and buffering. These results illustrate the importance of direct measurements of pCO2 in highly polluted rivers, especially during the monsoon season. For river systems lacking pCO2 measurements, we suggest that carbonate equilibria-based models be complemented with corrective measures: 1) presenting pCO2 values calculated from low pH values (pH < 6.5 for monsoon and pH < 6.3 for dry season) together with the pH range to warn potential overestimation; 2) using pre-established regressions between measured pCO2 and environmental variables to correct pCO2 values, particularly during wet periods when large changes in pH and acid buffering are expected.
Special Education and General Education Teacher Perceptions of Collaborative Teaching Responsibilities and Attitudes Towards an Inclusive Environment in Jordan
Authors: Alabdallat Bassam , Alkhamra Hatem , Alkhamra Rana
Published: December 2021

The purpose of this study was to investigate how general and special education instructors perceive their collaborative teaching responsibilities and their attitudes toward inclusive environments. A self-administered questionnaire was distributed to 300 teachers in accordance with the social interdependence theory and cooperative learning conceptual framework. The survey was composed of two parts. The first section examined collaborative teaching duties for both instructors. It included 29 items and four categories (planning, instruction, evaluation, and behavior management). The second section included 15 items to assess attitudes toward inclusion. The study enrolled a total of 233 teachers (123 in special education and 110 in general education) with a response rate of 78%. The results showed that there was agreement between general and special education on only one of the four domains (instruction). Additionally, special education teachers expressed a more favorable attitude toward inclusion than did general education teachers. The current situation’s implications were explored with an emphasis on the necessity for additional shared practical activities among teachers.
Ensemble Forecasting Frame Based on Deep Learning and Multi-Objective Optimization for Planning Solar Energy Management: A Case Study
Authors: Liu Yongjiu , Li Li , Zhou Shenglin
Published: December 2021

There are many prediction models that have been adopted to predict uncertain and non-linear photovoltaic power time series. Nonetheless, most models neglected the validity of data preprocessing and ensemble learning strategies, which leads to low forecasting precision and low stability of photovoltaic power. To effectively enhance photovoltaic power forecasting accuracy and stability, an ensemble forecasting frame based on the data pretreatment technology, multi-objective optimization algorithm, statistical method, and deep learning methods is developed. The proposed forecasting frame successfully integrates the advantages of multiple algorithms and validly depict the linear and nonlinear characteristic of photovoltaic power time series, which is conductive to achieving accurate and stable photovoltaic power forecasting results. Three datasets of 15-min photovoltaic power output data obtained from different time periods in Belgium were employed to verify the validity of the proposed system. The simulation results prove that the proposed forecasting frame positively surpasses all comparative hybrid models, ensemble models, and classical models in terms of prediction accuracy and stabilization. For one-, two-, and three-step predictions, the MAPE values obtained from the proposed frame were less than 2, 3, and 5%, respectively. Discussion results also verify that the proposed forecasting frame is obviously different from other comparative models, and is more stable and high-efficiency. Thus, the proposed frame is highly serviceable in elevating photovoltaic power forecasting performance and can be used as an efficient instrument for intelligent grid programming.
Abiotic Drivers of Seedling Bank Diversity in Subtropical Forests of Southern China
Authors: Martini Francesco , Zou Chaobo , Song Xiaoyang , Goodale Uromi Manage
Published: December 2021

Abiotic factors are important to shape plant community composition and diversity through processes described as environmental filtering. Most studies on plant diversity in forests focus on adult trees, while the abiotic drivers of forest seedling community characteristics are less understood. Here, we studied seedling banks’ composition, richness, diversity, and abundance, and investigated their relationships with microsite abiotic conditions along a wide elevational gradient. We sampled seedling communities in 312 1-m2 quadrats, distributed in 13 one-ha plots in four subtropical forests in south China, covering an elevation gradient of 1500 m, for 2 years. We measured light availability, slope, and 11 soil nutrients for each seedling quadrat. We used analysis of similarities and multivariate analysis of variance to compare the composition and abiotic drivers of the four forests’ seedling communities. We then used mixed models and structural equation modeling to test the direct and indirect effects of abiotic factors on seedling species richness, diversity, and abundance. The differences in seedling community composition among these forests were mostly explained by differences in elevations and soil nutrients. Seedling diversity as Shannon and Simpson diversity index decreased with increasing elevation and increased with increasing slope, but seedling abundance and species richness did not. Elevation had an indirect effect on Simpson’s diversity index through modulating the direct effects of soil properties. Our findings show that soil properties play a prominent role in favoring differentiation in species composition among the four forests we studied and provide additional evidence to decreasing species diversity with elevation. However, this was reflected in decreasing Shannon and Simpson indices rather than species richness, which is more commonly studied. Whether and to what extent future environmental changes in climate and soil acidification will alter future forest composition and diversity needs to be investigated.
Investigating the Causal Relationship Between Physical Activity and Chronic Back Pain: A Bidirectional Two-Sample Mendelian Randomization Study
Authors: Gao Shaowei , Zhou Huaqiang , Luo Siyu , Cai Xiaoying , Ye Fang , He Qiulan , Huang Chanyan , Zheng Xiaoyang , Li Ying , Du Zhanxin , Wang Yaqing , Qi Zhihui , Wang Zhongxing
Published: December 2021

Background: Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP.

Materials and Methods: This two-sample MR used independent genetic variants associated with physical activity and CBP as genetic instruments from large genome-wide association studies (GWASs). The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results.

Results: The MR set parallel GWAS cohorts, among which, those involved in the primary analysis were comprised of 337,234 participants for physical activity and 158,025 participants (29,531 cases) for CBP. No evidence of a causal relationship was found in the direction of physical activity to CBP [odds ratio (OR), 0.98; 95% CI, 0.85–1.13; p = 0.81]. In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (β = −0.07; 95% CI, −0.12 to −0.01; p = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls.

Conclusion: The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.
Resprouters Versus Reseeders: Are Wild Rooibos Ecotypes Genetically Distinct?
Authors: Brooks J. , Makunga N. P. , Hull K. L. , Brink-Hull M. , Malgas R. , Roodt-Wilding R.
Published: December 2021

Aspalathus linearis (Burm. F.) R. Dahlgren (Fabaceae) or rooibos, is a strict endemic species, limited to areas of the Cederberg (Western Cape) and the southern Bokkeveld plateau (Northern Cape) in the greater Cape Floristic Region (CFR) of South Africa. Wild rooibos, unlike the cultivated type, is variable in morphology, biochemistry, ecology and genetics, and these ecotypes are broadly distinguished into two main groups, namely, reseeders and resprouters, based on their fire-survival strategy. No previous assessment of genetic diversity or population structure using microsatellite markers has been conducted in A. linearis. This study aimed to test the hypothesis that wild rooibos ecotypes are distinct in genetic variability and that the ecotypes found in the Northern Cape are differentiated from those in the Cederberg that may be linked to a fire-survival strategy as well as distinct morphological and phytochemical differences. A phylogeographical and population genetic analyses of both chloroplast (trnLF intergenic region) and newly developed species-specific nuclear markers (microsatellites) was performed on six geographically representative wild rooibos populations. From the diversity indices, it was evident that the wild rooibos populations have low-to-moderate genetic diversity (He: 0.618–0.723; Ho: 0.528–0.704). The Jamaka population (Cederberg, Western Cape) had the lowest haplotype diversity (H = 0.286), and the lowest nucleotide diversity (π = 0.006) even though the data revealed large variations in haplotype diversity (h = 0.286–0.900) and nucleotide diversity (π = 0.006–0.025) between populations and amongst regions where wild rooibos populations are found. Our data suggests that populations of rooibos become less diverse from the Melkkraal population (Suid Bokkeveld, Northern Cape) down towards the Cederberg (Western Cape) populations, possibly indicative of clinal variation. The largest genetic differentiation was between Heuningvlei (Cederberg, Western Cape) and Jamaka (FST = 0.101) localities within the Cederberg mountainous region, and, Blomfontein (Northern Cape) and Jamaka (Cederberg) (FST = 0.101). There was also a significant isolation by distance (R2 = 0.296, p = 0.044). The presence of three main clusters is also clearly reflected in the discriminant analysis of principal components (DAPC) based on the microsatellite marker analyses. The correct and appropriate management of wild genetic resources of the species is urgently needed, considering that the wild Cederberg populations are genetically distinct from the wild Northern Cape plants and are delineated in accordance with ecological functional traits of reseeding or resprouting, respectively. The haplotype divergence of the ecotypes has also provided insights into the genetic history of these populations and highlighted the need for the establishment of appropriate conservation strategies for the protection of wild ecotypes.
Daratumumab Prevents Experimental Xenogeneic Graft-Versus-Host Disease by Skewing Proportions of T Cell Functional Subsets and Inhibiting T Cell Activation and Migration
Authors: Gao Yang , Shan Wei , Gu Tianning , Zhang Jie , Wu Yibo , Li Xiaoqing , Zeng Xiangjun , Zhou Hongyu , Chen Zhi , Xiao Haowen
Published: December 2021

Graft-versus-host disease (GVHD) remains the major cause of mortality and morbidity in non-relapse patients after allogeneic hematopoietic cell transplantation (allo-HCT). As the number of patients undergoing allo-HCT increases, it will become imperative to determine safe and effective treatment options for patients with GVHD, especially those who become refractory to systemic steroid therapy. Daratumumab (Dara), a humanized IgG1 (ĸ subclass) monoclonal antibody targeting the CD38 epitope, is used for the treatment of multiple myeloma. CD38 is a multifunctional ectoenzyme that behaves either as an enzyme, a cell adhesion molecule or a cell surface receptor involved in cell signaling. CD38 is also expressed on various immune effector and suppressor cells. However, the role of CD38 in the immune response remains elusive. We questioned whether CD38 is a potential therapeutic target against alloreactive T cells in the GVHD pathological process. Here, we investigated the impact of Dara on xenogeneic GVHD (xeno-GVHD) and graft-versus-leukemia (GVL) effects in a humanized murine model of transplantation, where human peripheral blood mononuclear cells were adoptively transplanted into immunocompromised NOD.SCID.gc-null (NSG) mice. Mice receiving Dara treatment experienced less weight loss, longer survival and lower GVHD scores compared with those in the control group. Histological evaluations, flow cytometry, RNA-sequencing and RT-qPCR analysis revealed that Dara efficaciously mitigated GVHD through multiple mechanisms including inhibition of the proliferation, activation and differentiation of CD8+ cytotoxic T cells, reduced expression of cytotoxic effector molecules, pro-inflammatory cytokines, chemokines and chemoattractant receptors by T cells and promotion of immunosuppressive T cells. More importantly, Dara preserved the GVL effect in a humanized mouse model of leukemia by metabolic reprograming of T cells to promote the induction of Th17, Th1/17and Tc1/17 cells. Our findings indicate that Dara may be an attractive therapeutic option to separate GVHD from GVL effects in patients with hematopoietic malignancies receiving allo-HCT.
Comparative Analysis of Chloroplast Genomes of Thalassiosira Species
Authors: Liu Kuiyan , Chen Yang , Cui Zongmei , Liu Shuya , Xu Qing , Chen Nansheng
Published: December 2021

Thalassiosira is a species-rich genus in Bacillariophyta with important ecological contribution to primary productivity but can also pose negative impact on ecology by developing harmful algal blooms (HABs). However, genomic resources of only a few Thalassiosira species are currently available. Here, we constructed complete chloroplast genomes (cpDNAs) of six Thalassiosira strains (representing six Thalassiosira species T. rotula, T. profunda, T. nordenskioeldii, T. tenera, T. weissflogii, and Thalassiosira sp.), and compared them with published cpDNAs of other diatoms. Comparative analysis revealed that Thalassiosira cpDNAs have generally conventional and conserved quadripartite structure with important exceptions. Gene orders of cpDNAs of Thalassiosira sp. (CNS00561) and T. oceanica were different from that of other Thalassiosira species. Additionally, endosymbiotic gene transfers (EGT) were found to occur in the evolution of Thalassiosira cpDNAs. Furthermore, genomic regions of cpDNAs were found to be highly variable, which could be used to construct molecular markers for distinguishing Thalassiosira species with high resolution and high specificity. This study also demonstrated that Thalassiosira species emerged roughly around 51 MYA and diversified 17–28 MYA. Thalassiosira cpDNAs are not only valuable as super-barcode for phylogenetic analysis, but also important for functional and evolutionary analysis of diatoms.
Establishing in vitro and in vivo Co-culture Models of Staphylococcus epidermidis and Enterococcus faecalis to Evaluate the Effect of Topical Fluoroquinolone on Ocular Microbes
Authors: Kim Han Woo , Kim Jiyeun Kate , Park Indal , Lee Sang Joon
Published: December 2021

Purpose: To establish in vitro and in vivo ocular co-culture models of Staphylococcus epidermidis and Enterococcus faecalis and to study how various concentrations of moxifloxacin affect the survival of these two endophthalmitis-causing bacteria.

Methods: Standard strains of S. epidermidis and E. faecalis were used. Color detection agar plates were employed to distinguish their colonies. To establish the in vitro and in vivo co-culture models, S. epidermidis and E. faecalis were co-cultivated at different ratios for various periods. For the in vivo model, various volumes and concentrations of either a mono-culture or co-culture were inoculated into the lower conjunctival sac of rabbits. Finally, the newly developed in vitro and in vivo co-culture models were subjected to the moxifloxacin treatment to access its effect on S. epidermidis and E. faecalis.

Results: When S. epidermidis and E. faecalis were cultured separately in tryptic soy broth, their growth peaked and plateaued at approximately 16 and 6 h, respectively. When they were co-cultured, the growth peak of S. epidermidis got delayed, whereas the growth peak of E. faecalis did not change. The number of E. faecalis was significantly higher in the co-culture than that in the mono-culture. Treatment with moxifloxacin in the in vitro co-culture model rapidly decreased the number of S. epidermidis cells at doses ≥ 0.125 μg/ml. In contrast, the number of E. faecalis did not change significantly up to 16 μg/ml moxifloxacin. In in vivo co-culture (at 1:1), the S. epidermidis count decreased in a pattern similar to that seen in in vivo mono-culture and was barely detectable at 24 h after inoculation. In contrast, the of E. faecalis count increased up to 16 h and then decreased. When moxifloxacin was applied (zero, one, or two times) to this model, the S. epidermidis count decreased in proportion to the number of treatments. In contrast, the E. faecalis count increased with moxifloxacin treatment.

Conclusions: The in vitro and in vivo co-culture models of S. epidermidis and E. faecalis were established to determine the influence of moxifloxacin eye drops on these bacteria. The results clearly show that the moxifloxacin eye drops can make E. faecalis dominant on the ocular surface.
Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review
Authors: Fonseca-Correa Jorge I. , Correa-Rotter Ricardo
Published: December 2021

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.
TRIM29 in Cutaneous Squamous Cell Carcinoma
Authors: Hsu Che-Yuan , Yanagi Teruki , Ujiie Hideyuki
Published: December 2021

Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.
Case Report: Circulating Anti-SARS-CoV-2 Antibodies Do Not Cross-React With Pemphigus or Pemphigoid Autoantigens
Authors: Kasperkiewicz Michael , Bednarek Marta , Tukaj Stefan
Published: December 2021

It is hypothesized that SARS-CoV-2 has the potential to elicit autoimmunity due to molecular mimicry between immunogenic proteins of the virus and human extracellular molecules. While in silico and in vitro evaluation of such immune cross-reactivity of human antibodies to SARS-CoV-2 proteins with several different tissue antigens has been described, there is limited information specifically pertaining to the immunological effects of COVID-19 and vaccines against SARS-CoV-2 on the development of autoimmune bullous diseases (AIBDs). Twelve seropositive post-COVID-19 individuals and 12 seropositive healthy volunteers who received two doses of the mRNA COVID-19 vaccine from Pfizer-BioNTech have been included in this case series investigation. Serum samples of these blood donors were tested for autoantibodies to the main immunobullous autoantigens, i.e., desmoglein 1, desmoglein 3, envoplakin, BP180, BP230, and type VII collagen. Our study revealed that none of the 24 anti-SARS-CoV-2 IgG-positive subjects had concomitant antibody reactivity with any of the tested autoantigens. These results argue against a relationship between SARS-CoV-2 infection/vaccines and AIBDs with respect to disease-triggering antibody cross-reactivity.
TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy
Authors: Nai Yaru , Du Li , Shen Meiying , Li Tingting , Huang Jingjing , Han Xiaojian , Luo Feiyang , Wang Wang , Pang Da , Jin Aishun
Published: December 2021

Tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) has limited expression in normal tissues but was highly expressed in various types of tumors, making it an attractive target for cancer immunotherapy. Here, we utilized the single-chain variable fragment (scFv) from our previously identified TRAIL-R1–targeting monoclonal antibody (TR1419) with antitumor efficacy and produced the TR1419 chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1419-28BBζ CAR-T cells exhibited greater target sensitivity and proliferative capability, with slightly higher PD-1 expression after antigen stimulation. Importantly, we found that the TR1419 CAR-T cells could induce TRAIL-R1–positive tumor cell death via a dual mechanism of the death receptor–dependent apoptosis as well as the T-cell–mediated cytotoxicity. Altogether, the TR1419 CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1–positive tumors.
Discovery Sulfoglycomics and Identification of the Characteristic Fragment Ions for High-Sensitivity Precise Mapping of Adult Zebrafish Brain–Specific Glycotopes
Authors: Tseng Huan-Chuan , Hsiao Cheng-Te , Yamakawa Nao , Guérardel Yann , Khoo Kay-Hooi
Published: December 2021

Mass spectrometry–based high-sensitivity mapping of terminal glycotopes relies on diagnostic MS2 and/or MS3 ions that can differentiate linkage and define the location of substituents including sulfates. Unambiguous identification of adult zebrafish glycotopes is particularly challenging due to the presence of extra β4-galactosylation on the basic building block of Galβ1-4GlcNAc that can be fucosylated and variably sialylated by N-acetyl, N-glycolyl, or deaminated neuraminic acids. Building on previous groundwork that have identified various organ-specific N- and O-glycans of adult zebrafish, we show here that all the major glycotopes of interest can be readily mapped by direct nano-LC-MS/MS analysis of permethylated glycans. Homing in on the brain-, intestine-, and ovary-derived samples, organ-specific glycomic reference maps based on overlaid extracted ion chromatograms of resolved glycan species, and composite charts of summed intensities of diagnostic MS2 ions representing the distribution and relative abundance of each of the glycotopes and sialic acid variants were established. Moreover, switching to negative mode analysis of sample fractions enriched in negatively charged glycans, we show, for the first time, that a full range of sulfated glycotopes is expressed in adult zebrafish. In particular, 3-O-sulfation of terminal Gal was commonly found, whereas terminal sulfated HexNAc as in GalNAcβ1-4GlcNAc (LacdiNAc), and 3-O-sulfated hexuronic acid as in HNK-1 epitope (SO3-3GlcAβ1-3Galβ1-4GlcNAc) were identified only in the brain and not in the intestine or ovaries analyzed in parallel. Other characteristic structural features of sulfated O- and N-glycans along with their diagnostic ions detected in this discovery mode sulfoglycomic work collectively expand our adult zebrafish glycome atlas, which can now allow for a more complete navigation and probing of the underlying sulfotransferases and glycosyltransferases, in search of the functional relevance of zebrafish-specific glycotopes. Of particular importance is the knowledge of glycomic features distinct from those of humans when using adult zebrafish as an alternative vertebrate model, rather than mouse, for brain-related glyco-neurobiology studies.
Exploring Kv1.2 Channel Inactivation Through MD Simulations and Network Analysis
Authors: Costa Flavio , Guardiani Carlo , Giacomello Alberto
Published: December 2021

The KCNA2 gene encodes the Kv1.2 channel, a mammalian Shaker-like voltage-gated K+channel, whose defections are linked to neuronal deficiency and childhood epilepsy. Despite the important role in the kinetic behavior of the channel, the inactivation remained hereby elusive. Here, we studied the Kv1.2 inactivationviaa combined simulation/network theoretical approach that revealed two distinct pathways coupling the Voltage Sensor Domain and the Pore Domain to the Selectivity Filter. Additionally, we mutated some residues implicated in these paths and we explained microscopically their function in the inactivation mechanism by computing a contact map. Interestingly, some pathological residues shown to impair the inactivation lay on the paths. In summary, the presented results suggest two pathways as the possible molecular basis of the inactivation mechanism in the Kv1.2 channel. These pathways are consistent with earlier mutational studies and known mutations involved in neuronal channelopathies.
Manganese Dynamics in Mouse Brain After Systemic MnCl2 Administration for Activation-Induced Manganese-Enhanced MRI
Authors: Tanihira Hiroki , Fujiwara Tomonori , Kikuta Satomi , Homma Noriyasu , Osanai Makoto
Published: December 2021

Activation-induced manganese-enhanced MRI (AIM-MRI) is an attractive tool for non-invasively mapping whole brain activities. Manganese ions (Mn2+) enter and accumulate in active neurons via calcium channels. Mn2+ shortens the longitudinal relaxation time (T1) of H+, and the longitudinal relaxation rate R1 (1/T1) is proportional to Mn2+ concentration. Thus, AIM-MRI can map neural activities throughout the brain by assessing the R1 map. However, AIM-MRI is still not widely used, partially due to insufficient information regarding Mn2+ dynamics in the brain. To resolve this issue, we conducted a longitudinal study looking at manganese dynamics after systemic administration of MnCl2 by AIM-MRI with quantitative analysis. In the ventricle, Mn2+ increased rapidly within 1 h, remained high for 3 h, and returned to near control levels by 24 h after administration. Microdialysis showed that extracellular Mn returned to control levels by 4 h after administration, indicating a high concentration of extracellular Mn2+ lasts at least about 3 h after administration. In the brain parenchyma, Mn2+ increased slowly, peaked 24–48 h after administration, and returned to control level by 5 days after a single administration and by 2 weeks after a double administration with a 24-h interval. These time courses suggest that AIM-MRI records neural activity 1–3 h after MnCl2 administration, an appropriate timing of the MRI scan is in the range of 24–48 h following systemic administration, and at least an interval of 5 days or a couple of weeks for single or double administrations, respectively, is needed for a repeat AIM-MRI experiment.
Theta Oscillations at Subthalamic Region Predicts Hypomania State After Deep Brain Stimulation in Parkinson's Disease
Authors: Chen Yi-Chieh , Wu Hau-Tieng , Tu Po-Hsun , Yeh Chih-Hua , Liu Tzu-Chi , Yeap Mun-Chun , Chao Yi-Ping , Chen Po-Lin , Lu Chin-Song , Chen Chiung-Chu
Published: December 2021

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for the motor impairments of patients with advanced Parkinson's disease. However, mood or behavioral changes, such as mania, hypomania, and impulsive disorders, can occur postoperatively. It has been suggested that these symptoms are associated with the stimulation of the limbic subregion of the STN. Electrophysiological studies demonstrate that the low-frequency activities in ventral STN are modulated during emotional processing. In this study, we report 22 patients with Parkinson's disease who underwent STN DBS for treatment of motor impairment and presented stimulation-induced mood elevation during initial postoperative programming. The contact at which a euphoric state was elicited by stimulation was termed as the hypomania-inducing contact (HIC) and was further correlated with intraoperative local field potential recorded during the descending of DBS electrodes. The power of four frequency bands, namely, θ (4–7 Hz), α (7–10 Hz), β (13–35 Hz), and γ (40–60 Hz), were determined by a non-linear variation of the spectrogram using the concentration of frequency of time (conceFT). The depth of maximum θ power is located approximately 2 mm below HIC on average and has significant correlation with the location of contacts (r = 0.676, p < 0.001), even after partializing the effect of α and β, respectively (r = 0.474, p = 0.022; r = 0.461, p = 0.027). The occurrence of HIC was not associated with patient-specific characteristics such as age, gender, disease duration, motor or non-motor symptoms before the operation, or improvement after stimulation. Taken together, these data suggest that the location of maximum θ power is associated with the stimulation-induced hypomania and the prediction of θ power is frequency specific. Our results provide further information to refine targeting intraoperatively and select stimulation contacts in programming.
Theoretical Relationship Between Two Measures of Spike Synchrony: Correlation Index and Vector Strength
Authors: Kessler Dominik , Carr Catherine E. , Kretzberg Jutta , Ashida Go
Published: December 2021

Information processing in the nervous system critically relies on temporally precise spiking activity. In the auditory system, various degrees of phase-locking can be observed from the auditory nerve to cortical neurons. The classical metric for quantifying phase-locking is the vector strength (VS), which captures the periodicity in neuronal spiking. More recently, another metric, called the correlation index (CI), was proposed to quantify the temporally reproducible response characteristics of a neuron. The CI is defined as the peak value of a normalized shuffled autocorrelogram (SAC). Both VS and CI have been used to investigate how temporal information is processed and propagated along the auditory pathways. While previous analyses of physiological data in cats suggested covariation of these two metrics, general characterization of their connection has never been performed. In the present study, we derive a rigorous relationship between VS and CI. To model phase-locking, we assume Poissonian spike trains with a temporally changing intensity function following a von Mises distribution. We demonstrate that VS and CI are mutually related via the so-called concentration parameter that determines the degree of phase-locking. We confirm that these theoretical results are largely consistent with physiological data recorded in the auditory brainstem of various animals. In addition, we generate artificial phase-locked spike sequences, for which recording and analysis parameters can be systematically manipulated. Our analysis results suggest that mismatches between empirical data and the theoretical prediction can often be explained with deviations from the von Mises distribution, including skewed or multimodal period histograms. Furthermore, temporal relations of spike trains across trials can contribute to higher CI values than predicted mathematically based on the VS. We find that, for most applications, a SAC bin width of 50 ms seems to be a favorable choice, leading to an estimated error below 2.5% for physiologically plausible conditions. Overall, our results provide general relations between the two measures of phase-locking and will aid future analyses of different physiological datasets that are characterized with these metrics.
Combined Analysis of the Effects of Exposure to Blue Light in Ducks Reveals a Reduction in Cholesterol Accumulation Through Changes in Methionine Metabolism and the Intestinal Microbiota
Authors: Xia Daiyang , Yang Lin , Cui Jiajie , Li Yu , Jiang Xianzhi , Meca Giuseppe , Wang Shunxiang , Feng Yan , Zhao Yujie , Qin Jiangfan , Zhu Yongwen , Ye Hui , Wang Wence
Published: December 2021

Graphical Abstract

Blue light improves lipid metabolism by altering metabolism and gut microbes.
Cord Blood Thyroid Hormones and Neurodevelopment in 2-Year-Old Boys and Girls
Authors: Fan Pianpian , Chen Yuanzhi , Luo Zhong-Cheng , Shen Lixiao , Wang Weiye , Liu Zhiwei , Zhang Jun , Ouyang Fengxiu
Published: December 2021

Objective: Thyroid hormones are essential for neurodevelopment in early life. However, the impact of mild alterations in neonatal thyroid hormones on infant neurodevelopment and its sex dimorphism is unclear. We aimed to assess whether mild variations in neonatal thyroid hormones of term-born newborns with maternal euthyroid are related to neurodevelopment in 2-year-old boys and girls.

Methods: This study used data from 452 singleton term-born infants of mothers with normal thyroid function in Shanghai, China, and their follow-up measure at the age of 2 years. Cord serum concentrations of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibody (TPOAb) were measured by chemiluminescent microparticle immunoassays and classified into three groups: the low (1st, Q1), middle (2nd−4th, Q2–Q4), and high (5th, Q5) quintiles. Neurodevelopment indices were assessed using the Ages and Stages Questionnaire, third edition (ASQ-3), at 24 months of age.

Results: Compared to infants with thyroid hormones in the middle (Q2–Q4), boys with FT4 in the lowest quintile had 5.08 (95% CI: 1.37, 8.78) points lower scores in the communication domain, 3.25 (0.25,6.25) points lower scores in the fine motor domain, and 3.84 (0.04, 7.64) points lower scores in the personal-social domain, respectively. Boys with FT3 in the highest quintile had 4.46 (0.81, 8.11) points increase in the personal-social domain. These associations were not observed in girls. No associations were observed between cord blood serum TSH and ASQ-assessed neurodevelopment in the boys or the girls.

Conclusions: Mild alterations in thyroid hormones of newborns were associated adversely with neurodevelopment in boys, suggesting the importance of optimal thyroid hormone status for neurodevelopment in early life.