bluuebunny/crossref_metadata_2025 huggingface dataset:
Rural–Urban differences in Use of Rhythm Control Therapies in Patients with Incident Atrial Fibrillation: A Finnish Nationwide Cohort Study
Authors: Teppo Konsta , Jaakkola Jussi , Biancari Fausto , Halminen Olli , Linna Miika , Haukka Jari , Putaala Jukka , Mustonen Pirjo , Kinnunen Janne , Luojus Alex , Itäinen-Strömberg Saga , Hartikainen Juha , Aro Aapo L. , Airaksinen K. E. Juhani , Lehto Mika
Published: September 2022

Background: Rural–urban disparities have been reported in the access, utilization, and quality of healthcare. We aimed to assess whether use of antiarrhythmic therapies (AATs) in patients with atrial fibrillation (AF) differs between those with rural and urban residence. Methods: The registry-based FinACAF cohort covers all patients with AF from all levels of care in Finland. Patients were divided into rural and urban categories and into urbanization degree tertiles based on their municipality of residence at the time of AF diagnosis. The primary outcome was the use of any AAT, including cardioversion, catheter ablation, and fulfilled antiarrhythmic drug (AAD) prescription. Results: We identified 177,529 patients (49.9% female, mean age 73.0 (SD13.0) years) with incident AF during 2010–2018. Except for AADs, the differences in AAT use were nonsignificant when patients were stratified according to the rural–urban classification system (urban vs. rural adjusted incidence rate ratios (aIRRs) with 95% CIs for any AAT 1.01 (0.99–1.03), AADs 1.11 (1.07–1.15), cardioversion 1.01 (0.98–1.03), catheter ablation 1.05 (0.98–1.12)). However, slightly higher use of all rhythm control modalities was observed in the highest urbanization degree tertile when compared to the lowest tertile (aIRRs with 95% Cis for any AAT 1.06 (1.03–1.08), AADs 1.18 (1.14–1.23), cardioversion 1.05 (1.02–1.08), catheter ablation 1.10 (1.02–1.19)). Conclusions: This nationwide retrospective cohort study observed that urban residence is associated with higher use of AADs in patients with incident AF. Otherwise, the observed disparities were only marginal, suggesting that in the use of rhythm control therapies, no large rural–urban inequity exists in Finland.
Participatory and Spatial Analyses of Environmental Justice Communities’ Concerns about a Proposed Storm Surge and Flood Protection Seawall
Authors: Taylor Judith , Levine Norman S. , Muhammad Ernest , Porter Dwayne E. , Watson Annette M. , Sandifer Paul A.
Published: September 2022

In response to increasing threats from sea-level rise and storm surge, the City of Charleston, South Carolina, and the US Army Corps of Engineers (USACE) propose constructing a seawall around the Charleston peninsula. The proposed seawall will terminate close to lower wealth, predominantly minority communities. These communities are identified as environmental justice (EJ) communities due to their history of inequitable burdens of industrial and urban pollution and proximity to highways and US Environmental Protection Agency (EPA) designated Superfund sites. The present study documents community concerns and opinions related to the proposed seawall, existing flooding problems, and other issues. The project was guided by knowledge co-production and participant-observation approaches and included interviews with community members, collection of locality-specific data, GIS mapping to visualize key issues, development of an ArcGIS Story Map, and participation in public meetings. Community concerns are reported in the voices of community members and fell into eight major themes: community connections, drainage, impacts of road infrastructure, displacement, increasing vulnerability, sense of exclusion and isolation, mistrust of government, and civic engagement. Community members were significantly engaged in the study and are the owners of the results. As one of the first US East Coast cities pursuing major structural adaptation for flooding, Charleston is likely to become a model for other cities considering waterfront protection measures. We demonstrate the importance of meaningful engagement to ensure that climate adaptation will benefit all, including marginalized communities, and have as few unintended negative consequences as possible. Bringing more people to the table and creating vibrant, long-term partnerships between academic institutions and community-based organizations that include robust links to governmental organizations should be among the first steps in building inclusive, equitable, and climate resilient cities.
Determining the Efficiency of the Sponge City Construction Pilots in China Based on the DEA-Malmquist Model
Authors: Zhang Heng , Chang Qian , Li Sui , Huang Jiandong
Published: September 2022

Sponge city construction (SCC) has improved the quality of the urban water ecological environment, and the policy implementation effect of SCC pilots is particularly remarkable. Based on the data envelopment analysis (DEA) model, this study employed the related index factors such as economy, ecology, infrastructure, and the population of the pilot city as the input, and the macro factors of SCC as the output, to scientifically evaluate the relative efficiency between the SCC pilots in China. Eleven representative SCC pilots were selected for analysis from the perspectives of static and dynamic approaches, and comparisons based on the horizontal analysis of the efficiency of SCC pilots were conducted and some targeted policy suggestions are put forward, which provide a reliable theoretical model and data support for the efficiency evaluation of SCC. This paper can be used as a reference for construction by providing a DEA model for efficiency evaluation methods and thus helps public sector decision makers choose the appropriate construction scale for SCC pilots.
Women during Lactation Reduce Their Physical Activity and Sleep Duration Compared to Pregnancy
Authors: Cabrera-Domínguez Gema , de la Calle María , Herranz Carrillo Gloria , Ruvira Santiago , Rodríguez-Rodríguez Pilar , Arribas Silvia M. , Ramiro-Cortijo David
Published: September 2022

Sleep, mental health and physical activity are fundamental for wellbeing, and some of these factors are interrelated. However, these aspects are not usually considered during pregnancy and lactation, which are particularly vulnerable periods. Therefore, our aims were to conduct a cross sectional study to assess the psychological capital, quality of life, sleep hygiene and physical activity in a cohort of women during pregnancy and lactation periods. Women were recruited from Spanish maternity and lactation non-profit associations and social networks through an online platform with the following inclusion criteria: pregnancy (in any period of gestation) or breastfeeding period (≤6 months postpartum). The cohort was categorized into ≤12 weeks of gestation (n = 32), >12 weeks of gestation (n = 119) and lactation (n = 60). The women self-reported the sociodemographic data, obstetric complications and full breastfeeding or mixed practices. In addition, women responded to the psychological capital instrument, the health survey form, the Pittsburg sleep quality index and the pregnancy physical activity questionnaire. Overall, the groups were similar in sociodemographic variables. Women in the lactation period perceived lower social support compared to the gestation period. No statistically differences were found between groups in the psychological capital nor in the general health survey form. However, the models adjusted by employment and civil and economic status and perceived social support, demonstrated that the sleep duration negatively associated with the lactation period (β = 1.13 ± 0.56; p-Value = 0.016), and the household tasks were associated with this period (β = 2147.3 ± 480.7; p-Value < 0.001). A decrease in physical daily activities were associated with both the end of gestation and the lactation periods. In addition, the decreasing total activity was associated with the lactation period (β = 1683.67 ± 688.05; p-Value = 0.016). In conclusion, during lactation, the poorer sleep and physical activity, together with a lower social support of the woman, may lead to deficient mental health adjustment. Our data suggest that women are at higher risk of vulnerability in lactation compared to the gestation period.
Implementation of a Standard Care Program of Therapeutic Exercise in Metastatic Breast Cancer Patients
Authors: Pajares Bella , Roldán-Jiménez Cristina , Alba Emilio , Cuesta-Vargas Antonio I.
Published: September 2022

Background: There is little information on the feasibility and benefit of therapeutic exercise (TE) in women with metastatic breast cancer (MBC). The aim of this article is to describe the implementation of a TE intervention in MBC patients, and to determine the recruitment, compliance and improvement in outcomes after its completion. Methods: The “Therapeutic Exercise program in MBC” (TEP-MBC) consists of 1 h of individualized TE supervised by a physiotherapist in a group format, consisting of four groups of seven to eight participants. TEP-MBC was delivered twice a week, lasting 12 weeks (22 sessions), with patients considered to have completed the program when attending at least 17 sessions (>75% attendance). After referral, patients underwent a clinical interview and a physical and functional assessment. This information was complemented with patient-reported outcomes. Data about referral, compliance and assessment were collected. Results: Only 11 of the 30 patients completed the program. Drop-out was mainly related to personal issues and symptoms arising from the disease or treatment. All patients who completed the program improved cancer-related fatigue and increased their functional parameters. Conclusions: The TEP-MBC was safe and feasible in patients with MBC, although with low compliance. The high variability in baseline measures reflects the heterogeneous level of function.
How Biochar Derived from Pond Cypress (Taxodium Ascendens) Evolved with Pyrolysis Temperature and Time and Their End Efficacy Evaluation
Authors: Zhang Shuai , Hu Haibo , Jia Xiangdong , Wang Xia , Chen Jianyu , Cheng Can , Jia Xichuan , Wu Zhaoming , Zhu Li
Published: September 2022

Biomass type, pyrolysis temperature, and duration can affect biochar properties simultaneously. To further clarify the mechanism of this interaction, the branch and leaf parts of Pond cypress (Taxodium ascendens) were separately pyrolyzed at four peak temperatures (350 °C, 450 °C, 650 °C, and 750 °C) for three different durations (0.5 h, 1 h, and 2 h) in this study. The resulting biochar properties were measured, which included the yield, specific surface area (SSA), pH, EC (electricity conductivity), the bulk and surface elemental composition, and the contents of moisture, ash, fixed carbon, and volatile matter. The results showed that the pyrolysis temperature was more determinant for the modification of all biochar, but the residence time had a significant effect on the yield, pH, and SSA of branch-based biochar (B-biochar) at specific temperatures. However, such a phenomenon only happened on the pH of leaf-based biochar (L-biochar). Results: (1) With the temperature at 350 and 650 °C, the residence time had a significant effect on the yield of B-biochar. (2) The pH of B-biochar and L-biochar varied considerably between durations when the heating temperature hit 650 and 750 °C. (3) The SSA of B-biochar possessed an obvious fluctuation with the time during the pyrolysis from 650 to 750 °C. According to the properties measured above, the principal component and the cluster analysis classified the 24 types of biochar made in this experiment into four groups and revealed that an obvious disparity existed between B-biochar and L-biochar that were pyrolyzed at temperatures ranging from 450 to 750 °C, which suggested that biomass type was the primary factor for biochar-making. All this information can provide valuable references for the optimization of biochar-making in the real world.
Icariin Alleviates Escherichia coli Lipopolysaccharide-Mediated Endometritis in Mice by Inhibiting Inflammation and Oxidative Stress
Authors: Shaukat Aftab , Shaukat Irfan , Rajput Shahid Ali , Shukat Rizwan , Hanif Sana , Huang Shucheng , Aleem Muhammad Tahir , Li Kun , Li Qiao , Chen Chao , Zhang Xinxin , Lv Haimiao , Yao Zhiqiu , Yang Liguo
Published: September 2022

Icariin (ICA) is a naturally occurring phytochemical agent primarily extracted from Epimedium Brevicornum Maxim (Family Berberidaceae) with a broad spectrum of bioactivities. Endometritis is a uterine disease that causes enormous losses in the dairy industry worldwide. In this study, anti-inflammatory and anti-oxidant properties of ICA were investigated against lipopolysaccharide (LPS)-induced endometritis in mice to investigate possible underlying molecular mechanisms. Sixty heathy female Kunming mice were randomly assigned to four groups (n = 15), namely control, LPS, LPS + ICA, and ICA groups. The endometritis was induced by intrauterine infusion of 50 µL of LPS (1 mg/mL). After 24 h of onset of LPS-induced endometritis, ICA groups were injected thrice by ICA intraperitoneally six hours apart. Histopathological examination, enzyme linked immunosorbent assay (ELISA), real time quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry were used in this study. Histological alterations revealed that ICA markedly mitigated uterine tissue injury caused by LPS. The results showed that the ICA inhibited the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and boosted the production of anti-inflammatory cytokines (IL-10). Additionally, ICA modulated the expression of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (Gpx1) induced by LPS. The administration of ICA significantly (p < 0.05) improved the mRNA and protein expression of Toll-like receptor (TLR) 4. The western blotting and ELISA finding revealed that the ICA repressed LPS-triggered NF-κB pathway activation. Moreover, ICA improved the antioxidant defense system via activation of the Nrf2 pathway. The results revealed that ICA up-regulated the mRNA and protein expression of Nuclear erythroid-2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) under LPS exposure. Conclusively, our findings strongly suggested that ICA protects endometritis caused by LPS by suppressing TLR4-associated NF-κB and Nrf2 pathways. Altogether, these innovative findings may pave the way for future studies into the therapeutic application of ICA to protect humans and animals against endometritis.
omicsGAT: Graph Attention Network for Cancer Subtype Analyses
Authors: Baul Sudipto , Ahmed Khandakar Tanvir , Filipek Joseph , Zhang Wei
Published: September 2022

The use of high-throughput omics technologies is becoming increasingly popular in all facets of biomedical science. The mRNA sequencing (RNA-seq) method reports quantitative measures of more than tens of thousands of biological features. It provides a more comprehensive molecular perspective of studied cancer mechanisms compared to traditional approaches. Graph-based learning models have been proposed to learn important hidden representations from gene expression data and network structure to improve cancer outcome prediction, patient stratification, and cell clustering. However, these graph-based methods cannot rank the importance of the different neighbors for a particular sample in the downstream cancer subtype analyses. In this study, we introduce omicsGAT, a graph attention network (GAT) model to integrate graph-based learning with an attention mechanism for RNA-seq data analysis. The multi-head attention mechanism in omicsGAT can more effectively secure information of a particular sample by assigning different attention coefficients to its neighbors. Comprehensive experiments on The Cancer Genome Atlas (TCGA) breast cancer and bladder cancer bulk RNA-seq data and two single-cell RNA-seq datasets validate that (1) the proposed model can effectively integrate neighborhood information of a sample and learn an embedding vector to improve disease phenotype prediction, cancer patient stratification, and cell clustering of the sample and (2) the attention matrix generated from the multi-head attention coefficients provides more useful information compared to the sample correlation-based adjacency matrix. From the results, we can conclude that some neighbors play a more important role than others in cancer subtype analyses of a particular sample based on the attention coefficient.
Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma
Authors: Li Yujie , Zhang Ke , Peng Linjia , Chen Lianyu , Gao Huifeng , Chen Hao
Published: September 2022

Pancreatic adenocarcinoma (PAAD) is a highly heterogeneous and immunosuppressive cancer. This study investigated the diversity of DNA damage repair (DDR) and immune microenvironment in PAAD by transcriptomic and genomic analysis. Patients with PAAD were divided into two DDR-based subtypes with distinct prognosis and molecular characteristics. The differential expression genes were mostly enriched in DDR and immune-related pathways. In order to distinguish high- and low-risk groups clinically, a DDR- and immune-based 5-gene prognostic signature (termed DPRS) was established. Patients in the high-risk group had inferior prognosis, a low level of immune checkpoint gene expression and low sensitivity to DDR-associated inhibitors. Furthermore, single-cell sequencing was used to observe the performance of the DDR-based signature in a high dimension, and immunohistochemistry was used to verify the relationship between the genes we identified and the prognosis of patients with PAAD. In conclusion, the DDR heterogeneity of PAAD was demonstrated, and a novel DDR- and immune-based risk-scoring model was constructed, which indicated the feasibility of DPRS in predicting prognosis and drug response in PAAD patients.
Mechanics of Reversible Deformation during Leaf Movement and Regulation of Pulvinus Development in Legumes
Authors: Nakata Miyuki T. , Takahara Masahiro
Published: September 2022

Plant cell deformation is a mechanical process that is driven by differences in the osmotic pressure inside and outside of the cell and is influenced by cell wall properties. Legume leaf movements result from reversible deformation of pulvinar motor cells. Reversible cell deformation is an elastic process distinct from the irreversible cell growth of developing organs. Here, we begin with a review of the basic mathematics of cell volume changes, cell wall function, and the mechanics of bending deformation at a macro scale. Next, we summarize the findings of recent molecular genetic studies of pulvinar development. We then review the mechanisms of the adaxial/abaxial patterning because pulvinar bending deformation depends on the differences in mechanical properties and physiological responses of motor cells on the adaxial versus abaxial sides of the pulvinus. Intriguingly, pulvini simultaneously encompass morphological symmetry and functional asymmetry along the adaxial/abaxial axis. This review provides an introduction to leaf movement and reversible deformation from the perspective of mechanics and molecular genetics.
miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections
Authors: Kansakar Urna , Gambardella Jessica , Varzideh Fahimeh , Avvisato Roberta , Jankauskas Stanislovas S. , Mone Pasquale , Matarese Alessandro , Santulli Gaetano
Published: September 2022

T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.
Molasses-Silver Nanoparticles: Synthesis, Optimization, Characterization, and Antibiofilm Activity
Authors: Dorgham Rabab A. , Abd Al Moaty Mohamed N. , Chong Khim Phin , Elwakil Bassma H.
Published: September 2022

Biofilms are matrix-enclosed communities of bacteria that are highly resistant to antibiotics. Adding nanomaterials with antibacterial activity to the implant surfaces may be a great solution against biofilm formation. Due to its potent and widespread antibacterial effect, silver nanoparticles were considered the most potent agent with different biological activities. In the present investigation, silver nanoparticles (AgNPs) were newly synthesized as antibiofilm agents using sugarcane process byproduct (molasses) and named Mo-capped AgNPs. The synthesized nanoparticles showed promising antimicrobial activity against S. aureus ATCC 6538 and C. albicans DAY185. Statistically designed optimization through response surface methodology was evaluated for maximum activity and better physical characteristics, namely the nanoparticles’ size and polydispersity index (PDI), and it was revealed that molasses concentration was the main effective factor. Minimal biofilm eradication concentration (MBEC) of Mo-capped AgNPs against S. aureus ATCC 6538 and C. albicans DAY185 was 16 and 32 µg/mL, respectively. Scanning electron microscope study of Mo-capped AgNP-treated biofilm revealed that AgNPs penetrated the preformed biofilm and eradicated the microbial cells. The optimally synthesized Mo-capped AgNPs were spherically shaped, and the average size diameter ranged between 29 and 88 nm with high proportions of Ag+ element (78.0%) recorded. Fourier-transform infrared spectroscopy (FTIR) analysis indicated the importance of molasses ingredients in capping and stabilizing the produced silver nanoparticles.
Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance
Authors: Vladu Alina Florentina , Ficai Denisa , Ene Alexandra Gabriela , Ficai Anton
Published: September 2022

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of β-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erβ. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.
Lower Plasmatic Levels of Saturated Fatty Acids and a Characteristic Fatty Acid Composition in the Ovary Could Contribute to the High-Fertility Phenotype in Dummerstorf Superfertile Mice
Authors: Calanni-Pileri Michela , Weitzel Joachim M. , Dannenberger Dirk , Langhammer Martina , Michaelis Marten
Published: September 2022

In recent decades, fertility traits in humans as well as in farm animals have decreased worldwide. As such, it is imperative to know more about the genetics and physiology of increased or high fertility. However, most of the current animal models with reproductive phenotypes describe lower fertility or even infertility (around 99%). The “Dummerstorf high-fertility lines” (FL1 and FL2) are two unique mouse lines selected for higher reproductive performances, more specifically for higher number of pups per litter. We recently described how those superfertile mice managed to increase their reproductive phenotype by doubling the ovulation rate and consequently the litter size compared to the unselected mice of the same founder population. FLs show an unusual estrous cycle length and atypical levels of hormones that link reproduction and metabolism, such as insulin in FL1 and leptin in FL2. Moreover, we described that their higher ovulation rate is mostly due to a higher quality of their oocytes rather than their sheer quantity, as they are characterized by a higher quantity of high-quality oocytes in antral follicles, but the quantity of follicles per ovary is not dissimilar compared to the control. In the present study, we aimed to analyze the lipid composition of the fertility lines from plasma to the gonads, as they can connect the higher reproductive performances with their metabolic atypicalities. As such, we analyzed the fat content of FLs and fatty acid composition in plasma, liver, fat, oocytes of different quality, and granulosa cells. We demonstrated that those mice show higher body weight and increased body fat content, but at the same time, they manage to decrease the lipid content in the ovarian fat compared to the abdominal fat, which could contribute to explaining their ovarian quality. In addition, we illustrate the differences in fatty acid composition in those tissues, especially a lower level of saturated fatty acids in plasma and a different lipid microenvironment of the ovary. Our ongoing and future research may be informative for farm animal biology as well as human reproductive medicine, mostly with cases that present characteristics of lower fertility that could be reversed following the way-of-managing of Dummerstorf high-fertility lines.
The Role of Thymoquinone in Inflammatory Response in Chronic Diseases
Authors: Liu Yan , Huang Lei , Kim Mi-Yeon , Cho Jae Youl
Published: September 2022

Anti-inflammatory therapies have been shown to be effective in the prevention of various cardiovascular diseases, tumors, and cancer complications. Thymoquinone (TQ), the main active constituent of Nigella sativa, has shown promising therapeutic properties in many in vivo and in vitro models. However, TQ has poor bioavailability and is hydrophobic, prohibiting clinical trials with TQ alone. Studies have explored the combination of TQ with biological nanomaterials to improve its bioavailability. The TQ nanoparticle formulation shows better bioavailability than free TQ, and these formulations are ready for clinical trials to determine their potential as therapeutic agents. In this paper, we review current knowledge about the interaction between TQ and the inflammatory response and summarize the research prospects in Korea and abroad. We discuss the different biological activities of TQ and various combination therapies of TQ and nanomaterials in clinical trials.
Microglial CD74 Expression Is Regulated by TGFβ Signaling
Authors: Jahn Jannik , Bollensdorf Antonia , Kalischer Christopher , Piecha Robin , Weiß-Müller Jana , Potru Phani Sankar , Ruß Tamara , Spittau Björn
Published: September 2022

Microglia play important roles during physiological and pathological situations in the CNS. Several reports have described the expression of Cd74 in disease-associated and aged microglia. Here, we demonstrated that TGFβ1 controled the expression of Cd74 in microglia in vitro and in vivo. Using BV2 cells, primary microglia cultures as well as Cx3cr1CreERT2:R26-YFP:Tgfbr2fl/fl in combination with qPCR, flow cytometry, and immunohistochemistry, we were able to provide evidence that TGFβ1 inhibited LPS-induced upregulation of Cd74 in microglia. Interestingly, TGFβ1 alone was able to mediate downregulation of CD74 in vitro. Moreover, silencing of TGFβ signaling in vivo resulted in marked upregulation of CD74, further underlining the importance of microglial TGFβ signaling during regulation of microglia activation. Taken together, our data indicated that CD74 is a marker for activated microglia and further demonstrated that microglial TGFβ signaling is important for regulation of Cd74 expression during microglia activation.
The Protective Effects on Ischemia–Reperfusion Injury Mechanisms of the Thoracic Aorta in Daurian Ground Squirrels (Spermophilus dauricus) over the Torpor–Arousal Cycle of Hibernation
Authors: Han Yuting , Miao Weilan , Hao Ziwei , An Ning , Yang Yingyu , Zhang Ziwen , Chen Jiayu , Storey Kenneth B. , Lefai Etienne , Chang Hui
Published: September 2022

Hibernators are a natural model of vascular ischemia–reperfusion injury; however, the protective mechanisms involved in dealing with such an injury over the torpor–arousal cycle are unclear. The present study aimed to clarify the changes in the thoracic aorta and serum in summer-active (SA), late-torpor (LT) and interbout-arousal (IBA) Daurian ground squirrels (Spermophilus dauricus). The results show that total antioxidant capacity (TAC) was unchanged, but malondialdehyde (MDA), hydrogen peroxide (H2O2), interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) were significantly increased for the LT group, whereas the levels of superoxide dismutase (SOD) and interleukin-10 (IL-10) were significantly reduced in the LT group as compared with the SA group. Moreover, the levels of MDA and IL-1β were significantly reduced, whereas SOD and IL-10 were significantly increased in the IBA group as compared with the SA group. In addition, the lumen area of the thoracic aorta and the expression of the smooth muscle cells (SMCs) contractile marker protein 22α (SM22α) were significantly reduced, whereas the protein expression of the synthetic marker proteins osteopontin (OPN), vimentin (VIM) and proliferating cell nuclear antigen (PCNA) were significantly increased in the LT group as compared with the SA group. Furthermore, the smooth muscle layer of the thoracic aorta was significantly thickened, and PCNA protein expression was significantly reduced in the IBA group as compared with the SA group. The contractile marker proteins SM22α and synthetic marker protein VIM underwent significant localization changes in both LT and IBA groups, with localization of the contractile marker protein α-smooth muscle actin (αSMA) changing only in the IBA group as compared with the SA group. In tunica intima, the serum levels of heparin sulfate (HS) and syndecan-1 (Sy-1) in the LT group were significantly reduced, but the serum level of HS in the IBA group increased significantly as compared with the SA group. Protein expression and localization of endothelial nitric oxide synthase (eNOS) was unchanged in the three groups. In summary, the decrease in reactive oxygen species (ROS) and pro-inflammatory factors and increase in SOD and anti-inflammatory factors during the IBA period induced controlled phenotypic switching of thoracic aortic SMCs and restoration of endothelial permeability to resist ischemic and hypoxic injury during torpor of Daurian ground squirrels.
Optical Activation of TrkB (E281A) in Excitatory and Inhibitory Neurons of the Mouse Visual Cortex
Authors: Lilja Antonia , Didio Giuliano , Hong Jongryul , Heo Won Do , Castrén Eero , Umemori Juzoh
Published: September 2022

The activation of tropomyosin receptor kinase B (TrkB), the receptor of brain-derived neurotrophic factor (BDNF), plays a key role in induced juvenile-like plasticity (iPlasticity), which allows restructuring of neural networks in adulthood. Optically activatable TrkB (optoTrkB) can temporarily and spatially evoke iPlasticity, and recently, optoTrkB (E281A) was developed as a variant that is highly sensitive to light stimulation while having lower basal activity compared to the original optoTrkB. In this study, we validate optoTrkB (E281A) activated in alpha calcium/calmodulin-dependent protein kinase type II positive (CKII+) pyramidal neurons or parvalbumin-positive (PV+) interneurons in the mouse visual cortex by immunohistochemistry. OptoTrkB (E281A) was activated in PV+ interneurons and CKII+ pyramidal neurons with blue light (488 nm) through the intact skull and fur, and through a transparent skull, respectively. LED light stimulation significantly increased the intensity of phosphorylated ERK and CREB even through intact skull and fur. These findings indicate that the highly sensitive optoTrkB (E281A) can be used in iPlasticity studies of both inhibitory and excitatory neurons, with flexible stimulation protocols in behavioural studies.
Psychostimulants Modafinil, Atomoxetine and Guanfacine Impair Bone Cell Differentiation and MSC Migration
Authors: Wagener Nele , Lehmann Wolfgang , Weiser Lukas , Jäckle Katharina , Di Fazio Pietro , Schilling Arndt F. , Böker Kai O.
Published: September 2022

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.
Exploration of N-Arylsulfonyl-indole-2-carboxamide Derivatives as Novel Fructose-1,6-bisphosphatase Inhibitors by Molecular Simulation
Authors: Zhao Yilan , Yang Honghao , Wu Fengshou , Luo Xiaogang , Sun Qi , Feng Weiliang , Ju Xiulian , Liu Genyan
Published: September 2022

A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure–activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.
Improved Understanding of Sugar Transport in Various Plants
Authors: Chen Li-Qing
Published: September 2022

A few recent reviews have addressed progress and perspectives in the field of sugar transport in plants rather comprehensively [...]
ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis
Authors: Laudadio Ilaria , Bastianelli Alex , Fulci Valerio , Carissimi Claudia , Colantoni Eleonora , Palone Francesca , Vitali Roberta , Lorefice Elisa , Cucchiara Salvatore , Negroni Anna , Stronati Laura
Published: September 2022

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.
Cytokine Secretion Dynamics of Isolated PBMC after Cladribine Exposure in RRMS Patients
Authors: Balasa Rodica , Maier Smaranda , Hutanu Adina , Voidazan Septimiu , Andone Sebastian , Oiaga Mirela , Manu Doina
Published: September 2022

Cladribine (CLD) treats multiple sclerosis (MS) by selectively and transiently depleting B and T cells with a secondary long-term reconstruction of the immune system. This study provides evidence of CLD’s immunomodulatory role in peripheral blood mononuclear cells (PBMCs) harvested from 40 patients with untreated relapsing-remitting MS (RRMS) exposed to CLD. We quantified cytokine secretion from PBMCs isolated by density gradient centrifugation with Ficoll–Paque using xMAP technology on a FlexMap 3D analyzer with a highly sensitive multiplex immunoassay kit. The PBMC secretory profile was evaluated with and without CLD exposure. PBMCs isolated from patients with RRMS for ≤12 months had significantly higher IL-4 but significantly lower IFN-γ and TNF-α secretion after CLD exposure. PBMCs isolated from patients with RRMS for >12 months had altered inflammatory ratios toward an anti-inflammatory profile and increased IL-4 but decreased TNF-α secretion after CLD exposure. CLD induced nonsignificant changes in IL-17 secretion in both RRMS groups. Our findings reaffirm CLD’s immunomodulatory effect that induces an anti-inflammatory phenotype.
Editorial for the Special Issue “New Drugs for Breast Cancer Treatment”
Authors: Acconcia Filippo
Published: September 2022

Breast cancer (BC) is the deadliest neoplastic disease for women worldwide [...]
The Inflammasome Activity of NLRP3 Is Independent of NEK7 in HEK293 Cells Co-Expressing ASC
Authors: Machtens Dominik Alexander , Bresch Ian Philipp , Eberhage Jan , Reubold Thomas Frank , Eschenburg Susanne
Published: September 2022

The cytosolic immune receptor NLRP3 (nucleotide-binding domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3) oligomerizes into the core of a supramolecular complex termed inflammasome in response to microbes and danger signals. It is thought that NLRP3 has to bind NEK7 (NIMA (never in mitosis gene a)-related kinase 7) to form a functional inflammasome core that induces the polymerization of the adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), which is a hallmark for NLRP3 activity. We reconstituted the NLRP3 inflammasome activity in modified HEK293 (human embryonic kidney 293) cells and showed that the ASC speck polymerization is independent of NEK7 in the context of this cell system. Probing the interfaces observed in the different, existing structural models of NLRP3 oligomers, we present evidence that the NEK7-independent, constitutively active NLRP3 inflammasome core in HEK293 cells may resemble a stacked-torus-like hexamer seen for NLRP3 lacking its PYD (pyrin domain).
Quantifying the Influence of Pollen Aging on the Adhesive Properties of Hypochaeris radicata Pollen
Authors: Huth Steven , Schwarz Lisa-Maricia , Gorb Stanislav N.
Published: September 2022

Although pollination is one of the most crucial biological processes that ensures plant reproduction, its mechanisms are poorly understood. Especially in insect-mediated pollination, a pollen undergoes several attachment and detachment cycles when being transferred from anther to insect and from insect to stigma. The influence of the properties of pollen, insect and floral surfaces on the adhesion forces that mediate pollen transfer have been poorly studied. Here, we investigate the adhesive properties of Hypochaeris radicata pollen and their dependence on pollen aging by quantifying the pull-off forces from glass slides using centrifugation and atomic force microscopy. We found that the properties of the pollenkitt—the viscous, lipid liquid on the surface of most pollen grains—influences the forces necessary to detach a pollen from hydrophilic surfaces. Our results show that aged H. radicata pollen form weaker adhesions to hydrophilic glass than fresh ones. On the other hand, when a pollen grain ages in contact with glass, the adhesion between the two surfaces increases over time. This study shows for the first time the pollen aging effect on the pollination mechanism.
An Experimental Investigation and Computer Modeling of Direct Tension Pullout Test of Reinforced Concrete Cylinder
Authors: Abbas Nadeem , Yousaf Muhammad , Akbar Muhammad , Saeed Muhammad Arsalan , Huali Pan , Hussain Zahoor
Published: September 2022

Executing the obligation of strengthened concrete is essential in investigating load exchanges from concrete to the inner reinforcing bar. The bond–displacement conduct and extreme pullout quality for pullout samples are essential information related to the durability of RC structures. The slip in the interface is basically due to a contrast in stresses between concrete and reinforcement. This distinction brings about the start of the split in encompassing concrete. This study examined the simple pullout solid 3D cylinder model strengthened by a reinforced steel bar, considered a line element for bond–slip conduct. The non-linear finite element model utilizing ANSYS software was established to concentrate on the concrete and steel reinforcement bond. Material nonlinearity because of cracking, crushing of concrete, and the steel reinforcing bar’s yielding were investigated. Test results showed that: a prediction model for early-age bond stress–slip relationship between steel bars and concrete was proposed based on modeling, which showed good agreement with test results. The precision of this model is explored by contrasting the finite element numerical analysis and that anticipated from test consequences of pullout examples. Immense homogeneity between the model and test results was found. This study could provide more accurate bond properties for structural analysis and design.
Early and Long-Term Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass Grafting in Patients with Severe Left Ventricular Dysfunction and a Giant Left Ventricle
Authors: Wang Chen , Jiang Yefan , Wang Qingpeng , Tian Rui , Wang Dashuai , Jiang Xionggang , Dong Nianguo , Chen Si , Chen Xinzhong
Published: September 2022

Introduction: No previous studies comparing the outcomes between off-pump coronary artery bypass grafting (off-pump CABG, OPCAB) and on-pump CABG (ONCAB) have been performed in patients with severe left ventricular dysfunction (LVD) and a giant left ventricle. We aimed to investigate whether such patients could benefit from OPCAB. Methods: From January 2011 to January 2021, a total of 98 patients with severe LVD and a giant left ventricle underwent isolated CABG (ONCAB 46, OPCAB 52) in Wuhan Union Hospital. The clinical data were collected retrospectively and propensity score matching was performed to adjust baseline characteristics. Results: After propensity matching, the two groups were comparable in baseline variables. The OPCAB group had a higher rate of incomplete revascularization than the ONCAB group (25.0% vs. 9.1%; p = 0.047). The 30-day mortality was similar between the matched groups (4.5% vs. 4.5%; p = 1.000) but the OPCAB group had a lower risk of postoperative IABP usage (9.1% vs. 25.0%; p = 0.047) and renal insufficiency (11.4% vs. 29.5%; p = 0.034). The long-term probability of survival (log-rank test, p = 0.450) was similar between the two groups but the OPCAB group had a lower probability of major adverse cardiovascular events (log-rank test, p = 0.038). Conclusions: For patients with severe LVD and a giant left ventricle, OPCAB reduced early postoperative complications while sacrificing long-term quality of life compared to those having ONCAB.