bluuebunny/crossref_metadata_2025 huggingface dataset:
Statin Use and Benefits of Thyroid Function: A Retrospective Cohort Study
Authors: Wang Yupeng , Li Qihang , Yuan Zhongshang , Ma Shizhan , Shao Shanshan , Wu Yafei , Wang Zhixiang , Li Qiu , Gao Ling , Zhao Meng , Zhao Jiajun
Published: March 2021

Purpose

Previous studies have suggested that cholesterol may influence thyroid function. Since statins are widely used for their cholesterol-lowering effect, we aimed to assess the association between statin use and thyroid function, and also to explore the role of the cholesterol-lowering effect in it.

Methods

We performed a retrospective cohort study derived from REACTION study. Eligible subjects receiving statin therapy were included in the statin group, and sex-, age-, total cholesterol (TC)-, and thyroid function-matched participants without lipid-lowering therapy were included in the control group. The median follow-up time was three years. Outcomes of thyroid function were evaluated at the end of follow-up. We used multivariable regression models to assess the association between statin use and outcomes of thyroid function, and also performed mediation analyses to explore the role of cholesterol in it.

Results

A total of 5,146 participants were screened, and 201 eligible subjects in the statin group and 201 well-matched subjects in the control group were analyzed. At the end of follow-up, TC and thyroid-stimulating hormone (TSH) levels in the statin group were lower than those in the control group (both p < 0.05), and the percentage of euthyroid subjects was higher in the statin group (88.06% vs. 76.12%, p = 0.002). The incidence rate of subclinical hypothyroidism (SCH) in euthyroid subjects was lower in the statin group (6.29% vs. 14.86%, p = 0.009), and the remission rate among subjects with SCH was higher in the statin group (50.00% vs. 15.38%, p = 0.008). In multivariable regression analyses, statin use was independently associated with lower TSH levels and higher odds to be euthyroid (OR 2.335, p = 0.004) at the end of follow-up. Mediation analyses showed the association between statin use and TSH levels were mediated by TC changes during follow-up.

Conclusion

Statin use was associated with benefits of thyroid function, and TC changes serve as a mediator of the association between statin use and TSH levels. Further studies are needed to clarify the possible underlying mechanism.
Landscape Structure Is a Major Driver of Bee Functional Diversity in Crops
Authors: Coutinho Jeferson G. E. , Hipólito Juliana , Santos Rafaela L. S. , Moreira Eduardo F. , Boscolo Danilo , Viana Blandina F.
Published: March 2021

Land-use change is having a negative effect on pollinator communities, and these changes in community structure may have unexpected impacts on the functional composition of those communities. Such changes in functional composition may impact the capacity of these assemblages to deliver pollination services, affecting the reproduction of native and wild plants. However, elucidating those relationships requires studies in multiple spatial scales because effects and consequences are different considering biological groups and interactions. In that sense, by using a multi-trait approach, we evaluated whether the landscape structure and/or local environmental characteristics could explain the functional richness, divergence, and dispersion of bee communities in agroecosystems. In addition, we investigated to what extent this approach helps to predict effects on pollination services. This study was conducted in an agroecosystem situated in the Chapada Diamantina region, State of Bahia, Brazil. Bees were collected using two complementary techniques in 27 sample units. They were classified according to their response traits (e.g., body size, nesting location) and effect traits (e.g., means of pollen transportation, specialty in obtaining resources). The Akaike information criterion was used to select the best models created through the additive combination of landscape descriptors (landscape diversity, mean patch shape, and local vegetation structure) at the local, proximal, and broad landscape levels. Our results indicate that both landscape heterogeneity and configuration matter in explaining the three properties of bee functional diversity. We indicate that functional diversity is positively correlated with compositional and configurational heterogeneity. These results suggest that landscape and local scale management to promote functional diversity in pollinator communities may be an effective mechanism for supporting increased pollination services.
Comparative Analysis of Testicular Histology and lncRNA–mRNA Expression Patterns Between Landes Geese (Anser anser) and Sichuan White Geese (Anser cygnoides)
Authors: Ran Mingxia , Huang Huaxuan , Hu Bo , Hu Shenqiang , Hu Jiwei , Li Liang , He Hua , Liu Hehe , Wang Jiwen
Published: March 2021

Landes geese and Sichuan White geese are two important genetic materials for commercial goose breeding. However, the differences in the male reproductive capacity between these two breeds and the potential molecular mechanisms and associated key genes have not been reported to date. The present study compared the testicular histology and mRNA–long non-coding RNA (lncRNA) expression patterns to reveal the differences in male reproductive performance between Sichuan White geese and Landes geese, as well as to explore the underlying molecular mechanisms. Histological results showed that the testicular organ index, semen volume, and long diameter of seminiferous tubules of Landes geese were significantly larger than those of Sichuan White geese. Analyses of mRNA-lncRNA expression profile showed that compared with Sichuan White geese, a total of 462 differentially expressed mRNAs (DEGs) (173 up-regulated and 289 down-regulated) and 329 differentially expressed lncRNAs (DE lncRNAs) (280 up-regulated, 49 down-regulated) were identified in Landes geese. Among these DEGs, there were 10 spermatogenesis-related and highly expressed (FPKM > 10) DEGs. Except for SEPP1, all of these DEGs were significantly up-regulated in the testes of Landes geese. Functional enrichment analysis indicated that the pathway related to metabolism progress and phosphoinositol signal is vitally responsible for differences in male reproductive performance between Landes geese and Sichuan White geese. These results show that compared with Sichuan White geese, the spermatogenesis in the testis of Landes geese was more active, which may be mainly related to the inositol phosphate signal. These data contribute to a better understanding of the mechanisms underlying different male reproductive performances between Landes geese and Sichuan White geese. This knowledge might eventually provide a theoretical basis for improving male reproductive performance in geese.
Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection
Authors: Lightbourn Casey O. , Wolf Dietlinde , Copsel Sabrina N. , Wang Ying , Pfeiffer Brent J. , Barreras Henry , Bader Cameron S. , Komanduri Krishna V. , Perez Victor L. , Levy Robert B.
Published: March 2021

Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.
Distribution of Chromophytic Phytoplankton in the Eddy-Induced Upwelling Region of the West Pacific Ocean Revealed Using rbcL Genes
Authors: Pujari Laxman , Narale Dhiraj , Kan Jinjun , Wu Chao , Zhang Guicheng , Ding Changling , Li Liuyang , Sun Jun
Published: March 2021

Marine chromophytic phytoplankton are a diverse group of algae and contribute significantly to the total oceanic primary production. However, the spatial distribution of chromophytic phytoplankton is understudied in the West Pacific Ocean (WPO). In this study, we have investigated the community structure and spatial distribution of chromophytic phytoplankton using RuBisCO genes (Form IDrbcL). Our results showed that Haptophyceae, Pelagophyceae, Cyanophyceae, Xanthophyceae, and Bacillariophyceae were the dominant groups. Further, chromophytic phytoplankton can be distinguished between upwelling and non-upwelling zones of the WPO. Surface and 75 m depths of a non-upwelling area were dominated byProchlorococcusstrains, whereas chromophytic phytoplankton were homogenously distributed at the surface layer in the upwelling zone. Meanwhile,Pelagomonas-like sequences were dominant at DCM (75 m) and 150 m depths of the upwelling zone. Non-metric multidimensional scaling (NMDS) analysis did not differentiate between chromophytic phytoplankton in the upwelling and non-upwelling areas, however, it showed clear trends of them at different depths. Further, redundancy analysis (RDA) showed the influence of physicochemical parameters on the distribution of chromophytic phytoplankton. Along with phosphate (p< 0.01), temperature and other dissolved nutrients were important in driving community structure. The upwelling zone was impacted by a decrease in temperature, salinity, and re-supplement of nutrients, wherePelagomonas-like sequences outnumbered other chromophytic groups presented.
Therapeutic Effects of Probiotic Minas Frescal Cheese on the Attenuation of Ulcerative Colitis in a Murine Model
Authors: Cordeiro Bárbara F. , Alves Juliana L. , Belo Giovanna A. , Oliveira Emiliano R. , Braga Marina P. , da Silva Sara H. , Lemos Luisa , Guimarães Jonas T. , Silva Ramon , Rocha Ramon S. , Jan Gwénaël , Le Loir Yves , Silva Marcia Cristina , Freitas Mônica Q. , Esmerino Erick A. , Gala-García Alfonso , Ferreira Enio , Faria Ana Maria C. , Cruz Adriano G. , Azevedo Vasco , do Carmo Fillipe L. R.
Published: March 2021

Inflammatory bowel diseases (IBDs) constitute disturbances of gastrointestinal tract that cause irreversible changes in the structure and function of tissues. Ulcerative colitis (UC), the most frequent IBD in the population, is characterized by prominent inflammation of the human colon. Functional foods containing probiotic bacteria have been studied as adjuvants to the treatment or prevention of IBDs. The selected probiotic strain Lactococcus lactis NCDO 2118 (L. lactis NCDO 2118) exhibits immunomodulatory effects, with promising results in UC mouse model induced by dextran sodium sulfate (DSS). Additionally, cheese is a dairy food that presents high nutritional value, besides being a good delivery system that can be used to improve survival and enhance the therapeutic effects of probiotic bacteria in the host. Therefore, this work investigated the probiotic therapeutic effects of an experimental Minas Frescal cheese containing L. lactis NCDO 2118 in DSS-induced colitis in mice. During colitis induction, mice that consumed the probiotic cheese exhibited reduced in the severity of colitis, with attenuated weight loss, lower disease activity index, limited shortening of the colon length, and reduced histopathological score. Moreover, probiotic cheese administration increased gene expression of tight junctions’ proteins zo-1, zo-2, ocln, and cln-1 in the colon and increase IL-10 release in the spleen and lymph nodes. In this way, this work demonstrates that consumption of probiotic Minas Frescal cheese, containing L. lactis NCDO 2118, prevents the inflammatory process during DSS-induced colitis in mice, opening perspectives for the development of new probiotic functional foods for personalized nutrition in the context of IBD.
Specialization of the Reiterated Copies of the Heterodimeric Integration Host Factor Genes in Geobacter sulfurreducens
Authors: Andrade Angel , Hernández-Eligio Alberto , Tirado Ana Lilia , Vega-Alvarado Leticia , Olvera Maricela , Morett Enrique , Juárez Katy
Published: March 2021

Integration host factor (IHF) is a widely distributed small heterodimeric protein member of the bacterial Nucleoid-Associated Proteins (NAPs), implicated in multiple DNA regulatory processes. IHF recognizes a specific DNA sequence and induces a large bend of the nucleic acid. IHF function has been mainly linked with the regulation of RpoN-dependent promoters, where IHF commonly recognizes a DNA sequence between the enhancer-binding region and the promoter, facilitating a close contact between the upstream bound activator and the promoter bound, RNA polymerase. In most proteobacteria, the genes encoding IHF subunits (ihfA and ihfB) are found in a single copy. However, in some Deltaproteobacteria, like Geobacter sulfurreducens, those genes are duplicated. To date, the functionality of IHF reiterated encoding genes is unknown. In this work, we achieved the functional characterization of the ihfA-1, ihfA-2, ihfB-1, and ihfB-2 from G. sulfurreducens. Unlike the ΔihfA-2 or ΔihfB-1 strains, single gene deletion in ihfA-1 or ihfB-2, provokes an impairment in fumarate and Fe(III) citrate reduction. Accordingly, sqRT-PCR experiments showed that ihfA-1 and ihfB-2 were expressed at higher levels than ihfA-2 and ihfB-1. In addition, RNA-Seq analysis of the ΔihfA-1 and ΔihfB-2 strains revealed a total of 89 and 122 differentially expressed genes, respectively. Furthermore, transcriptional changes in 25 genes were shared in both mutant strains. Among these genes, we confirmed the upregulation of the pilA-repressor, GSU1771, and downregulation of the triheme-cytochrome (pgcA) and the aconitate hydratase (acnA) genes by RT-qPCR. EMSA experiments also demonstrated the direct binding of IHF to the upstream promoter regions of GSU1771, pgcA and acnA. PilA changes in ΔihfA-1 and ΔihfB-2 strains were also verified by immunoblotting. Additionally, heme-staining of subcellular fractions in ΔihfA-1 and ΔihfB-2 strains revealed a remarkable deficit of c-type cytochromes. Overall, our data indicate that at least during fumarate and Fe(III) citrate reduction, the functional IHF regulator is likely assembled by the products of ihfA-1 and ihfB-2. Also, a role of IHF controlling expression of multiple genes (other than RpoN-dependent) affects G. sulfurreducens physiology and extracellular electron transfer.
Effects of Deep Brain Stimulation in the Subthalamic Nucleus on Neurocognitive Function in Patients With Parkinson's Disease Compared With Medical Therapy: A Meta-Analysis
Authors: Wang Jiazhen , Pan Ru , Cui Ying , Wang Zhigang , Li Qinghua
Published: March 2021

Background: DBS has been shown to significantly affect motor symptoms in Parkinson's disease (PD). However, some studies have suggested that it may have adverse effects on patients' neurocognitive function. To clarify this operation's effect on neurocognitive function, we collected studies containing neurocognitive function evaluation for qualitative and quantitative analysis.

Methods: We searched relevant clinical studies through Pubmed and Embase databases and extracted and sorted out information such as sample size, post-operative scores, pre-operative and post-operative evaluation interval, PD course, and exclusion criteria, from articles meeting the standards. The magnitude and variance of the DBS group's combined effects and the drug therapy group in each neurocognitive domain were calculated and analyzed by the random-effects model.

Results: Compared with the drug treatment group, the verbal fluency of patients in the experimental group was significantly decreased at least moderately (ES = −0.553), in which the phonemic fluency declines greatly (ES = −0.842), learning and memory ability was slightly decreased (ES = −0.305), and other neurocognitive functions were not significantly decreased.

Conclusion: STN-DBS can affect verbal fluency and damage learning and memory. There was no significant correlation between the above effects and disease progression itself, and it was more likely to be associated with STN-DBS. It is suggested that post-operative patients should be trained and evaluated regularly for their verbal fluency and learning and memory ability. The safety of STN-DBS is acceptable for the majority of patients with motor symptoms.
Intra-Arterial Stem Cell Transplantation in Experimental Stroke in Rats: Real-Time MR Visualization of Transplanted Cells Starting With Their First Pass Through the Brain With Regard to the Therapeutic Action
Authors: Namestnikova Daria D. , Gubskiy Ilya L. , Revkova Veronica A. , Sukhinich Kirill K. , Melnikov Pavel A. , Gabashvili Anna N. , Cherkashova Elvira A. , Vishnevskiy Daniil A. , Kurilo Victoria V. , Burunova Veronica V. , Semkina Alevtina S. , Abakumov Maxim A. , Gubsky Leonid V. , Chekhonin Vladimir P. , Ahlfors Jan-Eric , Baklaushev Vladimir P. , Yarygin Konstantin N.
Published: March 2021

Cell therapy is an emerging approach to stroke treatment with a potential to limit brain damage and enhance its restoration after the acute phase of the disease. In this study we tested directly reprogrammed neural precursor cells (drNPC) derived from adult human bone marrow cells in the rat middle cerebral artery occlusion (MCAO) model of acute ischemic stroke using human placenta mesenchymal stem cells (pMSC) as a positive control with previously confirmed efficacy. Cells were infused into the ipsilateral (right) internal carotid artery of male Wistar rats 24 h after MCAO. The main goal of this work was to evaluate real-time distribution and subsequent homing of transplanted cells in the brain. This was achieved by performing intra-arterial infusion directly inside the MRI scanner and allowed transplanted cells tracing starting from their first pass through the brain vessels. Immediately after transplantation, cells were observed in the periphery of the infarct zone and in the brain stem, 15 min later small numbers of cells could be discovered deep in the infarct core and in the contralateral hemisphere, where drNPC were seen earlier and in greater numbers than pMSC. Transplanted cells in both groups could no longer be detected in the rat brain 48–72 h after infusion. Histological and histochemical analysis demonstrated that both the drNPC and pMSC were localized inside blood vessels in close contact with the vascular wall. No passage of labeled cells through the blood brain barrier was observed. Additionally, the therapeutic effects of drNPC and pMSC were compared. Both drNPC and pMSC induced substantial attenuation of neurological deficits evaluated at the 7th and 14th day after transplantation using the modified neurological severity score (mNSS). Some of the effects of drNPC and pMSC, such as the influence on the infarct volume and the survival rate of animals, differed. The results suggest a paracrine mechanism of the positive therapeutic effects of IA drNPC and pMSC infusion, potentially enhanced by the cell-cell interactions. Our data also indicate that the long-term homing of transplanted cells in the brain is not necessary for the brain’s functional recovery.
DRP1 Promotes BRAFV600E-Driven Tumor Progression and Metabolic Reprogramming in Colorectal Cancer
Authors: Padder Rayees Ahmad , Bhat Zafar Iqbal , Ahmad Zaki , Singh Neetu , Husain Mohammad
Published: March 2021

Background

Mitochondria are highly dynamic organelles which remain in a continuous state of fission/ fusion dynamics to meet the metabolic needs of a cell. However, this fission/fusion dynamism has been reported to be dysregulated in most cancers. Such enhanced mitochondrial fission is demonstrated to be positively regulated by some activating oncogenic mutations; such as those of KRAS (Kristen rat sarcoma viral oncogene homologue) or BRAF (B- rapidly accelerated fibrosarcoma), thereby increasing tumor progression/ chemotherapeutic resistance and metabolic deregulation. However, the underlying mechanism(s) are still not clear, thus highlighting the need to further explore possible mechanism(s) of intervention. We sought to investigate how BRAFV600E driven CRC (colorectal cancer) progression is linked to mitochondrial fission/fusion dynamics and whether this window could be exploited to target CRC progression.

Methods

Western blotting was employed to study the differences in expression levels of key proteins regulating mitochondrial dynamics, which was further confirmed by confocal microscopy imaging of mitochondria in endogenously expressing BRAFWT and BRAFV600E CRC cells. Proliferation assays, soft agar clonogenic assays, glucose uptake/lactate production, ATP/ NADPH measurement assays were employed to study the extent of carcinogenesis and metabolic reprograming in BRAFV600E CRC cells. Genetic knockdown (shRNA/ siRNA) and/or pharmacologic inhibition of Dynamin related protein1/Pyruvate dehydrogenase kinase1 (DRP1/PDK1) and/or BRAFV600E were employed to study the involvement and possible mechanism of these proteins in BRAFV600E driven CRC. Statistical analyses were carried out using Graph Pad Prism v 5.0, data was analyzed by unpaired t-test and two-way ANOVA with appropriate post hoc tests.

Results

Our results demonstrate that BRAFV600E CRC cells have higher protein levels of mitochondrial fission factor- DRP1/pDRP1S616 leading to a more fragmented mitochondrial state compared to those harboring BRAFWT. This fragmented mitochondrial state was found to confer glycolytic phenotype, clonogenic potential and metastatic advantage to cells harboring BRAFV600E. Interestingly, such fragmented mitochondrial state seemed positively regulated by mitochondrial PDK1 as observed through pharmacologic as well as genetic inhibition of PDK1.

Conclusion

In conclusion, our data suggest that BRAFV600E driven colorectal cancers have fragmented mitochondria which confers glycolytic phenotype and growth advantage to these tumors, and such phenotype is dependent at least in part on PDK1- thus highlighting a potential therapeutic target.
Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer
Authors: Chung Ivy , Zhou Kun , Barrows Courtney , Banyard Jacqueline , Wilson Arianne , Rummel Nathan , Mizokami Atsushi , Basu Sudipta , Sengupta Poulomi , Shaikh Badaruddin , Sengupta Shiladitya , Bielenberg Diane R. , Zetter Bruce R.
Published: March 2021

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.
Extracellular Vesicles for the Treatment of Radiation-Induced Normal Tissue Toxicity in the Lung
Authors: Montay-Gruel Pierre , Zhu Yafeng , Petit Benoit , Leavitt Ron , Warn Mike , Giedzinski Erich , Ollivier Jonathan , Sinclair David A. , Vozenin Marie-Catherine , Limoli Charles L.
Published: March 2021

Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice via the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts (P < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging (P < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (e.g., CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis.
Adipocytes Under Obese-Like Conditions Change Cell Cycle Distribution and Phosphorylation Profiles of Breast Cancer Cells: The Adipokine Receptor CAP1 Matters
Authors: Bergqvist Malin , Elebro Karin , Borgquist Signe , Rosendahl Ann H.
Published: March 2021

Background

Obesity and associated metabolic conditions impact adipocyte functionality with potential consequences for breast cancer risk and prognosis, but contributing mechanisms remain to be understood. The adipokine receptor adenylyl cyclase-associated protein-1 (CAP1) has been implicated in the progression of breast cancer, but results are conflicting and the underlying molecular mechanisms are still unknown. In this study, molecular and cellular effects in breast cancer cells by stimulation of adipocytes under normal or obese-like conditions, and potential involvement of CAP1, were assessed.

Material and Methods

Estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cells were exposed to adipocyte-secretome from adipocytes placed under pressures mimicking normal and obese-like metabolic conditions. Changes in phosphorylated kinase proteins and related biological pathways were assessed by phospho-antibody array and PANTHER analysis, cell proliferation were investigated through sulforhodamine B, cell cycle distribution by flow cytometry. Functional effects of CAP1 were subsequently examined following small interfering (si)RNA-mediated knockdown.

Results

Protein phosphorylations involved in important biological processes were enriched in T47D breast cancer cells in response to adipocyte secretome from obese-like compared with normal conditions. The obesity-associated adipocyte secretome further stimulated cell proliferation and a shift from cell cycle G1-phase to S- and G2/M-phase was observed. Silencing of CAP1 decreased cell proliferation in both T47D and MDA-MB-231 cells, and reduced the obesity-associated secretome-induction of phosphoproteins involved in cell proliferation pathways.

Conclusions

These results indicate that the adipocyte secretome and CAP1 are mechanistically important for the proliferation of both ER-positive and ER-negative breast cancer cells, and potential signaling mediators were identified. These studies provide biological insight into how obesity-associated factors could affect breast cancer.
Fecal Multidimensional Assay for Non-Invasive Detection of Colorectal Cancer: Fecal Immunochemical Test, Stool DNA Mutation, Methylation, and Intestinal Bacteria Analysis
Authors: Mo Shaobo , Wang Hui , Han Lingyu , Xiang Wenqiang , Dai Weixing , Zhao Pengfei , Pei Fengchun , Su Zhixi , Ma Chengcheng , Li Qi , Wang Zhimin , Cai Sanjun , Wang Hao , Liu Rui , Cai Guoxiang
Published: March 2021

Background

Fecal immunochemical test (FIT), DNA mutation, DNA methylation, and microbial dysbiosis all showed promising in colorectal cancer (CRC) non-invasive detection. We assessed CRC detection with an assay combining all these strategies and investigated the effect of clinical features on the performance of this comprehensive test.

Methods

We performed a multidimensional analysis study using stool samples collected from 108 patients with CRC, 18 patients with colorectal adenoma, and 36 individuals with no evidence of colorectal disease. The multidimensional analysis of stool samples including FIT, stool DNA (sDNA) tests for three methylated genes (Septin9, NDRG4, BMP3) and three mutated genes (KRAS, BRAF, PI3KCA) using next generation sequencing as well as detection of stool bacteria level of Fusobacterium nucleatum and Parvimonas micra using qPCR method. We used a linear support vector classification model to analyze the data.

Results

The sensitivity of FIT alone was 69.4% for CRC and 11.1% for adenoma. Separately, the sensitivity of the detection of intestinal bacteria, DNA mutation, and DNA methylation for CRC was 58.3, 50.0, and 51.9%, respectively. The combination of FIT and sDNA tests had a sensitivity of 81.5% for CRC (AUC: 0.93, better than FIT alone, P = 0.017) and 27.8% for adenoma with 94.4% specificity. Sensitivity of the multidimensional test to detect CRC with stage II (84.6%) and III (91.9%) CRC was relatively higher (88.2%) than that of patients with stage I (60.0%) and stage IV (75.0%) (P = 0.024). The rate of CRC detection increased with tumor size (P = 0.008) and age (P = 0.04). Interestingly, the rate of CRC detection was higher in smoking persons than non-smokers with marginal significance (P = 0.08).

Conclusions

The multidimensional assay of stool samples combining FIT and stool DNA tests further improved the diagnostic sensitivity for CRC. This could provide new approach for improvement of CRC screening and further demonstrations are warranted.
Evaluation of a New Tubular Finger Oxygen-Enriched Oil Inside-Coated Dressing Device in Pediatric Patients Undergoing Distal Hypospadias Repair: A Prospective Randomized Clinical Trial Part II
Authors: Esposito Ciro , Coppola Vincenzo , Del Conte Fulvia , Cerulo Mariapina , Esposito Giovanni , Crocetto Felice , Castagnetti Marco , Calignano Antonio , Escolino Maria
Published: March 2021

Background: This study was the second part of a prospective randomized clinical trial and aimed to evaluate the use of a tubular finger oxygen-enriched oil inside-coated dressing device and its effect on the post-operative outcome of children undergoing distal hypospadias repair.

Methods: A prospective single-blinded randomized clinical trial was carried out between September 2019 and September 2020. We included all patients with distal hypospadias, who received Snodgrass urethroplasty and preputioplasty. The patients were randomized in two groups according to the type of dressing: tubular finger oxygen-enriched oil inside-coated device (G1) and elastic net bandage with application of oxygen-enriched oil-based gel (G2). The patients were evaluated at 7, 14, 21, 30, and 60 post-operative day (POD).

Results: Sixty-four patients (median age 14 months) were included in the study and randomized in two groups, each of 32 patients. Post-operative preputial edema rate was significantly lower in G1 (3/32, 9.3%) compared with G2 (10/32, 31.2%) (p = 0.001). The median duration of preputial edema was significantly shorter in G1 compared with G2 (6 vs. 10.5 days) (p = 0.001). Penile diameter measurements at 4th, 7th, 14th POD proved that entity and duration of post-operative swelling were objectively decreased using the new dressing. The wound healing was significantly faster in G1 compared with G2 (14.2 vs. 18.5 days) (p = 0.001). The post-operative complications rate was significantly lower in G1 (0%) compared with G2 (3/32, 9.3%) (p = 0.001). Foreskin dehiscence occurred in two G2 patients (6.2%) whereas, breakdown of urethroplasty and preputioplasty occurred in one G2 patient (3.1%) due to scratching injuries. The dressing management was subjectively assessed by nurses to be easier in G1 patients compared with G2 ones (median score 1.2 vs. 3.5) (p = 0.001). The median treatment costs were significantly lower in G1 compared with G2 (55 vs. 87 eur) (p = 0.001). No adverse skin reactions occurred.

Conclusions: Post-operative dressing using tubular finger oxygen-enriched oil inside-coated device was highly effective, easy to manage, cheaper and associated with a lower rate of foreskin and urethral complications compared with the standard dressing method in pediatric patients undergoing distal hypospadias repair. It was also clinically safe without allergy or intolerance to the product.
Downregulation of Candidate Gene Expression and Neuroprotection by Piperine in Streptozotocin-Induced Hyperglycemia and Memory Impairment in Rats
Authors: Kumar Suresh , Chowdhury Suman , Razdan Ajay , Kumari Deepa , Purty Ram Singh , Ram Heera , Kumar Pramod , Nayak Prasunpriya , Shukla Sunil Dutt
Published: March 2021

There is accumulating evidence showing that hyperglycemia conditions like diabetes possess a greater risk of impairment to the neuronal system because high glucose levels exacerbate oxidative stress, accumulation of amyloid-beta peptides, and mitochondrial dysfunction, and impair cognitive functions and cause neurodegeneration conditions like Alzheimer’s diseases. Due to the extensive focus on pharmacological intervention to prevent neuronal cells’ impairment induced by hyperglycemia, the underlying molecular mechanism that links between Diabetes and Alzheimer’s is still lacking. Given this, the present study aimed to evaluate the protective effect of piperine on streptozotocin (STZ) induced hyperglycemia and candidate gene expression. In the present study, rats were divided into four groups: control (Vehicle only), diabetic control (STZ only), piperine treated (20 mg/kg day, i.p), and sitagliptin (Positive control) treated. The memory function was assessed by Morris water maze and probe test. After treatment, biochemical parameters such as HOMA index and lipid profile were estimated in the serum, whereas histopathology was evaluated in pancreatic and brain tissue samples. Gene expression studies were done by real-time PCR technique. Present data indicated that piperine caused significant memory improvement as compared to diabetic (STZ) control. The assessment of HOMA indices in serum samples showed that piperine and sitagliptin (positive control, PC) caused significant alterations of insulin resistance, β cell function, and insulin sensitivity. Assessment of brain and pancreas histopathology shows significant improvement in tissue architecture in piperine and sitagliptin treated groups compared to diabetic control. The gene expression profile in brain tissue shows significantly reduced BACE1, PSEN1, APAF1, CASPASE3, and CATALASE genes in the piperine and sitagliptin (PC) treated groups compared to Diabetic (STZ) control. The present study demonstrated that piperine not only improves memory in diabetic rats but also reduces the expression of specific AD-related genes that can help design a novel strategy for therapeutic intervention at the molecular level.
On Synthetic Instrument Response Functions of Time-Correlated Single-Photon Counting Based Fluorescence Lifetime Imaging Analysis
Authors: Xiao Dong , Sapermsap Natakorn , Safar Mohammed , Cunningham Margaret Rose , Chen Yu , Li David Day‐Uei
Published: March 2021

Time-correlated single-photon counting (TCSPC) has been the gold standard for fluorescence lifetime imaging (FLIM) techniques due to its high signal-to-noize ratio and high temporal resolution. The sensor system's temporal instrument response function (IRF) should be considered in the deconvolution procedure to extract the real fluorescence decay to compensate for the distortion on measured decays contributed by the system imperfections. However, to measure the instrument response function is not trivial, and the measurement setup is different from measuring the real fluorescence. On the other hand, automatic synthetic IRFs can be directly derived from the recorded decay profiles and provide appropriate accuracy. This paper proposed and examined a synthetic IRF strategy. Compared with traditional automatic synthetic IRFs, the new proposed automatic synthetic IRF shows a broader dynamic range and better accuracy. To evaluate its performance, we examined simulated data using nonlinear least square deconvolution based on both the Levenberg-Marquardt algorithm and the Laguerre expansion method for bi-exponential fluorescence decays. Furthermore, experimental FLIM data of cells were also analyzed using the proposed synthetic IRF. The results from both the simulated data and experimental FLIM data show that the proposed synthetic IRF has a better performance compared to traditional synthetic IRFs. Our work provides a faster and precise method to obtain IRF, which may find various FLIM-based applications. We also reported in which conditions a measured or a synthesized IRF can be applied.
Two-Tiered Response of Cardiorespiratory-Cerebrovascular Network to Orthostatic Challenge
Authors: Mukli Peter , Nagy Zoltan , Racz Frigyes Samuel , Portoro Istvan , Hartmann Andras , Stylianou Orestis , Debreczeni Robert , Bereczki Daniel , Eke Andras
Published: March 2021

Dynamic interdependencies within and between physiological systems and subsystems are key for homeostatic mechanisms to establish an optimal state of the organism. These interactions mediate regulatory responses elicited by various perturbations, such as the high-pressure baroreflex and cerebral autoregulation, alleviating the impact of orthostatic stress on cerebral hemodynamics and oxygenation. The aim of this study was to evaluate the responsiveness of the cardiorespiratory-cerebrovascular networks by capturing linear and nonlinear interdependencies to postural changes. Ten young healthy adults participated in our study. Non-invasive measurements of arterial blood pressure (from that cardiac cycle durations were derived), breath-to-breath interval, cerebral blood flow velocity (BFV, recorded by transcranial Doppler sonography), and cerebral hemodynamics (HbT, total hemoglobin content monitored by near-infrared spectroscopy) were performed for 30-min in resting state, followed by a 1-min stand-up and a 1-min sit-down period. During preprocessing, noise was filtered and the contribution of arterial blood pressure was regressed from BFV and HbT signals. Cardiorespiratory-cerebrovascular networks were reconstructed by computing pair-wise Pearson-correlation or mutual information between the resampled signals to capture their linear and/or nonlinear interdependencies, respectively. The interdependencies between cardiac, respiratory, and cerebrovascular dynamics showed a marked weakening after standing up persisting throughout the sit-down period, which could mainly be attributed to strikingly attenuated nonlinear coupling. To summarize, we found that postural changes induced topological changes in the cardiorespiratory-cerebrovascular network. The dissolution of nonlinear networks suggests that the complexity of key homeostatic mechanisms maintaining cerebral hemodynamics and oxygenation is indeed sensitive to physiological perturbations such as orthostatic stress.
DNA Methylation Sustains “Inflamed” Memory of Peripheral Immune Cells Aggravating Kidney Inflammatory Response in Chronic Kidney Disease
Authors: Chen Xiao-Jun , Zhang Hong , Yang Fei , Liu Yu , Chen Guochun
Published: March 2021

The incidence of chronic kidney disease (CKD) has rapidly increased in the past decades. A progressive loss of kidney function characterizes a part of CKD even with intensive supportive treatment. Irrespective of its etiology, CKD progression is generally accompanied with the development of chronic kidney inflammation that is pathologically featured by the low-grade but chronic activation of recruited immune cells. Cumulative evidence support that aberrant DNA methylation pattern of diverse peripheral immune cells, including T cells and monocytes, is closely associated with CKD development in many chronic disease settings. The change of DNA methylation profile can sustain for a long time and affect the future genes expression in the circulating immune cells even after they migrate from the circulation into the involved kidney. It is of clinical interest to reveal the underlying mechanism of how altered DNA methylation regulates the intensity and the time length of the inflammatory response in the recruited effector cells. We and others recently demonstrated that altered DNA methylation occurs in peripheral immune cells and profoundly contributes to CKD development in systemic chronic diseases, such as diabetes and hypertension. This review will summarize the current findings about the influence of aberrant DNA methylation on circulating immune cells and how it potentially determines the outcome of CKD.
Phasic Neuronal Firing in the Rodent Nucleus of the Solitary Tract ex vivo
Authors: Chrobok Lukasz , Wojcik Michal , Klich Jasmin Daniela , Pradel Kamil , Lewandowski Marian Henryk , Piggins Hugh David
Published: March 2021

Phasic pattern of neuronal activity has been previously described in detail for magnocellular vasopressin neurons in the hypothalamic paraventricular and supraoptic nuclei. This characteristic bistable pattern consists of alternating periods of electrical silence and elevated neuronal firing, implicated in neuropeptide release. Here, with the use of multi-electrode array recordings ex vivo, we aimed to study the firing pattern of neurons in the nucleus of the solitary tract (NTS) – the brainstem hub for homeostatic, cardio-vascular, and metabolic processes. Our recordings from the mouse and rat hindbrain slices reveal the phasic activity pattern to be displayed by a subset of neurons in the dorsomedial NTS subjacent to the area postrema (AP), with the inter-spike interval distribution closely resembling that reported for phasic magnocellular vasopressin cells. Additionally, we provide interspecies comparison, showing higher phasic frequency and firing rate of phasic NTS cells in mice compared to rats. Further, we describe daily changes in their firing rate and pattern, peaking at the middle of the night. Last, we reveal these phasic cells to be sensitive to α2 adrenergic receptors activation and to respond to electrical stimulation of the AP. This study provides a comprehensive description of the phasic neuronal activity in the rodent NTS and identifies it as a potential downstream target of the AP noradrenergic system.
Linking Plant Secondary Metabolites and Plant Microbiomes: A Review
Authors: Pang Zhiqiang , Chen Jia , Wang Tuhong , Gao Chunsheng , Li Zhimin , Guo Litao , Xu Jianping , Cheng Yi
Published: March 2021

Plant secondary metabolites (PSMs) play many roles including defense against pathogens, pests, and herbivores; response to environmental stresses, and mediating organismal interactions. Similarly, plant microbiomes participate in many of the above-mentioned processes directly or indirectly by regulating plant metabolism. Studies have shown that plants can influence their microbiome by secreting various metabolites and, in turn, the microbiome may also impact the metabolome of the host plant. However, not much is known about the communications between the interacting partners to impact their phenotypic changes. In this article, we review the patterns and potential underlying mechanisms of interactions between PSMs and plant microbiomes. We describe the recent developments in analytical approaches and methods in this field. The applications of these new methods and approaches have increased our understanding of the relationships between PSMs and plant microbiomes. Though the current studies have primarily focused on model organisms, the methods and results obtained so far should help future studies of agriculturally important plants and facilitate the development of methods to manipulate PSMs–microbiome interactions with predictive outcomes for sustainable crop productions.
Prolyl Hydroxylase Paralogs in Nicotiana benthamiana Show High Similarity With Regard to Substrate Specificity
Authors: Mócsai Réka , Göritzer Kathrin , Stenitzer David , Maresch Daniel , Strasser Richard , Altmann Friedrich
Published: March 2021

Plant glycoproteins display a characteristic type ofO-glycosylation where short arabinans or larger arabinogalactans are linked to hydroxyproline. The conversion of proline to 4-hydroxyproline is accomplished by prolyl-hydroxylases (P4Hs). Eleven putativeNicotiana benthamianaP4Hs, which fall in four homology groups, have been identified by homology searches using knownArabidopsis thalianaP4H sequences. One member of each of these groups has been expressed in insect cells using the baculovirus expression system and applied to synthetic peptides representing theO-glycosylated region of erythropoietin (EPO), IgA1, Art v 1 and theArabidopsis thalianaglycoprotein STRUBBELIG. Unlike the situation in the mossPhyscomitrella patens, where one particular P4H was mainly responsible for the oxidation of erythropoietin, the tobacco P4Hs exhibited rather similar activities, albeit with biased substrate preferences and preferred sites of oxidation. From a biotechnological viewpoint, this result means that silencing/knockout of a singleP4HinN. benthamianacannot be expected to result in the abolishment of the plant-specific oxidation of prolyl residues in a recombinant protein.