bluuebunny/crossref_metadata_2025 huggingface dataset:
Malonyl-proteome profiles of Staphylococcus aureus reveal lysine malonylation modification in enzymes involved in energy metabolism
Authors: Shi Yanan , Zhu Jingjing , Xu Yan , Tang Xiaozhao , Yang Zushun , Huang Aixiang
Published: January 2021

Background

Protein lysine malonylation, a novel post-translational modification (PTM), has been recently linked with energy metabolism in bacteria. Staphylococcus aureus is the third most important foodborne pathogen worldwide. Nonetheless, substrates and biological roles of malonylation are still poorly understood in this pathogen.

Results

Using anti-malonyl-lysine antibody enrichment and high-resolution LC-MS/MS analysis, 440 lysine-malonylated sites were identified in 281 proteins of S. aureus strain. The frequency of valine in position − 1 and alanine at + 2 and + 4 positions was high. KEGG pathway analysis showed that six categories were highly enriched, including ribosome, glycolysis/gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), valine, leucine, isoleucine degradation, and aminoacyl-tRNA biosynthesis. In total, 31 malonylated sites in S. aureus shared homology with lysine-malonylated sites previously identified in E. coli, indicating malonylated proteins are highly conserved among bacteria. Key rate-limiting enzymes in central carbon metabolic pathways were also found to be malonylated in S. aureus, namely pyruvate kinase (PYK), 6-phosphofructokinase, phosphoglycerate kinase, dihydrolipoyl dehydrogenase, and F1F0-ATP synthase. Notably, malonylation sites were found at or near protein active sites, including KH domain protein, thioredoxin, alanine dehydrogenase (ALD), dihydrolipoyl dehydrogenase (LpdA), pyruvate oxidase CidC, and catabolite control protein A (CcpA), thus suggesting that lysine malonylation may affect the activity of such enzymes.

Conclusions

Data presented herein expand the current knowledge on lysine malonylation in prokaryotes and indicate the potential roles of protein malonylation in bacterial physiology and metabolism.
Prognostic significance of enlarged paraaortic lymph nodes detected during left-sided colorectal cancer surgery: a single-center retrospective cohort study
Authors: Lee Jaram , Park Hyeong-min , Lee Soo Young , Kim Chang Hyun , Kim Hyeong Rok
Published: January 2021

Background

Very few studies have been conducted on the treatment strategy for enlarged paraaortic lymph nodes (PALNs) incidentally detected during surgery. The purpose of this study was to investigate the benefit of lymph node dissection in patients with incidentally detected enlarged PALNs.

Methods

We retrospectively reviewed patients with left colon and rectal cancer who underwent surgical resection with PALN dissection between January 2010 and December 2018. The predictive factors for pathologic PALN metastasis (PALNM) were analyzed, and survival analyses were conducted to identify prognostic factors.

Results

Among 263 patients included, 19 (7.2%) showed pathologic PALNM and 5 (26.33%) had enlarged PALNs incidentally detected during surgery. These 5 patients accounted for 2.2% of 227 patients who had no evidence of PALNM on preoperative radiologic examination. Radiologic PALNM (odds ratio [OR] 12.737, 95% confidence interval [CI] 3.472–46.723) and radiologic distant metastasis other than PALNM (OR = 4.090, 95% CI 1.011–16.539) were independent predictive factors for pathologic PALNM. Pathologic T4 stage (hazard ratio [HR] 2.196, 95% CI 1.063–4.538) and R2 resection (HR 4.643, 95% CI 2.046–10.534) were independent prognostic factors for overall survival (OS). In patients undergoing R0 resection, pathologic PALNM was not associated with 5-year OS (90% vs. 82.2%, p = 0.896).

Conclusion

Dissection of enlarged PALNs incidentally detected during colorectal surgery may benefit patients with favorable survival outcomes.
Assessing progress in the national health financing system towards universal health coverage in Iran: a mixed-method study protocol
Authors: Anjomshoa Mina , Akbari Sari Ali , Takian Amirhossein
Published: January 2021

Introduction

Health financing systems have a key role in achieving universal health coverage (UHC) across the globe. However, little is known about how best to monitor health financing system progress towards UHC, especially in low- and middle-income countries. This is a protocol of a study that will aim to assess health financing system progress towards achieving UHC in Iran.

Methods

An explanatory mixed-method approach will be used in two phases. In the quantitative phase, the performance of the Iranian health financing system will be assessed using a well-established set of indicators to draw on progress over 5-year intervals starting in the year 2000 up to the present. Data will be extracted from the global health expenditure database using a specific form and will be classified in accordance with each indicator. A qualitative phase will then take place considering the Kutzin et al. framework and by using health financing progress matrices. The qualitative phase will consist of two successive stages; first, a descriptive overview on the major health coverage schemes along with key attributes of each scheme. This initial mapping will be the underlying background for the second stage. In the second stage, the matrices comprised of a series of questions and relevant to the core functions of health financing and cross-cutting options will be invested in enhancing the evaluation of the ongoing reforms or policies. In this phase, data will be collected by reviewing national policy documents and in-depth interviews with key informants who will be recruited using purposive sampling. Finally, a policy discussion with key stakeholders will be held in order to review and verify the consistency between the current health financing policy and UHC goals.

Discussion

This study will provide a comprehensive image about the current status of the national health financing system progress towards achieving UHC in Iran. Such assessment will give detailed insight about the performance of the current financing system through identifying encountered challenges. Furthermore, some other defects in the design of the financing system are expected to appear. In all likelihood, the results will be fruitful enough to make informed decisions about interventions and policies in relation to UHC.

Ethics and dissemination

The study protocol has been approved by the Ethics Committee for Research at Tehran University of Medical Sciences. Informed consent will be obtained from all key informants and the data will be collected and transcribed anonymously in order to maintain utmost confidentiality. The results will be disseminated in peer-reviewed journals and presented in national and international conferences and meetings.
Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling
Authors: Pande Shivangi , Yang Xuehui , Friesel Robert
Published: January 2021

Interleukin-17 receptor D (IL17RD or IL-17RD) also known as Sef (similar expression to fibroblast growth factor), is a single pass transmembrane protein that is reported to regulate several signaling pathways . IL17RD was initially described as a feedback inhibitor of fibroblast growth factor (FGF) signaling during zebrafish and frog development. It was subsequently determined to regulate other receptor tyrosine kinase signaling cascades as well as several proinflammatory signaling pathways including Interleukin-17A (IL17A), Toll-like receptors (TLR) and Interleukin-1α (IL1α) in several vertebrate species including humans. This review will provide an overview of IL17RD regulation of signaling pathways and functions with emphasis on regulation of development and pathobiological conditions. We will also discuss gaps in our knowledge about IL17RD function to provide insight into opportunities for future investigation.
Evaluation of SARS-CoV-2 neutralizing antibodies using a vesicular stomatitis virus possessing SARS-CoV-2 spike protein
Authors: Tani Hideki , Kimura Miyuki , Tan Long , Yoshida Yoshihiro , Ozawa Tatsuhiko , Kishi Hiroyuki , Fukushi Shuetsu , Saijo Masayuki , Sano Kaori , Suzuki Tadaki , Kawasuji Hitoshi , Ueno Akitoshi , Miyajima Yuki , Fukui Yasutaka , Sakamaki Ippei , Yamamoto Yoshihiro , Morinaga Yoshitomo
Published: January 2021

Background

SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is now classified in the genus Coronavirus with closely related SARS-CoV. SARS-CoV-2 is highly pathogenic in humans and is classified as a biosafety level (BSL)-3 pathogen, which makes manipulating it relatively difficult due to its infectious nature.

Methods

To circumvent the need for BSL-3 laboratories, an alternative assay was developed that avoids live virus and instead uses a recombinant VSV expressing luciferase and possesses the full length or truncated spike proteins of SARS-CoV-2. Furthermore, to measure SARS-CoV-2 neutralizing antibodies under BSL2 conditions, a chemiluminescence reduction neutralization test (CRNT) for SARS-CoV-2 was developed. The neutralization values of the serum samples collected from hospitalized patients with COVID-19 or SARS-CoV-2 PCR-negative donors against the pseudotyped virus infection evaluated by the CRNT were compared with antibody titers determined from an enzyme-linked immunosorbent assay (ELISA) or an immunofluorescence assay (IFA).

Results

The CRNT, which used whole blood collected from hospitalized patients with COVID-19, was also examined. As a result, the inhibition of pseudotyped virus infection was specifically observed in both serum and whole blood and was also correlated with the results of the IFA.

Conclusions

In conclusion, the CRNT for COVID-19 is a convenient assay system that can be performed in a BSL-2 laboratory with high specificity and sensitivity for evaluating the occurrence of neutralizing antibodies against SARS-CoV-2.
Long-chain saturated fatty acid species are not toxic to human pancreatic β-cells and may offer protection against pro-inflammatory cytokine induced β-cell death
Authors: Thomas Patricia , Leslie Kaiyven A. , Welters Hannah J. , Morgan Noel G.
Published: January 2021

Obesity is a major risk factor for type 2 diabetes (T2D) although the causal links remain unclear. A feature shared by both conditions however is systemic inflammation and raised levels of circulating fatty acids (FFA). It is widely believed that in obese individuals genetically prone to T2D, elevated levels of plasma FFA may contribute towards the death and dysfunction of insulin-producing pancreatic β-cells in a process of (gluco)lipotoxicity. In support of this, in vitro studies have shown consistently that long-chain saturated fatty acids (LC-SFA) are toxic to rodent β-cells during chronic exposure (> 24 h). Conversely, shorter chain SFA and unsaturated species are well tolerated, suggesting that toxicity is dependent on carbon chain length and/or double bond configuration. Despite the wealth of evidence implicating lipotoxicity as a means of β-cell death in rodents, the evidence that a similar process occurs in humans is much less substantial. Therefore, the present study has evaluated the effects of chronic exposure to fatty acids of varying chain length and degree of saturation, on the viability of human β-cells in culture. We have also studied the effects of a combination of fatty acids and pro-inflammatory cytokines. Strikingly, we find that LC-FFA do not readily promote the demise of human β-cells and that they may even offer a measure of protection against the toxic effects of pro-inflammatory cytokines. Therefore, these findings imply that a model in which elevated circulating LC-FFA play a direct role in mediating β-cell dysfunction and death in humans, may be overly simplistic.
Changing course: supporting a shift to environmental strategies in a state prevention system
Authors: Ballard Parissa J. , Pankratz Melinda , Wagoner Kimberly G. , Cornacchione Ross Jennifer , Rhodes Scott D. , Azagba Sunday , Song Eunyoung Y. , Wolfson Mark
Published: January 2021

Background

This study examines how the North Carolina state prevention system responded to a policy shift from individual-level prevention strategies to environmental strategies from the perspective of the organizations implementing the policy shift.

Methods

We use two data sources. First, we conducted interviews to collect qualitative data from key informants. Second, we used prevention provider agency expenditure data from the year the shift was announced and the following year.

Results

The interviews allowed us to identify effective features of policy change implementation in complex systems, such as the need for clear communication and guidance about the policy changes. Our interview and expenditure analyses also underscore variation in the level of guidance and oversight provided by implementing agencies to prevention providers.

Conclusions

Our analyses suggest that more active monitoring and oversight may have facilitated more consistent implementation of the policy shift toward greater use of environmental prevention strategies.
Context-acceptability theories: example of family planning interventions in five African countries
Authors: Webster Jayne , Krishnaratne Shari , Hoyt Jenna , Demissie Shiferaw Dechasa , Spilotros Nathaly , Landegger Justine , Kambanje Misozi , Pryor Shannon , Moseti Easterlina , Marcus Seth , Gnintoungbe Marius , Curry Dora , Hamon Jessie K.
Published: January 2021

Background

Family planning (FP) can lengthen birth intervals and potentially reduce the risk of foetal death, low birthweight, prematurity, and being small for gestational age. Effective FP is most easily achieved through access to and acceptability of modern contraceptive methods (MCMs). This study aimed to identify mechanisms of acceptability and the contexts in which they are triggered and to generate theories to improve the selection and implementation of effective interventions by studying an intervention integrating FP with childhood immunisation services.

Methods

Qualitative interpretative synthesis of findings from realist evaluations of FP interventions in five African countries was guided by an analytical framework. Empirical mechanisms of acceptability were identified from semi-structured interviews and focus group discussions with key stakeholders (N= 253). The context in which these mechanisms were triggered was also defined. Empirical mechanisms of acceptability were matched to constructs of a theoretical framework of acceptability. Context-acceptability theories (CATs) were developed, which summarised constructs of acceptability triggered for specific actors in specified contexts. Examples of interventions that may be used to trigger acceptability for these actors were described.

Results

Seven CATs were developed for contexts with strong beliefs in religious values and with powerful religious leaders, a traditional desire for large families, stigmatisation of MCM use, male partners who are non-accepting of FP, and rumours or experiences of MCM side effects. Acceptability mechanisms included alignment with values and beliefs without requiring compromise, actors’ certainty about their ability to avoid harm and make the intervention work, and understanding the intervention and how it works. Additionally, acceptability by one group of actors was found to alter the context, triggering acceptability mechanisms amongst others.

Conclusions

This study demonstrated the value of embedding realist approaches within implementation research. CATs are transferable theories that answer the question: given the context, what construct of acceptability does an intervention need to trigger, or more simply, what intervention do we need to apply here to achieve our outcomes? CATs facilitate transfer of interventions across geographies within defined contexts.
Using brain functional magnetic resonance imaging to evaluate the effectiveness of acupuncture combined with mirror therapy on upper limb function in patients with cerebral ischemic stroke: a study protocol for a randomized, controlled trial
Authors: Xu Mingzhu , Lin Run , Luo Jing , Tang Chunzhi , Wang Shuhui , Wong John , Wu Meng , Huang Jianting , Shi Peng , Gao Ang , Bai Yuqian , Xie Ying , Luo Jun , Yang Yunqiu , Cui Shaoyang
Published: January 2021

Background

Upper limb and hand motor dysfunction is one of the challenges in rehabilitation after cerebral ischemic stroke (CIS), and the clinical efficacy of rehabilitation needs to be improved. This study aims to combine Jin’s three-needle acupuncture (JTN) therapy with mirror therapy (MT) for hemiplegia after CIS, objectively evaluate the clinical effects and safety of JTN to treat upper limb dysfunction, and use functional magnetic resonance imaging (fMRI) of the brain to investigate the central mechanisms of the effects, which would provide a powerful evidence-based medical basis for further supporting the application of JTN combined with MT.

Methods/design

This trial will be a single-blind, randomized controlled study. Patients who meet the study criteria will be recruited and randomly assigned to either the combined treatment group (JTN+MT) or the JTN group. Both interventions will be conducted for 6 days per week and last for 4 weeks. The primary outcome will be the effective rate based on the Fugl–Meyer Assessment for Upper Extremity (FMA-UE). Other outcome measures will include scores on the motor assessment scale (MAS), action research arm test (ARAT), activities of daily living (ADL) scale, and fMRI analyses. For safety evaluation, adverse events will be observed and recorded.

Discussion

This study may help to identify the efficacy and safety of acupuncture combined with MT for upper limb dysfunction after CIS and explore the central mechanisms with brain fMRI.

Trial registration

Chinese Clinical Trial Registry ChiCTR-IOR-17012174. Registered on 5 April 2017.
Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance
Authors: Beck Daniel , Ben Maamar Millissia , Skinner Michael K.
Published: January 2021

Background

Environmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes.

Results

A rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations.

Conclusions

Many of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.
Circular RNAs in osteoarthritis: indispensable regulators and novel strategies in clinical implications
Authors: Zhang Wenchao , Qi Lin , Chen Ruiqi , He Jieyu , Liu Zhongyue , Wang Wanchun , Tu Chao , Li Zhihong
Published: January 2021

Over the past decades, circular RNAs (circRNAs) have emerged as a hot spot and sparked intensive interest. Initially considered as the transcriptional noises, further studies have indicated that circRNAs are crucial regulators in multiple cellular biological processes, and thus engage in the development and progression of many diseases including osteoarthritis (OA). OA is a prevalent disease that mainly affects those aging, obese and post-traumatic population, posing as a major source of socioeconomic burden. Recently, numerous circRNAs have been found aberrantly expressed in OA tissues compared with counterparts. More importantly, circRNAs have been demonstrated to interplay with components in OA microenvironments, such as chondrocytes, synoviocytes and macrophages, by regulation of their proliferation, apoptosis, autophagy, inflammation, or extracellular matrix reorganization. Herein, in this review, we extensively summarize the roles of circRNAs in OA microenvironment, progression, and putative treatment, as well as envision the future directions for circRNAs research in OA, with the aim to provide a novel insight into this field.
Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight
Authors: Robinson N. , Brown H. , Antoun Elie , Godfrey Keith M. , Hanson Mark A. , Lillycrop Karen A. , Crozier Sarah R. , Murray Robert , Pearce M. S. , Relton C. L. , Albani V. , McKay J. A.
Published: January 2021

Background

High early postnatal weight gain has been associated with childhood adiposity; however, the mechanism remains unknown. DNA methylation is a hypothesised mechanism linking early life exposures and subsequent disease. However, epigenetic changes associated with high early weight gain have not previously been investigated. Our aim was to investigate the associations between early weight gain, peripheral blood DNA methylation, and subsequent overweight/obese. Data from the UK Avon Longitudinal study of Parents and Children (ALSPAC) cohort were used to estimate associations between early postnatal weight gain and epigenome-wide DNA CpG site methylation (Illumina 450 K Methylation Beadchip) in blood in childhood (n = 125) and late adolescence (n = 96). High weight gain in the first year (a change in weight z‐scores > 0.67), both unconditional (rapid weight gain) and conditional on birthweight (rapid thrive), was related to individual CpG site methylation and across regions using the meffil pipeline, with and without adjustment for cell type proportions, and with 5% false discovery rate correction. Variation in methylation at high weight gain-associated CpG sites was then examined with regard to body composition measures in childhood and adolescence. Replication of the differentially methylated CpG sites was sought using whole-blood DNA samples from 104 children from the UK Southampton Women’s Survey.

Results

Rapid infant weight gain was associated with small (+ 1% change) increases in childhood methylation (age 7) for two distinct CpG sites (cg01379158 (NT5M) and cg11531579 (CHFR)). Childhood methylation at one of these CpGs (cg11531579) was also higher in those who experienced rapid weight gain and were subsequently overweight/obese in adolescence (age 17). Rapid weight gain was not associated with differential DNA methylation in adolescence. Childhood methylation at the cg11531579 site was also suggestively associated with rapid weight gain in the replication cohort.

Conclusions

This study identified associations between rapid weight gain in infancy and small increases in childhood methylation at two CpG sites, one of which was replicated and was also associated with subsequent overweight/obese. It will be important to determine whether loci are markers of early rapid weight gain across different, larger populations. The mechanistic relevance of these differentially methylated sites requires further investigation.
Alzheimer’s cerebrospinal biomarkers from Lumipulse fully automated immunoassay: concordance with amyloid-beta PET and manual immunoassay in Koreans
Authors: Moon Sohee , Kim Sujin , Mankhong Sakulrat , Choi Seong Hye , Vandijck Manu , Kostanjevecki Vesna , Jeong Jee Hyang , Yoon Soo Jin , Park Kyung Won , Kim Eun-Joo , Yoon Bora , Kim Hee Jin , Jang Jae-Won , Hong Jin Yong , Park Dong-Ho , Shaw Leslie M. , Kang Ju-Hee
Published: January 2021

Background

Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans.

Methods

Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated.

Results

Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840–0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876–0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature.

Conclusion

CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD)
Authors: Ridzuan Noridzzaida , Zakaria Norashikin , Widera Darius , Sheard Jonathan , Morimoto Mitsuru , Kiyokawa Hirofumi , Mohd Isa Seoparjoo Azmel , Chatar Singh Gurjeet Kaur , Then Kong-Yong , Ooi Ghee-Chien , Yahaya Badrul Hisham
Published: January 2021

Background

Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin.

Methods

In this study, we assessed the potential anti-inflammatory effects of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs in a rat model of COPD. EVs were isolated from hUC-MSCs and characterized by the transmission electron microscope, western blotting, and nanoparticle tracking analysis. As a model of COPD, male Sprague-Dawley rats were exposed to cigarette smoke for up to 12 weeks, followed by transplantation of hUC-MSCs or application of hUC-MSC-derived EVs. Lung tissue was subjected to histological analysis using haematoxylin and eosin staining, Alcian blue-periodic acid-Schiff (AB-PAS) staining, and immunofluorescence staining. Gene expression in the lung tissue was assessed using microarray analysis. Statistical analyses were performed using GraphPad Prism 7 version 7.0 (GraphPad Software, USA). Student’s t test was used to compare between 2 groups. Comparison among more than 2 groups was done using one-way analysis of variance (ANOVA). Data presented as median ± standard deviation (SD).

Results

Both transplantation of hUC-MSCs and application of EVs resulted in a reduction of peribronchial and perivascular inflammation, alveolar septal thickening associated with mononuclear inflammation, and a decreased number of goblet cells. Moreover, hUC-MSCs and EVs ameliorated the loss of alveolar septa in the emphysematous lung of COPD rats and reduced the levels of NF-κB subunit p65 in the tissue. Subsequent microarray analysis revealed that both hUC-MSCs and EVs significantly regulate multiple pathways known to be associated with COPD.

Conclusions

In conclusion, we show that hUC-MSC-derived EVs effectively ameliorate by COPD-induced inflammation. Thus, EVs could serve as a new cell-free-based therapy for the treatment of COPD.
The role of vitamin D in autoimmune diseases: could sex make the difference?
Authors: Dupuis Maria Luisa , Pagano Maria Teresa , Pierdominici Marina , Ortona Elena
Published: January 2021

Over the last decades, a central role for vitamin D in immune modulation has been well established. The active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with vitamin D receptor, exerts different activities on the innate and adaptive immune system, among which suppression of inflammation and promotion of tolerogenic responses. Vitamin D insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, a number of studies recently showed a cross-talk between vitamin D and the sex hormone estrogen. Estrogen-mediated effects on immune response may favor a Th1 profile or a Th2 profile, depending on hormone concentration. Thus, estrogen-mediated effects appear to be variable on autoimmunity depending on its concentration but also on the pathogenic mechanisms underlying the different autoimmune diseases (i.e., Th1- or Th2-mediated diseases). Notably, estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males. On the other hand, vitamin D has been shown to downregulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level. Overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men. Future studies are needed to expand current knowledge on the immunomodulatory role of vitamin D in a sex and gender perspective, paving the way to a more personalized therapeutic approach in autoimmune diseases.
Extracellular vesicles in bone and periodontal regeneration: current and potential therapeutic applications
Authors: Gholami Leila , Nooshabadi Vajihe Taghdiri , Shahabi Shiva , Jazayeri Marzieh , Tarzemany Rana , Afsartala Zohreh , Khorsandi Khatereh
Published: January 2021

Oral mesenchymal stem cells (MSCs) and their secretomes are considered important factors in the field of medical tissue engineering and cell free biotherapy due to their ease of access, differentiation potential, and successful therapeutic outcomes. Extracellular vesicles (EVs) and the conditioned medium (CM) from MSCs are gaining more attraction as an alternative to cell-based therapies due to the less ethical issues involved, and their easier acquisition, preservation, long term storage, sterilization, and packaging. Bone and periodontal regenerative ability of EVs and CM have been the focus of some recent studies. In this review, we looked through currently available literature regarding MSCs’ EVs or conditioned medium and their general characteristics, function, and regenerative potentials. We will also review the novel applications in regenerating bone and periodontal defects.
RETRACTED ARTICLE: Research on intelligent medical big data system based on Hadoop and blockchain
Authors: Zhang Xiangfeng , Wang Yanmei
Published: January 2021

In order to improve the intelligence of the medical system, this paper designs and implements a secure medical big data ecosystem on top of the Hadoop big data platform. It is designed against the background of the increasingly serious trend of the current security medical big data ecosystem. In order to improve the efficiency of traditional medical rehabilitation activities and enable patients to maximize their understanding of their treatment status, this paper designs a personalized health information system that allows patient users to understand their treatment and rehabilitation status anytime and anywhere, and all medical health data distributed in different independent medical institutions to ensure that these data are stored independently. As a distributed accounting technology for multi-party maintenance and backup information security, blockchain is a good breakthrough point for innovation in medical data sharing. In this paper, the system realizes the personal health data centre on the Hadoop big data platform, and the original distributed data are stored and analyzed centrally through the data synchronization module and the independent data acquisition system. Utilizing the advantages of the Hadoop big data platform, the personalized health information system for stroke has designed to provide personalized health management services for patients and facilitate the management of patients by medical staff.
Mathematical analysis of nonlinear integral boundary value problem of proportional delay implicit fractional differential equations with impulsive conditions
Authors: Ali Arshad , Shah Kamal , Abdeljawad Thabet , Mahariq Ibrahim , Rashdan Mostafa
Published: January 2021

The current study is devoted to deriving some results about existence and stability analysis for a nonlinear problem of implicit fractional differential equations (FODEs) with impulsive and integral boundary conditions. The concerned problem involves proportional type delay term. By using Schaefer’s fixed point theorem and Banach’s contraction principle, the required conditions are developed. Also, different kinds of Ulam stability results are derived by using nonlinear analysis. Providing a pertinent example, we demonstrate our main results.
Conservational tree growing by smallholder farm households: evidence from Gamo highlands of Southern Ethiopia
Authors: Massa Malebo Mancha , Mosa Abdulaziz
Published: January 2021

Deforestation and environmental degradation were identified among the leading factors worsening risk exposure in developing countries. Conservational tree growing was found a permissible option and an awake up policy direction to curve down the problem in Ethiopia. However, the uptake of this practice is far from complete and the art has not been made to a level that could make households self-reliant at least in tree resources, particularly in the highlands. The objective of this study was to identify the decisive factors that influence conservational tree growing behavior of smallholder farm households in Gamo highlands of Southern Ethiopia. The study was based on survey data collected from 11 villages in 2011/2012. A multi-stage sampling technique was used to select 335 farm households. Structured interview questionnaires and observations were used to collect primary data. Descriptive and inferential statistics and logistic regression model were used to analyze the data. The key findings showed that a host of factors significantly influenced smallholders’ decision to practice conservational tree growing. The study found that tree growing experience, farm size, and availability of suitable land area for tree growing and cash income from sales of trees were the significant factors explaining the variation in conservational tree growing behavior of households. We also observed old-aged trees in traditionally protected areas. Among others, funeral and mystical sites host large number of long-lived indigenous tree species than private farms in Gamo highlands of southern Ethiopia. Based on the findings, the study concluded that intra-farmer experience sharing, and support to efficient indigenous institutions and rural tree markets as potential entry points for mitigating deforestation and developing environmentally sustainable agriculture.
Lessons learned from the prenatal microbiome controversy
Authors: Blaser Martin J. , Devkota Suzanne , McCoy Kathy D. , Relman David A. , Yassour Moran , Young Vincent B.
Published: January 2021

For more than a century, the prenatal environment was considered sterile. Over the last few years, findings obtained with next-generation sequencing approaches from samples of the placenta, the amniotic fluid, meconium, and even fetal tissues have challenged the dogma of a sterile womb, and additional reports have emerged that used culture, microscopy, and quantitative PCR to support the presence of a low-biomass microbial community at prenatal sites. Given the substantial implications of prenatal exposure to microbes for the development and health of the host, the findings have gathered substantial interest from academics, high impact journals, the public press, and funding agencies. However, an increasing number of studies have challenged the prenatal microbiome identifying contamination as a major issue, and scientists that remained skeptical have pointed to inconsistencies with in utero colonization, the impact of c-sections on early microbiome assembly, and the ability to generate germ-free mammals. A lively academic controversy has emerged on the existence of the wider importance of prenatal microbial communities. Microbiome has asked experts to discuss these issues and provide their thoughts on the implications. To allow for a broader perspective of this discussion, we have specifically selected scientists, who have a long-standing expertise in microbiome sciences but who have not directly been involved in the debate so far.
Polinton-like viruses are abundant in aquatic ecosystems
Authors: Bellas Christopher M. , Sommaruga Ruben
Published: January 2021

Background

Polintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses. Originally considered as transposons, they have been found to encode virus capsid genes, suggesting they may actually be integrated viruses; however, an extracellular form has yet to be detected. Recently, circa 25 Polinton-like viruses have been discovered in environmental metagenomes and algal genomes, which shared distantly related genes to both Polintons and virophages (Lavidaviridae). These entities could be the first members of a major class of ancient eukaryotic viruses; however, owing to the lack of available genomes for analysis, information on their global diversity, evolutionary relationships, eukaryotic hosts, and status as free virus particles is limited.

Results

Here, we analysed the metaviromes of an alpine lake to show that Polinton-like virus genome sequences are abundant in the water column. We identify major capsid protein genes belonging to 82 new Polinton-like viruses and use these to interrogate publicly available metagenomic datasets, identifying 543 genomes and a further 16 integrated into eukaryotic genomes. Using an analysis of shared gene content and major capsid protein phylogeny, we define large groups of Polinton-like viruses and link them to diverse eukaryotic hosts, including a new group of viruses, which possess all the core genes of virophages and infect oomycetes and Chrysophyceae.

Conclusions

Our study increased the number of known Polinton-like viruses by 25-fold, identifying five major new groups of eukaryotic viruses, which until now have been hidden in metagenomic datasets. The large enrichment (> 100-fold) of Polinton-like virus sequences in the virus-sized fraction of this alpine lake and the fact that their viral major capsid proteins are found in eukaryotic host transcriptomes support the hypothesis that Polintons in unicellular eukaryotes are viruses. In summary, our data reveals a diverse assemblage of globally distributed viruses, associated with a wide range of unicellular eukaryotic hosts. We anticipate that the methods we have developed for Polinton-like virus detection and the database of over 20,000 genes we present will allow for continued discovery and analysis of these new viral groups.
A semi-tryptic peptide centric metaproteomic mining approach and its potential utility in capturing signatures of gut microbial proteolysis
Authors: Yan Zhixiang , He Feixiang , Xiao Fei , He Huanhuan , Li Dan , Cong Li , Lin Lu , Zhu Huijin , Wu Yanyan , Yan Ru , Li Xiaofeng , Shan Hong
Published: January 2021

Background

Proteolysis regulation allows gut microbes to respond rapidly to dynamic intestinal environments by fast degradation of misfolded proteins and activation of regulatory proteins. However, alterations of gut microbial proteolytic signatures under complex disease status such as inflammatory bowel disease (IBD, including Crohn’s disease (CD) and ulcerative colitis (UC)), have not been investigated. Metaproteomics holds the potential to investigate gut microbial proteolysis because semi-tryptic peptides mainly derive from endogenous proteolysis.

Results

We have developed a semi-tryptic peptide centric metaproteomic mining approach to obtain a snapshot of human gut microbial proteolysis signatures. This approach employed a comprehensive meta-database, two-step multiengine database search, and datasets with high-resolution fragmentation spectra to increase the confidence of semi-tryptic peptide identification. The approach was validated by discovering altered proteolysis signatures of Escherichia coli heat shock response. Utilizing two published large-scale metaproteomics datasets containing 623 metaproteomes from 447 fecal and 176 mucosal luminal interface (MLI) samples from IBD patients and healthy individuals, we obtain potential signatures of altered gut microbial proteolysis at taxonomic, functional, and cleavage site motif levels. The functional alterations mainly involved microbial carbohydrate transport and metabolism, oxidative stress, cell motility, protein synthesis, and maturation. Altered microbial proteolysis signatures of CD and UC mainly occurred in terminal ileum and descending colon, respectively. Microbial proteolysis patterns exhibited low correlations with β-diversity and moderate correlations with microbial protease and chaperones levels, respectively. Human protease inhibitors and immunoglobulins were mainly negatively associated with microbial proteolysis patterns, probably because of the inhibitory effects of these host factors on gut microbial proteolysis events.

Conclusions

This semi-tryptic peptide centric mining strategy offers a label-free approach to discover signatures of in vivo gut microbial proteolysis events if experimental conditions are well controlled. It can also capture in vitro proteolysis signatures to facilitate the evaluation and optimization of experimental conditions. Our findings highlight the complex and diverse proteolytic events of gut microbiome, providing a unique layer of information beyond taxonomic and proteomic abundance.
Group therapy on in utero colonization: seeking common truths and a way forward
Authors: Silverstein Rachel B. , Mysorekar Indira U.
Published: January 2021

The human microbiome refers to the genetic composition of microorganisms in a particular location in the human body. Emerging evidence over the past many years suggests that the microbiome constitute drivers of human fate almost at par with our genome and epigenome. It is now well accepted after decades of disbelief that a broad understanding of human development, health, physiology, and disease requires understanding of the microbiome along with the genome and epigenome. We are learning daily of the interdependent relationships between microbiome/microbiota and immune responses, mood, cancer progression, response to therapies, aging, obesity, antibiotic usage, and overusage and much more. The next frontier in microbiome field is understanding when does this influence begin? Does the human microbiome initiate at the time of birth or are developing human fetuses already primed with microbes and their products in utero. In this commentary, we reflect on evidence gathered thus far on this question and identify the unknown common truths. We present a way forward to continue understanding our microbial colleagues and our interwoven fates.
High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice
Authors: Serrano Joan , Smith Kathleen R. , Crouch Audra L. , Sharma Vandana , Yi Fanchao , Vargova Veronika , LaMoia Traci E. , Dupont Lydia M. , Serna Vanida , Tang Fenfen , Gomes-Dias Laisa , Blakeslee Joshua J. , Hatzakis Emmanuel , Peterson Scott N. , Anderson Matthew , Pratley Richard E. , Kyriazis George A.
Published: January 2021

Background

Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host.

Results

We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance.

Conclusions

Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice.

Trial registration

Trial registration numberNCT03032640, registered on January 26, 2017.