bluuebunny/crossref_metadata_2025 huggingface dataset:
A Transient Hermaphroditic Stage in Early Male Gonadal Development in Little Yellow Croaker, Larimichthys polyactis
Authors: Xie Qing-Ping , Li Bing-Bing , Zhan Wei , Liu Feng , Tan Peng , Wang Xu , Lou Bao
Published: January 2021

Animal taxa show remarkable variability in sexual reproduction, where separate sexes, or gonochorism, is thought to have evolved from hermaphroditism for most cases. Hermaphroditism accounts for 5% in animals, and sequential hermaphroditism has been found in teleost. In this study, we characterized a novel form of the transient hermaphroditic stage in little yellow croaker (Larimichthys polyactis) during early gonadal development. The ovary and testis were indistinguishable from 7 to 40 days post-hatching (dph). Morphological and histological examinations revealed an intersex stage of male gonads between 43 and 80 dph, which consist of germ cells, somatic cells, efferent duct, and early primary oocytes (EPOs). These EPOs in testis degenerate completely by 90 dph through apoptosis yet can be rescued by exogenous 17-β-estradiol. Male germ cells enter the mitotic flourishing stage before meiosis is initiated at 180 dph, and they undergo normal spermatogenesis to produce functional sperms. This transient hermaphroditic stage is male-specific, and the ovary development appears to be normal in females. This developmental pattern is not found in the sister speciesLarimichthys croceaor any other closely related species. Further examinations of serum hormone levels indicate that the absence of 11-ketotestosterone and elevated levels of 17-β-estradiol delineate the male intersex gonad stage, providing mechanistic insights on this unique phenomenon. Our research is the first report on male-specific transient hermaphroditism and will advance the current understanding of fish reproductive biology. This unique gonadal development pattern can serve as a useful model for studying the evolutionary relationship between hermaphroditism and gonochorism, as well as teleost sex determination and differentiation strategies.
Additive Effects of VDBP and 1,25(OH)2D3 on the Viability and Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts
Authors: Zhang Yeyong , Li Shufeng , Zhuo Feng , Wang Hongxing , Geng Xiubin , Xu Bing , Yin Luxu , Sun Huaqiang , Yan Xinfeng
Published: January 2021

Aim

This study is to investigate the additive effect of Vitamin D-binding protein (VDBP) and 1,25(OH)2D3 on the viability and apoptosis of synovial cells from patients with rheumatoid arthritis (RA).

Methods

Synovial tissues and synovial fluid of patients with RA and osteoarthritis (OA) were collected. The expression of VDBP was analyzed with immunohistochemistry and ELISA. CCK-8 assay was applied to detect cell viability. Flow cytometry was used to analyze cell cycle and apoptosis.

Results

Immunohistochemical results showed that the expression of VDBP in the synovium of RA patients was significantly lower than that of OA (P<0.05). Similarly, ELISA results presented a lower expression of VDBP in the synovial fluid of RA patients. The results of CCK-8 assay showed that both 1,25(OH)2D3 and VDBP significantly inhibited the viability of rheumatoid arthritis synovial fibroblasts (RASF) (P<0.05). The treatment with 1,25(OH)2D3+VDBP led to more significantly inhibited viability of RASF, compared with 1,25(OH)2D3 alone (P<0.05). The results of flow cytometry showed that 1,25(OH)2D3 and VDBP both promoted the apoptosis of RASF (P<0.05) and 1,25(OH)2D3+VDBP led to a higher proportion of RASF apoptosis, compared with 1,25(OH)2D3 alone (P<0.05). However, 1,25(OH)2D3 and VDBP had no significant effect on the cell cycle of RASF. Additionally, 1,25(OH)2D3 promoted the expression of VDBP in RASF, but not concentration-dependently.

Conclusion

VDBP is reduced in the synovial tissue and synovial fluid of RA patients and can inhibit viability of RASF and promote the apoptosis of RASF. The 1,25(OH)2D3 can upregulate the expression of VDBP in RASF. Additionally, VDBP can enhance the effects of 1,25(OH)2D3 on viability and apoptosis of RASF.
Rotten to the Cortex: Ceramide-Mediated Lipotoxicity in Diabetic Kidney Disease
Authors: Nicholson Rebekah J. , Pezzolesi Marcus G. , Summers Scott A.
Published: January 2021

Diabetic kidney disease (DKD) is a prevalent and progressive comorbidity of diabetes mellitus that increases one’s risk of developing renal failure. Progress toward development of better DKD therapeutics is limited by an incomplete understanding of forces driving and connecting the various features of DKD, which include renal steatosis, fibrosis, and microvascular dysfunction. Herein we review the literature supporting roles for bioactive ceramides as inducers of local and systemic DKD pathology. In rodent models of DKD, renal ceramides are elevated, and genetic and pharmacological ceramide-lowering interventions improve kidney function and ameliorate DKD histopathology. In humans, circulating sphingolipid profiles distinguish human DKD patients from diabetic controls. These studies highlight the potential for ceramide to serve as a central and therapeutically tractable lipid mediator of DKD.
Changes in Community Composition Induced by Experimental Warming in an Alpine Meadow: Beyond Plant Functional Type
Authors: Hu Xiaoli , Zhou Wenlong , Li Xiaonuo , Niklas Karl J. , Sun Shucun
Published: January 2021

Climate warming exerts profound effects on plant community composition. However, responses to climate warming are often reported at the community and functional type levels, but not at the species level. To test whether warming-induced changes are consistent among community, functional type, and species levels, we examined the warming-induced changes at different levels in an alpine meadow from 2015 to 2018. The warming was achieved by deploying six (open top) chambers [including three non-warmed chambers and three warmed chambers; 15 × 15 × 2.5 m (height) for each] that resulted in a small increase in mean annual temperature (0.3–0.5°C, varying with years) with a higher increase during the non-growing season (0.4–0.6°C) than in the growing season (0.03–0.47°C). The results show that warming increased plant aboveground biomass but did not change species richness, or Shannon diversity and evenness at the community level. At the functional type level, warming increased the relative abundance of grasses from 3 to 16%, but decreased the relative abundance of forbs from 89 to 79%; relative abundances of sedges and legumes were unchanged. However, for a given functional type, warming could result in contrasting effects on the relative abundance among species, e.g., the abundances of the forb species Geranium pylzowianum, Potentilla anserine, Euphrasia pectinate, and the sedge species Carex atrofusca increased in the warmed (compared to the non-warmed) chambers. More importantly, the difference in species identity between warmed and non-warmed chambers revealed warming-induced species loss. Specifically, four forb species were lost in both types of chambers, one additional forb species (Angelica apaensis) was lost in the non-warmed chambers, and two additional species (one forb species Saussurea stella and one sedge species Blysmus sinocompressus) were lost in the warmed chambers. Consequently, changes at the species level could not be deduced from the results at the community or functional type levels. These data indicate that species-level responses to climate changes must be more intensively studied. This work also highlights the importance of examining species identity (and not only species number) to study changes of community composition in response to climate warming.
Climatic Refugia and Geographical Isolation Contribute to the Speciation and Genetic Divergence in Himalayan-Hengduan Tree Peonies (Paeonia delavayi and Paeonia ludlowii)
Authors: Zhao Yu-Juan , Yin Gen-Shen , Pan Yue-Zhi , Tian Bo , Gong Xun
Published: January 2021

Himalaya and Hengduan Mountains (HHM) is a biodiversity hotspot, and very rich in endemic species. Previous phylogeographical studies proposed different hypotheses (vicariance and climate-driven speciation) in explaining diversification and the observed pattern of extant biodiversity, but it is likely that taxa are forming in this area in species-specific ways. Here, we reexplored the phylogenetic relationship and tested the corresponding hypotheses within Paeonia subsect. Delavayanae composed of one widespread species (Paeonia delavayi) and the other geographically confined species (Paeonia ludlowii). We gathered genetic variation data at three chloroplast DNA fragments and one nuclear gene from 335 individuals of 34 populations sampled from HHM. We performed a combination of population genetic summary statistics, isolation-with-migration divergence models, isolation by environment, and demographic history analyses. We found evidence for the current taxonomic treatment that P. ludlowii and P. delavayi are two different species with significant genetic differentiation. The significant isolation by environment was revealed within all sampled populations but genetic distances only explained by geographical distances within P. delavayi populations. The results of population divergence models and demographic history analyses indicated a progenitor–derivative relationship and the Late Quaternary divergence without gene flow between them. The coalescence of all sampled cpDNA haplotypes could date to the Late Miocene, and P. delavayi populations probably underwent a severe bottleneck in population size during the last glacial period. Genetic variation in Paeonia subsect. Delavayanae is associated with geographical and environmental distances. These findings point to the importance of geological and climatic changes as causes of the speciation event and lineage diversification within Paeonia subsect. Delavayanae.
A Novel Glycolysis-Related Four-mRNA Signature for Predicting the Survival of Patients With Breast Cancer
Authors: Zhang Xiaolu , Wang Jia , Zhuang Jing , Liu Cun , Gao Chundi , Li Huayao , Ma Xiaoran , Li Jie , Sun Changgang
Published: January 2021

Background: Glycolysis is critical in the occurrence and development of tumors. Owing to the biological and clinical heterogeneity of patients with BRCA, the traditional predictive classification system is far from satisfactory. Survival and prognosis biomarkers related to glycolysis have broad application prospects for assessing the risk of patients and guiding their individualized treatment.

Methods: The mRNA expression profiles and clinical information of patients with BRCA were obtained from TCGA database, and glycolysis-related genes were obtained by GSEA. Patients with BRCA were randomly divided into the training cohort and testing cohort. Univariate and multivariate Cox analyses were used to establish and validate a new mRNA signature for predicting the prognosis of patients with BRCA.

Results: We established a four-gene breast cancer prediction signature that included PGK1, SDHC, PFKL, and NUP43. The patients with BRCA in the training cohort and testing cohort were divided into high-risk and low-risk groups based on the signature. The AUC values were 0.74 (training cohort), 0.806 (testing cohort) and 0.769 (entire cohort), thereby showing that the prediction performance of the signature is acceptable. Additionally, Cox regression analysis revealed that four-gene signature could independently predict the prognosis of BRCA patients without being affected by clinical factors.

Conclusion: We constructed a four-gene signature to predict the prognosis of patients with BRCA. This signature will aid in the early diagnosis and personalized treatment of breast cancer, but the specific associated biological mechanism requires further study.
The Role of the U5 snRNP in Genetic Disorders and Cancer
Authors: Wood Katherine A. , Eadsforth Megan A. , Newman William G. , O’Keefe Raymond T.
Published: January 2021

Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes – variants inPRPF6,PRPF8, andSNRP200are associated with retinitis pigmentosa (RP), while variants inEFTUD2andTXNL4Acause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (PRPF6,PRPF8,EFTUD2,DDX23, andSNRNP40) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes – RP, craniofacial defects or cancer – is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.
Supraphysiological Levels of IL-2 in Jak3-Deficient Mice Promote Strong Proliferative Responses of Adoptively Transferred Naive CD8+ T Cells
Authors: Lee Gil-Woo , Lee Sung-Woo , Kim Juhee , Ju Young-Jun , Kim Hee-Ok , Yun Cheol-Heui , Cho Jae-Ho
Published: January 2021

The antigen-independent, strong proliferative responses of naive CD8+ T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (γc) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for γc cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8+ T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8+ T cells. Consistent with this, Jak3–/– mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4+ T cells in Jak3–/– mice along with defective CD4+ T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3–/– mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.
Treg Therapies Revisited: Tolerance Beyond Deletion
Authors: Pilat Nina , Sprent Jonathan
Published: January 2021

Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or functionin vivocould provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbersin vivoor by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansionin vivoas well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.
Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases
Authors: Okude Haruna , Ori Daisuke , Kawai Taro
Published: January 2021

Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is essential for eliciting antiviral immune responses by inducing the production of type I interferons (IFNs) and proinflammatory cytokines. Such responses are a prerequisite for mounting innate and pathogen-specific adaptive immune responses. However, host cells also use nucleic acids as carriers of genetic information, and the aberrant recognition of self-nucleic acids by PRRs is associated with the onset of autoimmune or autoinflammatory diseases. In this review, we describe the mechanisms of nucleic acid sensing by PRRs, including Toll-like receptors, RIG-I-like receptors, and DNA sensor molecules, and their signaling pathways as well as the disorders caused by uncontrolled or unnecessary activation of these PRRs.
A Win-Win for Deep-Sea Corals and Fishing: Increasing Seafloor Protections While Restoring Fishing Opportunities Off the United States West Coast
Authors: Shester Geoffrey G. , Enticknap Ben , Mecum Brianne , Blacow-Draeger Ashley , Brock Tara , Murray Susan
Published: January 2021

On January 1, 2020, the United States (U.S.) government implemented new regulations increasing total closed areas to bottom trawl fishing by 363,513 km2, including a net increase of 44,498 km2 in essential fish habitat conservation areas at fishable depths (<1,280 m) along the West Coast continental shelf and upper slope. At the same time, the government reopened certain bottom trawl fishing grounds originally established to rebuild overfished groundfish. In combination with previously existing conservation areas, the result of these regulations is that bottom trawl fishing is now prohibited in 90% (739,491 km2) of ocean waters in the United States West Coast Exclusive Economic Zone, including 32.6% of shelf (<200 m) depth zones and 56.0% of upper slope depth zones (200-1,280 m), with a disproportionate focus on priority habitat features that are proxies for fish habitat, sensitivity to bottom trawling, and biodiversity. The final spatial management measures include 53 new or modified habitat conservation areas closed to bottom trawling in fishable depths (<1,280 m) and a precautionary prohibition on all bottom contact fishing gears at depths greater than 3,500 m. Together the final set of habitat conservation area closures and openings result in an overall increase in coastwide protections for hard, mixed, and soft substrates; seamounts; submarine canyons; and known and predicted coral, sponge, and pennatulid locations. Finer scale analyses indicate net increases or no change in coral and sponge observations inside protected areas across all regions and depth zones, despite some reductions in total area and hard substrate protected in certain regions. Based on historic bottom trawl effort data, we estimate that the opening of previously closed areas restores 24.6% of fishing effort that was displaced by bottom trawl closures implemented prior to 2020. Here we describe the involvement and approach of the conservation organization, Oceana, to protect seafloor habitats off the United States West Coast, which included a coastwide proposal to modify conservation areas, geospatial analyses, grassroots organizing, media stories, and scientific expeditions using remotely operated vehicles. Our comparison of the new versus previous assemblage of habitat conservation areas demonstrates increased overall habitat protection and fishing opportunities throughout depths and bioregions off the United States West Coast.
Guiana Dolphin (Sotalia guianensis) in the Maracaibo Lake System, Venezuela: Conservation, Threats, and Population Overview
Authors: Barrios-Garrido Hector , De Turris-Morales Kareen , Espinoza-Rodriguez Ninive Edilia
Published: January 2021

The Guiana dolphin (Sotalia guianensis) home range is located across Central and South American countries, in coastal habitats in the Caribbean and Atlantic Ocean. Its distribution is scattered, with multiple population centers which are under threats that vary based on local realities. We compiled and assessed biological data from multiple sources (published and unpublished data) to improve our understanding regarding the Maracaibo Lake Management Unit, which is an isolated and unique population core of this species. We identified at least two distinguishable population centers throughout the Maracaibo Lake System, one in the northern portion—in the Gulf of Venezuela, and another in the southern portion of the Maracaibo Lake itself. Both centers have differences in some biological aspects (e.g., group size and habitat use), but similarities in the human-induced pressures (e.g., intentional take, habitat degradation, and traditional use). We detailed the uses of Guiana dolphin (consumptive and non-consumptive) by community members, including the use as talismans for indigenous fishers and consumption of its meat as a religious belief (Easter period), and dolphin watching tours carried out by local companies. In one artisanal port, at least 15 animals are intentionally taken annually to be used for local consumption, shark-bait, or trade; however, we acknowledge that this annual take is likely an underestimate. Further research is needed to clarify how and at what magnitude mentioned and other key-threats are impacting over Guiana dolphin MU in the Maracaibo Lake System.
In-situ Image Analysis of Habitat Heterogeneity and Benthic Biodiversity in the Prince Gustav Channel, Eastern Antarctic Peninsula
Authors: Almond Peter M. , Linse Katrin , Dreutter Simon , Grant Susie M. , Griffiths Huw J. , Whittle Rowan J. , Mackenzie Melanie , Reid William D. K.
Published: January 2021

Habitat heterogeneity is important for maintaining high levels of benthic biodiversity. The Prince Gustav Channel, on the Eastern Antarctic Peninsula, is characterized by an array of habitat types, ranging from flat, mud-dominated sheltered bays to steep and rocky exposed slopes. The channel has undergone dramatic environmental changes in recent decades, with the southern end of the channel permanently covered by the Prince Gustav Ice Shelf until it completely collapsed in 1995. Until now the marine benthic fauna of the Prince Gustav Channel has remained unstudied. A shallow underwater camera system and Agassiz trawl were deployed at different locations across the channel to collect information on habitat type and heterogeneity, benthic community composition and macrofaunal biomass. The texture of the seafloor was found to have a significant influence on the benthos, with hard substrates supporting higher abundances and diversity. Suspension and filter feeding organisms, including porifera, crinoids, and anthozoans, were strongly associated with hard substrates, with the same being true for deposit feeders, such as holothurians, and soft sediments. Habitat heterogeneity was high across the Prince Gustav Channel, particularly on a local scale, and this was significant in determining patterns of benthic composition and abundance. Other physical variables including depth and seafloor gradient played significant, interactive roles in determining composition potentially mediated through other processes. Sites that were once covered by the Prince Gustav Ice Shelf held distinct and unique communities, suggesting that the legacy of the ice shelf collapse may still be reflected in the benthos. Biomass estimations suggest that critical thresholds of vulnerable marine ecosystem indicator taxa, as defined by the Commission for the Conservation of Antarctic Marine Living Resources, have been met at multiple locations within the Prince Gustav Channel, which has implications for the future establishment of no take zones and marine protected areas within the region.
Mortality Benefit of Remdesivir in COVID-19: A Systematic Review and Meta-Analysis
Authors: Bansal Vikas , Mahapure Kiran S. , Bhurwal Abhishek , Gupta Ishita , Hassanain Sahar , Makadia Janaki , Madas Nimisha , Armaly Paige , Singh Romil , Mehra Ishita , O'Horo John C. , Kashyap Rahul
Published: January 2021

Importance/Background: During current public health emergency of COVID-19 pandemic, repurposing of existing antiviral drugs may be an efficient strategy since there is no proven effective treatment. Published literature shows Remdesivir has broad-spectrum antiviral activity against numerous RNA viruses and has been recently recognized as a promising therapy against SARS-CoV-2.

Methods: A systematic search was conducted for full length manuscripts published between inception and July 19th, 2020 focussing on efficacy and safety of Remdesivir in COVID-19. The primary outcomes were defined as mortality rate and median days to recovery based on the available pooled data. The secondary outcome was adverse events rate and drug discontinuation rate.

Statistical Analysis: All outcomes were performed using Comprehensive Meta-Analysis software package (Bio stat, Englewood, NJ, USA).

Results: A total of 1,895 patients from 9 studies were included in this qualitative synthesis. In patients treated with Remdesivir, the mean recovery time was 15.84 days (95% CI 11.68–20, SE 2.12; I2 = 97.24) and the pooled mortality rate was 11.3% (95% CI 7.9–16%; I2 = 74.85). However, treatment with Remdesivir was associated with adverse effects (55.3%, 95% CI 31.5–76.9%; I2 = 97.66) eventually warranting the discontinuation of the drug (17.8%, 95% CI 8.6–33.1%; I2 = 95.64). The meta-analysis of three clinical trials indicated that administration of Remdesivir significantly reduces the mortality compared to the placebo (OR 0.70, 95% CI 0.58–0.84, p ≤ 0.001; I2 = 16.6).

Conclusions and Relevance: The result of contemporary meta-analysis suggests mortality benefit with Remdesivir in COVID-19 and median recovery time was over 2 weeks. The pooled mortality with Remdesivir was found to be very low, and this analysis can shed light on this potential treatment for COVID-19 patients.
Role of the Microbiome in Interstitial Lung Diseases
Authors: Chioma Ozioma S. , Hesse Laura E. , Chapman Austin , Drake Wonder P.
Published: January 2021

There are trillions of microorganisms in the human body, consisting of bacteria, viruses, fungi, and archaea; these collectively make up the microbiome. Recent studies suggest that the microbiome may serve as a biomarker for disease, a therapeutic target, or provide an explanation for pathophysiology in lung diseases. Studies describing the impact of the microorganisms found in the respiratory tract on lung health have been published and are discussed here in the context of interstitial lung diseases. Additionally, epidemiological and experimental evidence highlights the importance of cross-talk between the gut microbiota and the lungs, called the gut–lung axis. The gut-lung axis postulates that alterations in gut microbial communities may have a profound effect on lung disease. Dysbiosis in the microbial community of the gut is linked with changes in immune responses, homeostasis in the airways, and inflammatory conditions in the gastrointestinal tract itself. In this review, we summarize studies describing the role of the microbiome in interstitial lung disease and discuss the implications of these findings on the diagnosis and treatment of these diseases. This paper describes the impact of the microbial communities on the pathogenesis of lung diseases by assessing recent original research and identifying remaining gaps in knowledge.
Low-Density Granulocytes Affect T-SPOT.TB Assay by Inhibiting the Production of Interferon-γ in T Cells via PD-L1/PD-1 Pathway
Authors: Rao Jiayue , Su Rigu , Peng Yiping , Guo Yang , Huang Zikun , Ye Yutao , Gao Yujie , Liu Jun , Zhang Lu , Luo Qing , Li Junming
Published: January 2021

Background

T-SPOT TB (T-SPOT) assay is widely used for detection of Mycobacterium tuberculosis infection that is based on the detection of M. tuberculosis-specific interferon-γ-secreting T cells (ISCs) in peripheral blood mononuclear cells (PBMCs). Recently, high frequencies of low-density granulocytes (LDGs) were found in the PBMCs of tuberculosis patients. Whether these LDGs affect the detection of T-SPOT has not been investigated. The impact of LDGs on T-SPOT assay and related mechanism were investigated in this study.

Methods

The correlations between the frequencies of LDGs and the results of T-SPOT were analyzed. T-SPOT with LDG-removed PBMCs and PBMCs with exogenous addition of LDGs were performed. The possible mechanism was explored by detecting the levels of negative immune regulatory molecules on LDGs. The impact of programmed death ligand 1 (PD-L1) on T-SPOT was evaluated and confirmed by function blocking with neutralizing antibody.

Results

The positive rates of T-SPOT and ISCs in tuberculosis patients with low LDGs frequency (n = 22) were significantly higher than those with high LDGs frequency (n = 39). Removal or exogenous addition of LDGs significantly increased or decreased the ISCs and the positive rate of T-SPOT. The frequencies of interferon-γ-producing T cells were negatively correlated with the frequencies of LDGs. The expression of PD-L1 was significantly elevated on LDGs. Pretreatment of LDGs with anti-PD-L1 antibody significantly counteracted the impact of LDGs on T-SPOT. Treatment of PBMCs with anti-PD-L1 antibody resulted in comparable ISCs with that of LDG removal.

Conclusion

LDGs can inhibit the production of interferon-γ in T cells and decrease the positive rated of T-SPOT assay via highly expressed PD-L1.
Zooming Into the Microbiota of Home-Made and Industrial Kefir Produced in Greece Using Classical Microbiological and Amplicon-Based Metagenomics Analyses
Authors: Kazou Maria , Grafakou Andriana , Tsakalidou Effie , Georgalaki Marina
Published: January 2021

Kefir is a high nutritional fermented dairy beverage associated with a wide range of health benefits. It constitutes a unique symbiotic association, comprising mainly lactic acid bacteria, yeasts, and occasionally acetic acid bacteria, which is strongly influenced by the geographical origin of the grains, the type of milk used, and the manufacture technology applied. Until recently, kefir microbiota has been almost exclusively studied by culture-dependent techniques. However, high-throughput sequencing, alongside omics approaches, has revolutionized the study of food microbial communities. In the present study, the bacterial, and yeast/fungal microbiota of four home-made samples (both grains and drinks), deriving from well spread geographical regions of Greece, and four industrial beverages, was elucidated by culture-dependent and -independent analyses. In all samples, classical microbiological analysis revealed varying populations of LAB and yeasts, ranging from 5.32 to 9.60 log CFU mL–1 or g–1, and 2.49 to 7.80 log CFU mL–1 or g–1, respectively, while in two industrial samples no yeasts were detected. Listeria monocytogenes, Salmonella spp. and Staphylococcus spp. were absent from all the samples analyzed, whereas Enterobacteriaceae were detected in one of them. From a total of 123 isolates, including 91 bacteria and 32 yeasts, Lentilactobacillus kefiri, Leuconostoc mesenteroides, and Lactococcus lactis as well as Kluvyeromyces marxianus and Saccharomyces cerevisiae were the mostly identified bacterial and yeast species, respectively, in the home-made samples. On the contrary, Streptococcus thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, and Lacticaseibacillus rhamnosus along with Debaryomyces hansenii and K. marxianus were the main bacterial and yeast species, respectively, isolated from the industrial beverages. In agreement with the identification results obtained from the culture-dependent approaches, amplicon-based metagenomics analysis revealed that the most abundant bacterial genera in almost all home-made samples (both grains and drinks) were Lactobacillus and Lactococcus, while Saccharomyces, Kazachstania, and Kluvyeromyces were the predominant yeasts/fungi. On the other hand, Streptococcus, Lactobacillus, and Lactococcus as well as Kluvyeromyces and Debaryomyces dominated the bacterial and yeast/fungal microbiota, respectively, in the industrial beverages. This is the first report on the microbiota of kefir produced in Greece by a holistic approach combining classical microbiological, molecular, and amplicon-based metagenomics analyses.
Exploring Changes in the Microbiota of Aedes albopictus: Comparison Among Breeding Site Water, Larvae, and Adults
Authors: Scolari Francesca , Sandionigi Anna , Carlassara Martina , Bruno Antonia , Casiraghi Maurizio , Bonizzoni Mariangela
Published: January 2021

The mosquito body hosts highly diverse microbes, which influence different physiological traits of both larvae and adults. The composition of adult mosquito microbiota is tightly linked to that of larvae, which are aquatic and feed on organic detritus, algae and prokaryotic microorganisms present in their breeding sites. Unraveling the ecological features of larval habitats that shape the structure of bacterial communities and their interactions with the mosquito host is still a poorly investigated topic in the Asian tiger mosquito Aedes albopictus, a highly invasive species that is vector of numerous arboviruses, including Dengue, Chikungunya, and Zika viruses. In this study, we investigated the composition of the bacterial community present in the water from a natural larval breeding site in which we separately reared wild-collected larvae and hatched eggs of the Foshan reference laboratory strain. Using sequence analysis of bacterial 16S rRNA gene amplicons, we comparatively analyzed the microbiota of the larvae and that of adult mosquitoes, deriving information about the relative impact of the breeding site water on shaping mosquito microbiota. We observed a higher bacterial diversity in breeding site water than in larvae or adults, irrespective of the origin of the sample. Moreover, larvae displayed a significantly different and most diversified microbial community than newly emerged adults, which appeared to be dominated by Proteobacteria. The microbiota of breeding site water significantly increased its diversity over time, suggesting the presence of a dynamic interaction among bacterial communities, breeding sites and mosquito hosts. The analysis of Wolbachia prevalence in adults from Foshan and five additional strains with different geographic origins confirmed the described pattern of dual wAlbA and wAlbB strain infection. However, differences in Wolbachia prevalence were detected, with one strain from La Reunion Island showing up to 18% uninfected individuals. These findings contribute in further understanding the dynamic interactions between the ecology of larval habitats and the structure of host microbiota, as well as providing additional information relative to the patterns of Wolbachia infection.
Potential of Therapeutic Bacteriophages in Nosocomial Infection Management
Authors: Wu Nannan , Zhu Tongyu
Published: January 2021

Nosocomial infections (NIs) are hospital-acquired infections which pose a high healthcare burden worldwide. The impact of NIs is further aggravated by the global spread of antimicrobial resistance (AMR). Conventional treatment and disinfection agents are often insufficient to catch up with the increasing AMR and tolerance of the pathogenic bacteria. This has resulted in a need for alternative approaches and raised new interest in therapeutic bacteriophages (phages). In contrast to the limited clinical options available against AMR bacteria, the extreme abundance and biodiversity of phages in nature provides an opportunity to establish an ever-expanding phage library that collectively provides sustained broad-spectrum and poly microbial coverage. Given the specificity of phage-host interactions, phage susceptibility testing can serve as a rapid and cost-effective method for bacterial subtyping. The library can also provide a database for routine monitoring of nosocomial infections as a prelude to preparing ready-to-use phages for patient treatment and environmental sterilization. Despite the remaining obstacles for clinical application of phages, the establishment of phage libraries, pre-stocked phage vials prepared to good manufacturing practice (GMP) standards, and pre-optimized phage screening technology will facilitate efforts to make phages available as modern medicine. This may provide the breakthrough needed to demonstrate the great potential in nosocomial infection management.
A Signature of Five Long Non-Coding RNAs for Predicting the Prognosis of Alzheimer's Disease Based on Competing Endogenous RNA Networks
Authors: Huaying Cai , Xing Jin , Luya Jin , Linhui Ni , Di Sun , Xianjun Ding
Published: January 2021

Long non-coding RNAs (lncRNAs) play important roles in the pathogenesis of Alzheimer's disease (AD). However, the functions and regulatory mechanisms of lncRNA are largely unclear. Herein, we obtained 3,158 lncRNAs by microarray re-annotation. A global network of competing endogenous RNAs (ceRNAs) was developed for AD and normal samples were based on the gene expressions profiles. A total of 255 AD-deficient messenger RNA (mRNA)-lncRNAs were identified by the expression correlation analysis. Genes in the dysregulated ceRNAs were found to be mainly enriched in transcription factors and micro RNAs (miRNAs). Analysis of the disordered miRNA in the lncRNA-mRNA network revealed that 40 pairs of lncRNA shared more than one disordered miRNA. Among them, nine lncRNAs were closely associated with AD, Parkinson's disease, and other neurodegenerative diseases. Of note, five lncRNAs were found to be potential biomarkers for AD. Real-time quantitative reverse transcription PCR (qRT-PCR) assay revealed that PART1 was downregulated, while SNHG14 was upregulated in AD serum samples when compared to normal samples. This study elucidates the role of lncRNAs in the pathogenesis of AD and presents new lncRNAs that can be exploited to design diagnostic and therapeutic agents for AD.
Improvement of Multiparametric MR Image Segmentation by Augmenting the Data With Generative Adversarial Networks for Glioma Patients
Authors: Carver Eric Nathan , Dai Zhenzhen , Liang Evan , Snyder James , Wen Ning
Published: January 2021

Every year thousands of patients are diagnosed with a glioma, a type of malignant brain tumor. MRI plays an essential role in the diagnosis and treatment assessment of these patients. Neural networks show great potential to aid physicians in the medical image analysis. This study investigated the creation of synthetic brain T1-weighted (T1), post-contrast T1-weighted (T1CE), T2-weighted (T2), and T2 Fluid Attenuated Inversion Recovery (Flair) MR images. These synthetic MR (synMR) images were assessed quantitatively with four metrics. The synMR images were also assessed qualitatively by an authoring physician with notions that synMR possessed realism in its portrayal of structural boundaries but struggled to accurately depict tumor heterogeneity. Additionally, this study investigated the synMR images created by generative adversarial network (GAN) to overcome the lack of annotated medical image data in training U-Nets to segment enhancing tumor, whole tumor, and tumor core regions on gliomas. Multiple two-dimensional (2D) U-Nets were trained with original BraTS data and differing subsets of the synMR images. Dice similarity coefficient (DSC) was used as the loss function during training as well a quantitative metric. Additionally, Hausdorff Distance 95% CI (HD) was used to judge the quality of the contours created by these U-Nets. The model performance was improved in both DSC and HD when incorporating synMR in the training set. In summary, this study showed the ability to generate high quality Flair, T2, T1, and T1CE synMR images using GAN. Using synMR images showed encouraging results to improve the U-Net segmentation performance and shows potential to address the scarcity of annotated medical images.
Exploring Bottom-Up Visual Processing and Visual Hallucinations in Parkinson's Disease With Dementia
Authors: Murphy Nicholas , Killen Alison , Gupta Rajnish Kumar , Graziadio Sara , Rochester Lynn , Firbank Michael , Baker Mark R. , Allan Charlotte , Collerton Daniel , Taylor John-Paul , Urwyler Prabitha
Published: January 2021

Visual hallucinations (VH) are a common symptom of Parkinson's disease with dementia (PDD), affecting up to 65% of cases. Integrative models of their etiology posit that a decline in executive control of the visuo-perceptual system is a primary mechanism of VH generation. The role of bottom-up processing in the manifestation of VH in this condition is still not clear although visual evoked potential (VEP) differences have been associated with VH at an earlier stage of PD. Here we compared the amplitude and latency pattern reversal VEPs in healthy controls (n = 21) and PDD patients (n = 34) with a range of VH severities. PDD patients showed increased N2 latency relative to controls, but no significant differences in VEP measures were found for patients reporting complex VH (CVH) (n = 17) compared to those without VH. Our VEP findings support previous reports of declining visual system physiology in PDD and some evidence of visual system differences between patients with and without VH. However, we did not replicate previous findings of a major relationships between the integrity of the visual pathway and VH.
Resting-State Cerebello-Cortical Dysfunction in Parkinson's Disease
Authors: Palmer William C. , Cholerton Brenna A. , Zabetian Cyrus P. , Montine Thomas J. , Grabowski Thomas J. , Rane Swati
Published: January 2021

Purpose: Recently, the cerebellum's role in Parkinson's disease (PD) has been highlighted. Therefore, this study sought to test the hypothesis that functional connectivity (FC) between cerebellar and cortical nodes of the resting-state networks differentiates PD patients from controls by scanning participants at rest using functional magnetic resonance imaging (fMRI) and investigating connectivity of the cerebellar nodes of the resting-state networks.

Materials and Methods: Sixty-two PD participants off medication for at least 12 h and 33 normal controls (NCs) were scanned at rest using blood oxygenation level-dependent fMRI scans. Motor and cognitive functions were assessed with the Movement Disorder Society's Revision of the Unified Parkinson's Disease Rating Scale III and Montreal Cognitive Assessment, respectively. Connectivity was investigated with cerebellar seeds defined by Buckner's 7-network atlas.

Results: PD participants had significant differences in FC when compared to NC participants. Most notably, PD patients had higher FC between cerebellar nodes of the somatomotor network (SMN) and the corresponding cortical nodes. Cognitive functioning was differentially associated with connectivity of the cerebellar SMN and dorsal attention network. Further, cerebellar connectivity of frontoparietal and default mode networks correlated with the severity of motor function.

Conclusion: Our study demonstrates altered cerebello-cortical FC in PD, as well as an association of this FC with PD-related motor and cognitive disruptions, thus providing additional evidence for the cerebellum's role in PD.
Muscle Synergies in Patients With Multiple Sclerosis Reveal Demand-Specific Alterations in the Modular Organization of Locomotion
Authors: Janshen Lars , Santuz Alessandro , Arampatzis Adamantios
Published: January 2021

For patients with multiple sclerosis (MS), deficits in gait significantly reduce the quality of life. Using the concept of muscle synergies, this study investigated the modular organization of motor control during level and inclined walking in MS patients (MSP) compared with healthy participants (HP) to identify the potential demand-specific adjustments in motor control in MSP. We hypothesized a widening of the time-dependent activation patterns (motor primitives) in MSP to increase the overlap of temporally-adjacent muscle synergies, especially during inclined walking, as a strategy to increase the robustness of motor control, thus compensating pathology-related deficits. We analyzed temporal gait parameters and muscle synergies from myoelectric signals of 13 ipsilateral leg muscles using non-negative matrix factorization. Compared with HP, MSP demonstrated a widening in the time-dependent coefficients (motor primitives), as well as altered relative muscle contribution (motor modules), in certain synergies during level and inclined walking. Moreover, inclined walking revealed a demand-specific adjustment in the modular organization in MSP, resulting in an extra synergy compared with HP. This further increased the overlap of temporally-adjacent muscle synergies to provide sufficient robustness in motor control to accomplish the more demanding motor task while coping with pathology-related motor deficits during walking.
Brain Network Analysis of EEG Recordings Can Be Used to Assess Cognitive Function in Teenagers With 15q13.3 Microdeletion Syndrome
Authors: Stern Tehila , Crutcher Emeline H. , McCarthy John M. , Ali May A. , Issachar Gil , Geva Amir B. , Peremen Ziv , Schaaf Christian P.
Published: January 2021

15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual disability and autism. We assessed the ability of the EEG analysis algorithm Brain Network Analysis (BNA) to measure cognitive function in 15q13.3 deletion patients, and to differentiate between patient and control groups. EEG data was collected from 10 individuals with 15q13.3 microdeletion syndrome (14–18 years of age), as well as 30 age-matched healthy controls, as the subjects responded to Auditory Oddball (AOB) and Go/NoGo cognitive tasks. It was determined that BNA can be used to evaluate cognitive function in 15q13.3 microdeletion patients. This analysis also significantly differentiates between patient and control groups using 5 scores, all of which are produced from ERP peaks related to late cortical components that represent higher cognitive functions of attention allocation and response inhibition (P < 0.05).
Inflammatory Diseases Among Norwegian LRRK2 Mutation Carriers. A 15-Years Follow-Up of a Cohort
Authors: Aasly Jan O.
Published: January 2021

The first families with LRRK2 related Parkinson’s disease (PD) were presented around 15 years ago and numerous papers have described the characteristics of theLRRK2phenotype. The prevalence of autosomal dominant PD varies around the world mainly depending on local founder effects. The highest prevalence ofLRRK2G2019S PD in Norway is located to the central part of the country and most families could be traced back to common ancestors. The typical Norwegian LRRK2 phenotype is not different from classical PD and similar to that seen in most other LRRK2 families. The discovery of LRRK2 PD has allowed us to follow-up multi-incident families and to study their phenotype longitudinally. In the Norwegian LRRK2 families there has been a significantly higher incidence of inflammatory diseases like multiple sclerosis and rheumatoid arthritis that seen in other PD populations. Recent studies in LRRK2 mechanisms have indicated that this protein may be crucial in initiating disease processes. In this short survey of 100 Norwegian mutation carriers followed through more than 15 years are presented. The prevalence of inflammatory diseases among these cases is highlighted. The role of LRRK2 in the conversion process from carrier status to PD phenotype is still unknown and disease generating mechanisms important for initiating LRRK2 PD are still to be identified.