bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Insulin Resistance and β-cell Function With Bone Turnover Biomarkers in Dysglycemia Patients
Authors: Guo Hui , Wang Chiyu , Jiang Boren , Ge Shaohong , Cai Jian , Zhou Ying , Ying Rong , Zha Kexi , Zhou Ji , Wang Ningjian , Zhu Chunfang , Cao Chenyu , Zhang Liqin , Gu Tao , Zhao Yan , Lu Yingli , An Zengmei
Published: March 2021

Background

The interrelation between glucose and bone metabolism is complex and has not been fully revealed. This study aimed to investigate the association between insulin resistance, β-cell function and bone turnover biomarker levels among participants with abnormal glycometabolism.

Methods

A total of 5277 subjects were involved through a cross-sectional study (METAL study, http://www.chictr.org.cn, ChiCTR1800017573) in Shanghai, China. Homeostasis model assessment of insulin resistance (HOMA-IR) and β-cell dysfunction (HOMA-%β) were applied to elucidate the nexus between β-C-terminal telopeptide (β-CTX), intact N-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC). β-CTX, OC and P1NP were detected by chemiluminescence.

Results

HOMA-IR was negatively associated with β-CTX, P1NP and OC (regression coefficient (β) -0.044 (-0.053, -0.035), Q4vsQ1; β -7.340 (-9.130, -5.550), Q4vsQ1 and β -2.885 (-3.357, -2.412), Q4vsQ1, respectively, all P for trend <0.001). HOMA-%β was positively associated with β-CTX, P1NP and OC (β 0.022 (0.014, 0.031), Q4vsQ1; β 6.951 (5.300, 8.602), Q4vsQ1 and β 1.361 (0.921, 1.800), Q4vsQ1, respectively, all P for trend <0.001).

Conclusions

Our results support that lower bone turnover biomarker (β-CTX, P1NP and OC) levels were associated with a combination of higher prevalence of insulin resistance and worse β-cell function among dysglycemia patients. It is feasible to detect bone turnover in diabetes or hyperglycemia patients to predict the risk of osteoporosis and fracture, relieve patients’ pain and reduce the expenses of long-term cure.
Endocrine Disruptor Impacts on Fish From Chile: The Influence of Wastewaters
Authors: Barra Ricardo O. , Chiang Gustavo , Saavedra Maria Fernanda , Orrego Rodrigo , Servos Mark R. , Hewitt L. Mark , McMaster Mark E. , Bahamonde Paulina , Tucca Felipe , Munkittrick Kelly R.
Published: March 2021

Industrial wastewaters and urban discharges contain complex mixtures of chemicals capable of impacting reproductive performance in freshwater fish, called endocrine-disrupting compounds (EDCs). In Chile, the issue was highlighted by our group beginning over 15 years ago, by analyzing the impacts of pulp and paper mill effluents (PPME) in the Biobio, Itata, and Cruces River basins. All of the rivers studied are important freshwater ecosystems located in the Mediterranean region of Central Chile, each with a unique fish biodiversity. Sequentially, we developed a strategy based on laboratory assays, semicontrolled-field experiments (e.g., caging) and wild fish population assessments to explore the issue of reproductive impacts on both introduced and native fish in Chile. The integration of watershed, field, and laboratory studies was effective at understanding the endocrine responses in Chilean freshwater systems. The studies demonstrated that regardless of the type of treatment, pulp mill effluents can contain compounds capable of impacting endocrine systems. Urban wastewater treatment plant effluents (WWTP) were also investigated using the same integrated strategy. Although not directly compared, PPME and WWTP effluent seem to cause similar estrogenic effects in fish after waterborne exposure, with differing intensities. This body of work underscores the urgent need for further studies on the basic biology of Chilean native fish species, and an improved understanding on reproductive development and variability across Chilean ecosystems. The lack of knowledge of the ontogeny of Chilean fish, especially maturation and sexual development, with an emphasis on associated habitats and landscapes, are impediment factors for their conservation and protection against the threat of EDCs. The assessment of effects on native species in the receiving environment is critical for supporting and designing protective regulations and remediation strategies, and for conserving the unique Chilean fish biodiversity.
Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors
Authors: Landry Laurie G. , Anderson Amanda M. , Russ Holger A. , Yu Liping , Kent Sally C. , Atkinson Mark A. , Mathews Clayton E. , Michels Aaron W. , Nakayama Maki
Published: March 2021

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.
A Giant Borderline Phyllodes Tumor of Breast With Skin Ulceration Leading to Non-Insular Tumorigenic Hypoglycemia: A Case Report and Literature Review
Authors: Zhao Jinlu , Gao Meizhuo , Ren Yi , Cao Shaodong , Wang He , Ge Ruisheng
Published: March 2021

Phyllodes tumor (PT) is a special type of breast tumors, including three types: malignant, borderline, and benign. Most of these tumors form unilateral disease and can rapidly increase in size. The occurrence of axillary lymph node metastasis is rare. Tumor-associated hypoglycemia can be divided into non-islet cell tumor and insulinoma. In non-islet cell tumor hypoglycemia (NICTH), a considerable high molecular weight form of insulin like growth factor 2 (IGF-2) is formed, which abnormally binds to insulin receptors in the tissues and causes hypoglycemia. Breast phyllodes tumors with NICTH are rare and first reported in 1983. Surgical resection is the main treatment and hypoglycemia symptoms usually resolve after surgery. Nevertheless, prior to surgery, intravenous glucose infusion is used to maintain blood glucose levels. A female patient presented with a rapidly growing breast mass and was diagnosed with a phyllodes tumor with NICTH at our hospital in August 2020; she was successfully treated through surgical resection. We reviewed the relevant literature to investigate and analyze the relationship between NICTH and phyllodes tumors, as well as optimize its diagnosis and treatment.
Poor Metabolic Health Increases COVID-19-Related Mortality in the UK Biobank Sample
Authors: Morys Filip , Dagher Alain
Published: March 2021

Previous studies link obesity and components of metabolic health, such as hypertension or inflammation, to increased hospitalizations and mortality of patients with COVID-19. Here, in two overlapping samples of over 1,000 individuals from the UK Biobank we investigate whether metabolic health as measured by waist circumference, dyslipidemia, hypertension, type 2 diabetes, and systemic inflammation is related to increased COVID-19 infection and mortality rate. Using logistic regression and controlling for confounding variables such as socioeconomic status, age, sex or ethnicity, we find that individuals with worse metabolic health (measured on average eleven years prior to 2020) have an increased risk for COVID-19-related death (adjusted odds ratio: 1.75). We also find that specific factors contributing to increased mortality are increased serum glucose levels, systolic blood pressure and waist circumference.
Hydropeaking by Small Hydropower Facilities Affects Flow Regimes on Tributaries to the Pantanal Wetland of Brazil
Authors: Figueiredo Juliane Stella M. C. de , Fantin-Cruz Ibraim , Silva Geovanna Mikaelle S. , Beregula Renato Leandro , Girard Pierre , Zeilhofer Peter , Uliana Eduardo Morgan , Morais Eduardo Beraldo de , Tritico Hans M. , Hamilton Stephen K.
Published: March 2021

Hydroelectric facilities often release water at variable rates over the day to match electricity demand, resulting in short-term variability in downstream discharge and water levels. This sub-daily variability, known as hydropeaking, has mostly been studied at large facilities. The ongoing global proliferation of small hydropower (SHP) facilities, which in Brazil are defined as having installed capacities between 5 and 30 MW, raises the question of how these facilities may alter downstream flow regimes by hydropeaking. This study examines the individual and cumulative effects of hydropower facilities on tributaries in the upland watershed of the Pantanal, a vast floodplain wetland system located on the upper Paraguay River, mostly in Brazil. Simultaneous hourly discharge measurements from publicly available reference and downstream gage stations were analyzed for 11 reaches containing 24 hydropower facilities. Most of the facilities are SHPs and half are run-of-river designs, often with diversion channels (headraces). Comparison of daily data over an annual period, summarized by indicators of hydrological alteration (HA) that describe the magnitude, frequency, rate of change, and duration of flows, revealed differences at sub-daily scales attributable to hydropeaking by the hydropower facilities. Results showed statistically significant sub-daily HA in all 11 reaches containing hydropower facilities in all months. Discharge indicators that showed the highest percentage of days with increased variability were the mean rates of rise and fall, amplitude, duration of high pulses, maximum discharge, and number of reversals. Those that showed higher percentages of decreased variability included minimum discharge, number of high pulses, duration of stability, and number of low pulses. There was no correlation between HA values and physical characteristics of rivers or hydropower facilities (including installed capacity), and reaches with multiple facilities did not differ in HA from those with single facilities. This study demonstrates that SHPs as well as larger hydropower facilities cause hydrological alterations attributable to hydropeaking. Considering the rapid expansion of SHPs in tropical river systems, there is an urgent need to understand whether the ecological impacts of hydropeaking documented in temperate biomes also apply to these systems.
Pipefish Locally Adapted to Low Salinity in the Baltic Sea Retain Phenotypic Plasticity to Cope With Ancestral Salinity Levels
Authors: Goehlich Henry , Sartoris Linda , Wagner Kim-Sara , Wendling Carolin C. , Roth Olivia
Published: March 2021

Genetic adaptation and phenotypic plasticity facilitate the migration into new habitats and enable organisms to cope with a rapidly changing environment. In contrast to genetic adaptation that spans multiple generations as an evolutionary process, phenotypic plasticity allows acclimation within the life-time of an organism. Genetic adaptation and phenotypic plasticity are usually studied in isolation, however, only by including their interactive impact, we can understand acclimation and adaptation in nature. We aimed to explore the contribution of adaptation and plasticity in coping with an abiotic (salinity) and a biotic (Vibriobacteria) stressor using six different populations of the broad-nosed pipefishSyngnathus typhlethat originated from either high [14–17 Practical Salinity Unit (PSU)] or low (7–11 PSU) saline environments along the German coastline of the Baltic Sea. We exposed wild caught animals, to either high (15 PSU) or low (7 PSU) salinity, representing native and novel salinity conditions and allowed animals to mate. After male pregnancy, offspring was split and each half was exposed to one of the two salinities and infected withVibrio alginolyticusbacteria that were evolved at either of the two salinities in a fully reciprocal design. We investigated life-history traits of fathers and expression of 47 target genes in mothers and offspring. Pregnant males originating from high salinity exposed to low salinity were highly susceptible to opportunistic fungi infections resulting in decreased offspring size and number. In contrast, no signs of fungal infection were identified in fathers originating from low saline conditions suggesting that genetic adaptation has the potential to overcome the challenges encountered at low salinity. Offspring from parents with low saline origin survived better at low salinity suggesting genetic adaptation to low salinity. In addition, gene expression analyses of juveniles indicated patterns of local adaptation,trans-generational plasticity and developmental plasticity. In conclusion, our study suggests that pipefish are locally adapted to the low salinity in their environment, however, they are retaining phenotypic plasticity, which allows them to also cope with ancestral salinity levels and prevailing pathogens.
In silico Identification of 10 Hub Genes and an miRNA–mRNA Regulatory Network in Acute Kawasaki Disease
Authors: Ma Jin , Gui Huan , Tang Yunjia , Ding Yueyue , Qian Guanghui , Yang Mengjie , Wang Mei , Song Xiudao , Lv Haitao
Published: March 2021

Kawasaki disease (KD) causes acute systemic vasculitis and has unknown etiology. Since the acute stage of KD is the most relevant, the aim of the present study was to identify hub genes in acute KD by bioinformatics analysis. We also aimed at constructing microRNA (miRNA)–messenger RNA (mRNA) regulatory networks associated with acute KD based on previously identified differentially expressed miRNAs (DE-miRNAs). DE-mRNAs in acute KD patients were screened using the mRNA expression profile data of GSE18606 from the Gene Expression Omnibus. The functional and pathway enrichment analysis of DE-mRNAs were performed with the DAVID database. Target genes of DE-miRNAs were predicted using the miRWalk database and their intersection with DE-mRNAs was obtained. From a protein–protein interaction (PPI) network established by the STRING database, Cytoscape software identified hub genes with the two topological analysis methods maximal clique centrality and Degree algorithm to construct a miRNA-hub gene network. A total of 1,063 DE-mRNAs were identified between acute KD and healthy individuals, 472 upregulated and 591 downregulated. The constructed PPI network with these DE-mRNAs identified 38 hub genes mostly enriched in pathways related to systemic lupus erythematosus, alcoholism, viral carcinogenesis, osteoclast differentiation, adipocytokine signaling pathway and tumor necrosis factor signaling pathway. Target genes were predicted for the up-regulated and down-regulated DE-miRNAs, 10,203, and 5,310, respectively. Subsequently, 355, and 130 overlapping target DE-mRNAs were obtained for upregulated and downregulated DE-miRNAs, respectively. PPI networks with these target DE-mRNAs produced 15 hub genes, six down-regulated and nine upregulated hub genes. Among these, ten genes (ATM, MDC1, CD59, CD177, TRPM2, FCAR, TSPAN14, LILRB2, SIRPA, and STAT3) were identified as hub genes in the PPI network of DE-mRNAs. Finally, we constructed the regulatory network of DE-miRNAs and hub genes, which suggested potential modulation of most hub genes by hsa-miR-4443 and hsa-miR-6510-5p. SP1 was predicted to potentially regulate most of DE-miRNAs. In conclusion, several hub genes are associated with acute KD. An miRNA–mRNA regulatory network potentially relevant for acute KD pathogenesis provides new insights into the underlying molecular mechanisms of acute KD. The latter may contribute to the diagnosis and treatment of acute KD.
Gene and Transposable Element Expression Evolution Following Recent and Past Polyploidy Events in Spartina (Poaceae)
Authors: Giraud Delphine , Lima Oscar , Rousseau-Gueutin Mathieu , Salmon Armel , Aïnouche Malika
Published: March 2021

Gene expression dynamics is a key component of polyploid evolution, varying in nature, intensity, and temporal scales, most particularly in allopolyploids, where two or more sub-genomes from differentiated parental species and different repeat contents are merged. Here, we investigated transcriptome evolution at different evolutionary time scales among tetraploid, hexaploid, and neododecaploidSpartinaspecies (Poaceae, Chloridoideae) that successively diverged in the last 6–10 my, at the origin of differential phenotypic and ecological traits. Of particular interest are the recent (19th century) hybridizations between the two hexaploidsSpartina alterniflora(2n= 6x= 62) andS. maritima(2n= 6x= 60) that resulted in two sterile F1 hybrids:Spartina×townsendii(2n= 6x= 62) in England andSpartina×neyrautii(2n= 6x= 62) in France. Whole genome duplication ofS.×townsendiigave rise to the invasive neo-allododecaploid speciesSpartina anglica(2n= 12x= 124). New transcriptome assemblies and annotations for tetraploids and the enrichment of previously published reference transcriptomes for hexaploids and the allododecaploid allowed identifying 42,423 clusters of orthologs and distinguishing 21 transcribed transposable element (TE) lineages across the seven investigatedSpartinaspecies. In 4xand 6xmesopolyploids, gene and TE expression changes were consistent with phylogenetic relationships and divergence, revealing weak expression differences in the tetraploid sister speciesSpartina bakeriandSpartina versicolor(<2 my divergence time) compared to marked transcriptome divergence between the hexaploidsS. alternifloraandS. maritimathat diverged 2–4 mya. Differentially expressed genes were involved in glycolysis, post-transcriptional protein modifications, epidermis development, biosynthesis of carotenoids. Most detected TE lineages (exceptSINEelements) were found more expressed in hexaploids than in tetraploids, in line with their abundance in the corresponding genomes. Comparatively, an astonishing (52%) expression repatterning and deviation from parental additivity were observed following recent reticulate evolution (involving the F1 hybrids and the neo-allododecaploidS. anglica), with various patterns of biased homoeologous gene expression, including genes involved in epigenetic regulation. Downregulation of TEs was observed in both hybrids and accentuated in the neo-allopolyploid. Our results reinforce the view that allopolyploidy represents springboards to new regulatory patterns, offering to worldwide invasive species, such asS. anglica, the opportunity to colonize stressful and fluctuating environments on saltmarshes.
Exploring a Region on Chromosome 8p23.1 Displaying Positive Selection Signals in Brazilian Admixed Populations: Additional Insights Into Predisposition to Obesity and Related Disorders
Authors: Secolin Rodrigo , Gonsales Marina C. , Rocha Cristiane S. , Naslavsky Michel , De Marco Luiz , Bicalho Maria A. C. , Vazquez Vinicius L. , Zatz Mayana , Silva Wilson A. , Lopes-Cendes Iscia
Published: March 2021

We recently reported a deviation of local ancestry on the chromosome (ch) 8p23.1, which led to positive selection signals in a Brazilian population sample. The deviation suggested that the genetic variability of candidate genes located on ch 8p23.1 may have been evolutionarily advantageous in the early stages of the admixture process. In the present work, we aim to extend the previous work by studying additional Brazilian admixed individuals and examining DNA sequencing data from the ch 8p23.1 candidate region. Thus, we inferred the local ancestry of 125 exomes from individuals born in five towns within the Southeast region of Brazil (São Paulo, Campinas, Barretos, and Ribeirão Preto located in the state of São Paulo and Belo Horizonte, the capital of the state of Minas Gerais), and compared to data from two public Brazilian reference genomic databases, BIPMed and ABraOM, and with information from the 1000 Genomes Project phase 3 and gnomAD databases. Our results revealed that ancestry is similar among individuals born in the five Brazilian towns assessed; however, an increased proportion of sub-Saharan African ancestry was observed in individuals from Belo Horizonte. In addition, individuals from the five towns considered, as well as those from the ABRAOM dataset, had the same overrepresentation of Native-American ancestry on the ch 8p23.1 locus that was previously reported for the BIPMed reference sample. Sequencing analysis of ch 8p23.1 revealed the presence of 442 non-synonymous variants, including frameshift, inframe deletion, start loss, stop gain, stop loss, and splicing site variants, which occurred in 24 genes. Among these genes, 13 were associated with obesity, type II diabetes, lipid levels, and waist circumference (PRAG1, MFHAS1, PPP1R3B, TNKS, MSRA, PRSS55, RP1L1, PINX1, MTMR9, FAM167A, BLK, GATA4, and CTSB). These results strengthen the hypothesis that a set of variants located on ch 8p23.1 that result from positive selection during early admixture events may influence obesity-related disease predisposition in admixed individuals of the Brazilian population. Furthermore, we present evidence that the exploration of local ancestry deviation in admixed individuals may provide information with the potential to be translated into health care improvement.
Telomeric Double Strand Breaks in G1 Human Cells Facilitate Formation of 5′ C-Rich Overhangs and Recruitment of TERRA
Authors: Nelson Christopher B. , Alturki Taghreed M. , Luxton Jared J. , Taylor Lynn E. , Maranon David G. , Muraki Keiko , Murnane John P. , Bailey Susan M.
Published: March 2021

Telomeres, repetitive nucleoprotein complexes that protect chromosomal termini and prevent them from activating inappropriate DNA damage responses (DDRs), shorten with cell division and thus with aging. Here, we characterized the human cellular response to targeted telomeric double-strand breaks (DSBs) in telomerase-positive and telomerase-independent alternative lengthening of telomere (ALT) cells, specifically in G1 phase. Telomeric DSBs in human G1 cells elicited early signatures of a DDR; however, localization of 53BP1, an important regulator of resection at broken ends, was not observed at telomeric break sites. Consistent with this finding and previously reported repression of classical non-homologous end-joining (c-NHEJ) at telomeres, evidence for c-NHEJ was also lacking. Likewise, no evidence of homologous recombination (HR)-dependent repair of telomeric DSBs in G1 was observed. Rather, and supportive of rapid truncation events, telomeric DSBs in G1 human cells facilitated formation of extensive tracks of resected 5′ C-rich telomeric single-stranded (ss)DNA, a previously proposed marker of the recombination-dependent ALT pathway. Indeed, induction of telomeric DSBs in human ALT cells resulted in significant increases in 5′ C-rich (ss)telomeric DNA in G1, which rather than RPA, was bound by the complementary telomeric RNA, TERRA, presumably to protect these exposed ends so that they persist into S/G2 for telomerase-mediated or HR-dependent elongation, while also circumventing conventional repair pathways. Results demonstrate the remarkable adaptability of telomeres, and thus they have important implications for persistent telomeric DNA damage in normal human G1/G0 cells (e.g., lymphocytes), as well as for therapeutically relevant targets to improve treatment of ALT-positive tumors.
The Maternal and Child Health Handbook for Improving the Continuum of Care and Other Maternal and Child Health Indicators in Angola: An Implementation Study Protocol
Authors: Aoki Ai , Mochida Keiji , Kuramata Michiru , Sadamori Toru , Freitas Helga Reis , da Cunha João Domingos , Sapalalo Pedro , Tchicondingosse Lino , Balogun Olukunmi Omobolanle , Hiraoka Hisakazu , Aiga Hirotsugu , Takehara Kenji
Published: March 2021

Background: Reducing maternal, neonatal, and infant mortality tops the health targets of sustainable development goals. Many lifesaving interventions are being introduced in antenatal, delivery, and postnatal care. However, many low- and middle-income countries (LMICs) have not reached maternal and child health targets. The Maternal and Child Health Handbook (MCH-HB) is recommended as a home-based record to promote a continuum of care from pregnancy to early childhood, and is gaining increasing attention among LMICs. Several countries have adopted it as national health policy. To effectively utilize the MCH-HB in LMICs, implementation needs to be considered. Angola is an LIMC in Sub-Saharan Africa, where maternal and child health indicators are among the poorest. The Angolan Ministry of Health adopted the MCH-HB program in its national health policy and is currently conducting a cluster randomized controlled trial (MCH-HB RCT) to evaluate its impact on the continuum of care. This study aimed to evaluate implementation status, and barriers and facilitators of MCH-HB program implementation in Angola.

Methods: To evaluate implementation status comprehensively, the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework will be used. Four components other than effectiveness will be investigated. A cross-sectional survey will be conducted targeting all health facilities and officers in charge of the MCH-HB at the municipality health office in the intervention group after the MCH-HB RCT. Data from the cross-sectional survey, secondary MCH-HB RCT data, and operational MCH-HB RCT records will be analyzed. Health facilities will be classified into good-implementation and poor-implementation groups using RE-AIM indicators. To identify barriers to and facilitators of MCH-HB implementation, semi-structured interviews/focus group discussions will be conducted among health workers at a sub-sample of health facilities and all municipality health officers in charge of MCH-HB in the intervention group. The Consolidated Framework for Implementation Research will be adopted to develop interview items. Thematic analysis will be performed. By comparing good-implementation and poor-implementation health facilities, factors that differ between groups that contribute to successful implementation can be identified.

Discussion: This study's findings are expected to inform MCH-HB implementation policy and guidelines in Angola and in other countries that plan to adopt the MCH-HB program.
Deposition of Immune Complexes in Gingival Tissues in the Presence of Periodontitis and Systemic Lupus Erythematosus
Authors: Pires Julien Rodrigues , Nogueira Maria Renata Sales , Nunes Adauto José Ferreira , Degand Débora Regina Fernandes , Pessoa Larissa Costa , Damante Carla Andreotti , Zangrando Mariana Schutzer Ragghianti , Greghi Sebastião Luiz Aguiar , de Rezende Maria Lúcia Rubo , Sant'Ana Adriana Campos Passanezi
Published: March 2021

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease characterized by tissue damage and widespread inflammation in response to environmental challenges. Deposition of immune complexes in kidneys glomeruli are associated with lupus nephritis, determining SLE diagnosis. Periodontitis is a chronic inflammatory disease characterized by clinical attachment and bone loss, caused by a microbial challenge – host response interaction. Deposition of immune complex at gingival tissues is a common finding in the course of the disease. Considering that, the primary aim of this study is to investigate the deposition of immune complexes at gingival tissues of SLE patients compared to systemically healthy ones, correlating it to periodontal and systemic parameters. Twenty-five women diagnosed with SLE (SLE+) and 25 age-matched systemically healthy (SLE–) women were included in the study. Detailed information on overall patient's health were obtained from file records. Participants were screened for probing depth (PD), clinical attachment loss (CAL), gingival recession (REC), full-mouth bleeding score (FMBS) and plaque scores (FMPS). Bone loss was determined at panoramic X-ray images as the distance from cementenamel junction to alveolar crest (CEJ-AC). Gingival biopsies were obtained from the first 15 patients submitted to surgical periodontal therapy of each group, and were analyzed by optical microscopy and direct immunofluorescence to investigate the deposition of antigen-antibody complexes. Eleven (44%) patients were diagnosed with active SLE (SLE-A) and 14 (56%) with inactive SLE (LES-I). Mean PD, CAL and FMBS were significantly lower in SLE+ than SLE–(p< 0.05; Mann Whitney). The chronic use of low doses of immunosuppressants was associated with lower prevalence of CAL >3 mm. Immunofluorescence staining of markers of lupus nephritis and/or proteinuria was significantly increased in SLE+ compared to SLE–, even in the presence of periodontitis. These findings suggest that immunomodulatory drugs in SLE improves periodontal parameters. The greater deposition of antigen-antibody complexes in the gingival tissues of patients diagnosed with SLE may be a marker of disease activity, possibly complementing their diagnosis.
Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study
Authors: Riancho Javier , Setien Sonia , Sánchez de la Torre Jose Ramón , Torres-Barquin Marta , Misiego Mercedes , Pérez José Luis , Castillo-Triviño Tamara , Menéndez-García Cristina , Delgado-Alvarado Manuel
Published: March 2021

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.
Glomerular Immune Deposition in MPO-ANCA Associated Glomerulonephritis Is Associated With Poor Renal Survival
Authors: Lin Wei , Shen Chanjuan , Zhong Yong , Ooi Joshua D. , Eggenhuizen Peter , Zhou Ya-Ou , Luo Hui , Huang Jing , Chen Jin-Biao , Wu Ting , Meng Ting , Xiao Zhou , Ao Xiang , Peng Weisheng , Tang Rong , Yin Hongling , Xiao Xiangcheng , Zhou Qiaoling , Xiao Ping
Published: March 2021

Background

Rapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN).

Methods

Clinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed.

Results

In our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman’s capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively).

Conclusion

In conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.
Utilization of Host Cell Chromosome Conformation by Viral Pathogens: Knowing When to Hold and When to Fold
Authors: Majumder Kinjal , Morales Abigail J.
Published: March 2021

Though viruses have their own genomes, many depend on the nuclear environment of their hosts for replication and survival. A substantial body of work has therefore been devoted to understanding how viral and eukaryotic genomes interact. Recent advances in chromosome conformation capture technologies have provided unprecedented opportunities to visualize how mammalian genomes are organized and, by extension, how packaging of nuclear DNA impacts cellular processes. Recent studies have indicated that some viruses, upon entry into host cell nuclei, produce factors that alter host chromatin topology, and thus, impact the 3D organization of the host genome. Additionally, a variety of distinct viruses utilize host genome architectural factors to advance various aspects of their life cycles. Indeed, human gammaherpesviruses, known for establishing long-term reservoirs of latent infection in B lymphocytes, utilize 3D principles of genome folding to package their DNA and establish latency in host cells. This manipulation of host epigenetic machinery by latent viral genomes is etiologically linked to the onset of B cell oncogenesis. Small DNA viruses, by contrast, are tethered to distinct cellular sites that support virus expression and replication. Here, we briefly review the recent findings on how viruses and host genomes spatially communicate, and how this impacts virus-induced pathology.
Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Interacts With Colony-Stimulating Factor 1 Receptor (CSF1R) but Is Not Necessary for CSF1/CSF1R-Mediated Microglial Survival
Authors: Cheng Baoying , Li Xin , Dai Kai , Duan Shengshun , Rong Zhouyi , Chen Yingmin , Lü Liangcheng , Liu Zhaoji , Huang Xiaohua , Xu Huaxi , Zhang Yun-Wu , Zheng Honghua
Published: March 2021

Triggering receptor expressed on myeloid cells-2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) are crucial molecules for microgliopathy, which is characterized by microglia dysfunction and has recently been proposed as the neuropathological hallmark of neurological disorders. TREM2 and CSF1R are receptors expressed primarily in microglia in the brain and modulate microglial activation and survival. They are thought to be in close physical proximity. However, whether there is a direct interaction between these receptors remains elusive. Moreover, the physiological role and mechanism of the interaction of TREM2 and CSF1R remain to be determined. Here, we found that TREM2 interacted with CSF1R based on a co-immunoprecipitation assay. Additionally, we found that CSF1R knockdown significantly reduced the survival of primary microglia and increased the Trem2 mRNA level. In contrast, CSF1R expression was increased in Trem2-deficient microglia. Interestingly, administration of CSF1, the ligand of CSF1R, partially restored the survival of Trem2-deficient microglia in vitro and in vivo. Furthermore, CSF1 ameliorated Aβ plaques deposition in Trem2-/-; 5XFAD mouse brain. These findings provide solid evidence that TREM2 and CSF1R have intrinsic abilities to form complexes and mutually modulate their expression. These findings also indicate the potential role of CSF1 in therapeutic intervention in TREM2 variant-bearing patients with a high risk of Alzheimer’s disease (AD).
Depletion of Gut Microbiota Impairs Gut Barrier Function and Antiviral Immune Defense in the Liver
Authors: Guo Weina , Zhou Xin , Li Xiaoran , Zhu Qingfeng , Peng Jing , Zhu Bin , Zheng Xin , Lu Yinping , Yang Dongliang , Wang Baoju , Wang Junzhong
Published: March 2021

Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.
Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo
Authors: Adigbli George , Hua Peng , Uchiyama Masateru , Roberts Irene , Hester Joanna , Watt Suzanne M. , Issa Fadi
Published: March 2021

Humanized immune system (HIS) mouse models are useful tools for the in vivo investigation of human hematopoiesis. However, the majority of HIS models currently in use are biased towards lymphocyte development and fail to support long-term multilineage leucocytes and erythrocytes. Those that achieve successful multilineage reconstitution often require preconditioning steps which are expensive, cause animal morbidity, are technically demanding, and poorly reproducible. In this study, we address this challenge by using HSPC-NBSGW mice, in which NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice are engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs) without the need for preconditioning by sublethal irradiation. These HSPCs are enriched in long-term hematopoietic stem cells (LT-HSCs), while NBSGW mice are permissive to human hematopoietic stem cell (HSC) engraftment, thus reducing the cell number required for successful HIS development. B cells reconstitute with the greatest efficiency, including mature B cells capable of class-switching following allogeneic stimulation and, within lymphoid organs and peripheral blood, T cells at a spectrum of stages of maturation. In the thymus, human thymocytes are identified at all major stages of development. Phenotypically distinct subsets of myeloid cells, including dendritic cells and mature monocytes, engraft to a variable degree in the bone marrow and spleen, and circulate in peripheral blood. Finally, we observe human erythrocytes which persist in the periphery at high levels following macrophage clearance. The HSPC-NBSGW model therefore provides a useful platform for the study of human hematological and immunological processes and pathologies.
Immune Monitoring for Advanced Cell Therapy Trials in Transplantation: Which Assays and When?
Authors: Stark Helen L. , Wang Hayson C. , Kuburic Jasmina , Alzhrani Alaa , Hester Joanna , Issa Fadi
Published: March 2021

A number of immune regulatory cellular therapies, including regulatory T cells and mesenchymal stromal cells, have emerged as novel alternative therapies for the control of transplant alloresponses. Clinical studies have demonstrated their feasibility and safety, however developing our understanding of the impact of cellular therapeuticsin vivorequires advanced immune monitoring strategies. To accurately monitor the immune response, a combination of complementary methods is required to measure the cellular and molecular phenotype as well as the function of cells involved. In this review we focus on the current immune monitoring strategies and discuss which methods may be utilized in the future.
Ocean Acidification State in the Highly Eutrophic Tokyo Bay, Japan: Controls on Seasonal and Interannual Variability
Authors: Yamamoto-Kawai Michiyo , Ito Soichiro , Kurihara Haruko , Kanda Jota
Published: March 2021

Seasonal and interannual variabilities in the partial pressure of CO2 (pCO2), pH, and calcium carbonate saturation state (Ω) were investigated in the highly eutrophicated Tokyo Bay, Japan, based on monthly observations that were conducted from 2011 to 2017. There were large variabilities in these parameters for surface and bottom waters due to photosynthesis and respiration, respectively. Warming/cooling and freshwater input also altered the surface Ω. During the observation period, calcium carbonate undersaturation was observed twice in the anoxic bottom waters in summer. The data indicate that anaerobic remineralization under anoxic conditions lowers the Ω, causing undersaturation. These findings suggest that de-eutrophication can decelerate ocean acidification in the bottom waters of Tokyo Bay. However, if atmospheric CO2 exceeds 650 ppm, aragonite undersaturation will be a common feature in the summer bottom water, even if hypoxia/anoxia are alleviated by de-eutrophication.
Pollutants in the South Atlantic Ocean: Sources, Knowledge Gaps and Perspectives for the Decade of Ocean Science
Authors: Hatje Vanessa , Andrade Raiza L. B. , Oliveira Carina Costa de , Polejack Andrei , Gxaba Thandiwe
Published: March 2021

The current manuscript presents the main issues related to the “Clean Ocean” outcome that arose from the Regional South Atlantic (SA) Planning Workshop for the UN Decade of Ocean Science and five Brazilian Regional Planning Workshops. An interdisciplinary andtrans-sectoral group constituted by the academia, non-governmental agencies, the private sector, decision-makers, the navy, and local communities discussed the main anthropogenic drivers compromising the current environmental status of the SA and its ecological services, and debated the main research gaps, priorities and needs for improving technical and structural capacities in order to roadmap the Brazilian actions for the Decade of Ocean Science. The aim of this review is to contribute to a social solution-driven understanding of the ocean ecosystems, to create conditions to promote sustainable development and to secure a clean, healthy ocean. We are proposing a list of actions to be implemented by the Decade of Ocean Science that will have the pivotal role to promote technical and scientific capacity development, increase research infrastructure and institutional frameworks, develop national public policies aimed at reducing the input of pollutants and management of impacts, and warranting food security and ecosystem health. The earlier the actions in controlling pollutants are implemented, along with the identification of key sources and prevention of crossing of thresholds will help to avert worst-case scenarios, reducing the socio-economic disparities of impacts across nations and social groups and supporting the sustainable development of a pollutant-free ocean.
Preparation and Properties Study of Cr on FeCrAl Cladding Materials
Authors: Wang Peng , Qiao Yingjie , Qi Wen , Du Shiyu , Liu Zhen , Meng Fanping , Zhang Xiaohong , Wang Kun , Li Qiuwu , Yao Zhaoding , Bai Chengying , Wang XiaoDong
Published: March 2021

FeCrAl alloy is a promising candidate material for the fourth-generation reactor core cladding material. Adjustment of the Cr content is one of the effective ways to obtain enhanced performance for the FeCrAl alloy. In this work, Fe–xCr–6Al alloy (11 ≤ x ≤ 15) with different Cr content were successfully prepared by hot rolling. When Cr replacement of Fe atoms in Fe–xCr–6Al alloy rises from 11 to 15wt%, the lattice distortion of Fe–xCr–6Al alloy increases, and the mechanical properties and thermal conductivity of the Fe–xCr–6Al alloy are raised. Compared with Al content, Cr content has less effect on Fe–xCr–6Al oxidation resistance.
Epidemiology, Pathogenesis, and Clinical Approach in Group 5 Pulmonary Hypertension
Authors: Al-Qadi Mazen , LeVarge Barbara , Ford H. James
Published: March 2021

Pulmonary hypertension (PH) is recognized to be associated with a number of comorbid conditions. Based on these associations, PH is classified into 5 groups, considering common pathophysiologic drivers of disease, histopathologic features, clinical manifestations and course, and response to PH therapy. However, in some of these associated conditions, these characteristics are less well-understood. These include, among others, conditions commonly encountered in clinical practice such as sarcoidosis, sickle cell disease, myeloproliferative disorders, and chronic kidney disease/end stage renal disease. PH in these contexts presents a significant challenge to clinicians with respect to disease management. The most recent updated clinical classification schemata from the 6th World Symposium on PH classifies such entities in Group 5, highlighting the often unclear and/or multifactorial nature of PH. An in-depth review of the state of the science of Group 5 PH with respect to epidemiology, pathogenesis, and management is provided. Where applicable, future directions with respect to research needed to enhance understanding of the clinical course of these entities is also discussed.