bluuebunny/crossref_metadata_2025 huggingface dataset:
Curcumin β-D-Glucuronide Modulates an Autoimmune Model of Multiple Sclerosis with Altered Gut Microbiota in the Ileum and Feces
Authors: Khadka Sundar , Omura Seiichi , Sato Fumitaka , Nishio Kazuto , Kakeya Hideaki , Tsunoda Ikuo
Published: December 2021

We developed a prodrug type of curcumin, curcumin monoglucuronide (CMG), whose intravenous/intraperitoneal injection achieves a high serum concentration of free-form curcumin. Although curcumin has been reported to alter the gut microbiota and immune responses, it is unclear whether the altered microbiota could be associated with inflammation in immune-mediated diseases, such as multiple sclerosis (MS). We aimed to determine whether CMG administration could affect the gut microbiota at three anatomical sites (feces, ileal contents, and the ileal mucosa), leading to suppression of inflammation in the central nervous system (CNS) in an autoimmune model for MS, experimental autoimmune encephalomyelitis (EAE). We injected EAE mice with CMG, harvested the brains and spinal cords for histological analyses, and conducted microbiome analyses using 16S rRNA sequencing. CMG administration modulated EAE clinically and histologically, and altered overall microbiota compositions in feces and ileal contents, but not the ileal mucosa. Principal component analysis (PCA) of the microbiome showed that principal component (PC) 1 values in ileal contents, but not in feces, correlated with the clinical and histological EAE scores. On the other hand, when we analyzed the individual bacteria of the microbiota, the EAE scores correlated with significant increases in the relative abundance of two bacterial species at each anatomical site:Ruminococcus bromiiandBlautia (Ruminococcus) gnavusin feces,Turicibactersp. andAlistipes finegoldiiin ileal contents, andBurkholderiaspp. andAzoarcusspp. in the ileal mucosa. Therefore, CMG administration could alter the gut microbiota at the three different sites differentially in not only the overall gut microbiome compositions but also the abundance of individual bacteria, each of which was associated with modulation of neuroinflammation.
Association Between Heart Rate and Major Adverse Cardiovascular Events Among 9,991 Hypertentive Patients: A Multicenter Retrospective Follow-Up Study
Authors: Sun Ningling , Chen Yuanyuan , Xi Yang , Wang Hongyi , Wang Luyan
Published: December 2021

Objective: To assess the effect of heart rate at baseline on major adverse cardiovascular events (MACEs) among hypertensive patients in China.

Methods: A multicenter retrospective study was conducted with a 24 month follow-up period. A total of 10,031 hypertensive patients treated with standard antihypertensive drugs were grouped according to their heart rate before treatment: <65 beats per min (bpm), 65–69 bpm, 70–74 bpm, 75–79 bpm, and ≥80 bpm. The occurrence of any of MACEs was as the endpoint event during the 24 month follow-up period. The effect of heart rate at baseline on MACEs was analyzed using univate and multivariable Cox proportional regression analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs). The restricted cubic spline (RCS) model was used to fit the Cox proportional harzard model with 5 knots at the 5th, 25th, 50th, 75th, and 95th percentiles of heart rate.

Results: Totally 9,991 patients were finally enrolled with the mean systolic pressure (SBP)/diastolic pressure (DBP) of 130.59 ± 7.13/77.66 ± 5.99 mmHg at 24 month follow-up. The incidence of MACEs was 4.80% (n = 480). After adjustment for age, gender, baseline blood pressure, alcohol drinking, smoking, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease and antihypertensive drug use, patients with heart rate <65 bpm (HR = 1.450, 95% CI: 1.098–1.915) and ≥80 bpm (HR = 1.391, 95% CI: 1.056–11.832) showed 0.45 fold and 0.391 fold increases of MACE risks, compared with patients with heart rate of 70–74 bpm. Furthermore, MACE risks were increased by 86.0% and 65.4% in men, and 59.3% and 69.0% in elderly patients aged ≥65 years at heart rate <65 bpm or ≥80 bpm, respectively. We also found a non-liner U-shaped correlation between heart rate and the occurrence of MACEs.

Conclusions: Heart rate might be an independent risk factor for MACEs in hypertensive patients. An appropriate range of heart rate control may offer guidance to hypertension treatment.
Fulminant Giant Cell Myocarditis vs. Lymphocytic Myocarditis: A Comparison of Their Clinical Characteristics, Treatments, and Outcomes
Authors: Hu Yuxiao , Ren Jie , Dong Xueqi , Zhang Di , Qu Yi , Yang Chunxue , Sun Yang , Li Jinghui , Luo Fang , Wang Wei , Wang Huanhuan , Qing Ping , Zhao Shihua , Huang Jie , Yu Litian , Liu Yaxin , Tan Huiqiong
Published: December 2021

Objectives: Fulminant myocarditis (FM) is a rapidly progressive and frequently fatal form of myocarditis that has been difficult to classify. This study aims to compare the clinical characteristics, treatments and outcomes in patients with fulminant giant cell myocarditis (FGCM) and fulminant lymphocytic myocarditis (FLM).

Methods and Results: In our retrospective study, nine patients with FGCM (mean age 47.9 ± 7.5 years, six female) and 7 FLM (mean age 42.1 ± 12.3 years, four female) patients confirmed by histology in the last 11 years were included. Most patients with FGCM and FLM were NYHA functional class IV (56 vs. 100%, p = 0.132). Patients with FGCM had significantly lower levels of high-sensitivity C-reactive protein [hs-CRP, 4.4 (2.0–10.2) mg/L vs. 13.6 (12.6–14.6) mg/L, P = 0.004, data shown as the median with IQR], creatine kinase-myoglobin [CK-MB, 1.4 (1.0–3.2) ng/ml vs. 14.6 (3.0–64.9) ng/ml, P = 0.025, median with IQR], and alanine aminotransferase [ALT, 38.0 (25.0–61.5) IU/L vs. 997.0 (50.0–3,080.0) IU/L, P = 0.030, median with IQR] and greater right ventricular end-diastolic diameter (RVEDD) [2.9 ± 0.3 cm vs. 2.4 ± 0.6 cm, P = 0.034, mean ± SD] than those with FLM. No differences were observed in the use of intra-aortic balloon pump (44 vs. 43%, p = 1.000) and extracorporeal membrane oxygenation (11 vs. 43%, p = 0.262) between the two groups. The long-term survival rate was significantly lower in FGCM group compared with FLM group (0 vs. 71.4%, p = 0.022). A multivariate cox regression analysis showed the level of hs-CRP (hazard ratio = 0.871, 95% confidence interval: 0.761–0.996, P = 0.043) was an independent prognostic factor for FM patients. Furthermore, the level of hs-CRP had a good ability to discriminate between patients with FGCM and FLM (AUC = 0.94, 95% confidence interval: 0.4213–0.9964).

Conclusions: The inflammatory response and myocardial damage in the patients with FGCM were milder than those with FLM. Patients with FGCM had distinctly poorer prognoses compared with those with FLM. Our results suggest that hs-CRP could be a promising prognostic biomarker and a hs-CRP level of 11.71 mg/L is an appropriate cutoff point for the differentiating diagnosis between patients with FGCM and FLM.
A Population-Based Systematic Clinical Analysis With a Single-Center Case Series of Patients With Pulmonary Large Cell Neuroendocrine Carcinoma
Authors: Sun Xu , Wu Yijun , Shen Jing , Han Chang , Kang Kai , Liu Zhikai , Zhang Fuquan
Published: December 2021

Background and Objectives

This study aims to conduct an updated systematic analysis of patients with pulmonary large cell neuroendocrine carcinoma (PLCNC) in recent decades, concerning incidence and mortality trends, demographics, treatments, survival and death causes.

Methods

Patients who were diagnosed with PLCNC at the Peking Union Medical College Hospital (PUMCH) between 2000 to 2020 were retrospectively analyzed. The population-based Surveillance, Epidemiology, and End Results (SEER) database were also retrieved. Frequencies and average annual age-adjusted rates (AAR) of PLCNC patients were calculated and analyzed by Joint-point regression. Univariate and multivariate Cox regression were used for identifying prognostic factors. Predictive nomograms for overall survival (OS) and cancer-specific survival (CSS) were developed and then validated by calculating C-index values and drawing calibration curves. Survival curves were plotted using the Kaplan-Meier method and compared by log-rank test. Causes of death were also analyzed by time latency.

Results

A total of 56 PLCNC patients of the PUMCH cohort were included. Additionally, the PLCNC patients in the SEER database were also identified from different subsets. The AAR from 2001 to 2017 were 3.21 (95%CI: 3.12-3.30) per million. Its incidence and mortality rates in PLCNC patients increased at first but seemed to decline in recent years. Besides TNM stage and treatments, older age and male gender were independently associated with poorer survival, while marital status only affected CSS other than OS. The nomograms for OS and CSS presented great predictive ability and calibration performance. Surgery gave significantly more survival benefits to PLCNC patients, and chemotherapy might add survival benefits to stage II-IV. However, radiation therapy seemed to only improve stage III patients’ survival.

Conclusions

This study supported some previous studies in terms of incidence, survival, and treatment options. The mortality rates seemed to decline recently, after an earlier increase. Among PLCNC patients, most of the deaths occurred within the first five years, while other non-PLCNC diseases increased after that. Thus, careful management and follow-up of other comorbidities are of equal importance. Our study may partly solve the dilemma caused by PLCNC’s rarity and inspire more insights in future researches.
Alcohol Consumption Moderated the Association Between Levels of High Blood Lead or Total Urinary Arsenic and Bone Loss
Authors: Hsueh Yu-Mei , Huang Ya-Li , Chen Hsi-Hsien , Shiue Horng-Sheng , Lin Ying-Chin , Hsieh Ru-Lan
Published: December 2021

Metal exposure and lifestyle are important risk factors for osteoporosis. Our study aimed to investigate the association between red blood cell lead and cadmium, total urinary arsenic, and plasma selenium levels and bone mineral density (BMD). In addition, we explored whether alcohol and coffee consumption modified the association between BMD and metals and metalloids. In total, 437 participants who underwent adult or senile physical examinations were recruited. Bone loss was defined as a calcaneus BMD T-score of <-1. Blood cadmium and lead and plasma selenium levels were measured using inductively coupled plasma mass spectrometry. Levels of urinary arsenic species were determined using high-performance liquid chromatography–hydride generator–atomic absorption spectrometry. The total urinary arsenic level was defined as the sum of the levels of urinary arsenic species. The BMD T-scores decreased significantly with increasing blood lead levels. The BMD T-scores also showed a downward trend with increasing total urinary arsenic levels. The odds ratio (OR) and 95% confidence interval (CI) for bone loss in patients with blood lead levels >57.58 versus 35.74 μg/dL were 1.98 and 1.17–3.34. In addition, the greater the lead or arsenic exposure and alcohol intake was the higher the OR for bone loss with multivariate ORs of 2.57 (95% CI 1.45–4.56) and 2.96 (95% CI 1.67–5.22), respectively. To the best of our knowledge, this study is the first to demonstrate that high total urinary arsenic or blood lead levels and frequent or occasional alcohol consumption had a significant multiplicative interaction for increasing the OR for bone loss.
The Impact of Variable Retention Harvesting on Growth and Carbon Sequestration of a Red Pine (Pinus resinosa Ait.) Plantation Forest in Southern Ontario, Canada
Authors: Zugic Jessica I. , Pisaric Michael F. J. , McKenzie Shawn M. , Parker William C. , Elliott Ken A. , Arain M. Altaf
Published: December 2021

As atmospheric carbon dioxide concentrations continue to rise and global temperatures increase, there is growing concern about the sustainability, health, and carbon sequestration potential of forest ecosystems. Variable retention harvesting (VRH) has been suggested to be a potential method to increase forest biodiversity, growth, and carbon (C) sequestration. A field trial was established in an 88-year-old red pine (Pinus resinosa Ait.) plantation in southern Ontario, Canada, using a completely randomized design to examine the response of tree productivity and other forest values to five harvesting treatments: 33% aggregate retention (33A), 55% aggregate retention (55A), 33% dispersed retention (33D), and 55% dispersed retention (55D) in comparison to an unharvested control (CN). In this study, we explored the impacts of VRH on aboveground stem radial growth and annual C increment. Standard dendrochronological methods and allometric equations were used to quantify tree- and stand-level treatment effects during a five-year pre-harvest (2009–2013) and post-harvest (2014–2018) period. Tree-level growth and C increment were increased by the dispersed retention pattern regardless of retention level. At the stand level, the total C increment was highest at greater retention levels and did not vary with retention pattern. These results suggest that the choice of retention level and pattern can have a large influence on management objectives as they relate to timber production, climate change adaptation, and/or climate change mitigation.
Composition of Organic Carbon-Based Compounds in the Stem Wood of Quercus mongolica Seedlings Grown Under Elevated CO2 and/or O3 Concentrations
Authors: Ugawa Shin , Hashimoto Shoji , Hashida Koh , Tobita Hiroyuki , Kitao Mitsutoshi
Published: December 2021

In this study, we examined the composition of organic constituents of stem woody tissue together with tree growth in Quercus mongolica var. grosseserrata Blume seedlings raised under controlled CO2 and/or O3 concentrations in a Free-Air Concentration Enrichment system. After exposure to ambient air (control), elevated CO2 concentration (550 μmol mol–1 CO2), elevated O3 concentration (double that of the control), and a combination of elevated CO2 and O3 concentrations during a growing season, we measured the diameter and length of stem, and biomass of sampled seedlings and quantified the lignin, extractive, and holocellulose contents of the woody tissue of current-year stems. We confirmed that the growth of seedlings was enhanced under an elevated CO2 concentration condition. In line with this, the extractive content was lower in woody tissue formed under an elevated CO2 concentration than that formed under ambient air, whereas holocellulose content showed an inverse pattern. Elevated O3 concentration itself did not change the organic constituents of the woody tissue, but it reduced the influence of an elevated CO2 concentration. We thus assume that Q. mongolica formed woody tissue with a low extractive content under the high CO2 concentration condition, although this response was possibly mitigated by an elevated O3 concentration. Extractives contains antimicrobial components such as tannins, flavonoids, quinones, and terpenoids. The decrease in extractives within the widely distributed Q. mongolica in East Asia may have a non-negligible impact on C cycling in the future earth with high atmospheric CO2 concentration.
Integrated Transcriptome and Multiple Activated Pathways in Endometrial Cancer
Authors: Jin Qi , Jiang Xiaohua , Du Xin , Hu Weiping , Bai Shun , Wang Xian , Xu Bo , Zhao Weidong
Published: December 2021

Because the incidence of endometrial cancer is notably increasing worldwide, it has become the leading gynecologic cancer in the United States. Standard treatment results in the loss of reproductive function in women of childbearing age. Furthermore, advanced cancer stages are associated with poor overall survival. The aim of this study was to explore the abnormal expression profile of genes during the development of endometrial cancer, which is essential to provide a better understanding of the mechanisms involved. Five pairs of endometrial cancer tissues and normal endometrial tissues were subjected to next-generation transcriptome sequencing technology. Quantitative real-time PCR (RT-qPCR) was performed to validate the expression profile of key differentially expressed genes (2.0-fold change, adj. p < 0.05) (DEGs) identified in the RNA-seq result. GO and KEGG pathways were used for bioinformatic analyses. The transcriptomic sequencing results showed 1153 DEGs, including 673 upregulated and 480 downregulated genes, in the EC specimens. Decreased expression of ID1, IGF1, GDF7, SMAD9, TGF-beta and WNT4, as well as GDF5, INHBA and ERBB4 overexpression, were confirmed in EC using RT-qPCR. Additionally, EC tissue exhibited marked enrichment in genes promoting cellular adhesion, proliferation, migration and plasma membrane. KEGG analysis revealed changes in various pathways, such as the TGF-beta, PI3K-Akt, Wnt, and estrogen pathways. Our data describe the molecular events involved in the pathogenesis of EC, which may be potential diagnostic markers and targets of therapeutic interventions.
Prognostic Implications and Immune Infiltration Analysis of ALDOA in Lung Adenocarcinoma
Authors: Lu Guojun , Shi Wen , Zhang Yu
Published: December 2021

Background: aldolase A (ALDOA) has been reported to be involved in kinds of cancers. However, the role of ALDOA in lung adenocarcinoma has not been fully elucidated. In this study, we explored the prognostic value and correlation with immune infiltration of ALDOA in lung adenocarcinoma.

Methods: The expression of ALDOA was analyzed with the Oncomine database, the Cancer Genome Atlas (TCGA), and the Human Protein Atlas (HPA). Mann-Whitney U test was performed to examine the relationship between clinicopathological characteristics and ALDOA expression. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were conducted to describe the diagnostic and prognostic importance of ALDOA. The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct PPI networks and identify hub genes. Functional annotations and immune infiltration were conducted.

Results: The mRNA and protein expression of ALDOA were higher in lung adenocarcinoma than those in normal tissues. The overexpression of ALDOA was significantly correlated with the high T stage, N stage, M stage, and TNM stage. Kaplan-Meier showed that high expression of ALDOA was correlated with short overall survival (38.9 vs 72.5 months, p < 0.001). Multivariate analysis revealed that ALDOA (HR 1.435, 95%CI, 1.013–2.032, p = 0.042) was an independent poor prognostic factor for overall survival. Functional enrichment analysis showed that positively co-expressed genes of ALDOA were involved in the biological progress of mitochondrial translation, mitochondrial translational elongation, and negative regulation of cell cycle progression. KEGG pathway analysis showed enrichment function in carbon metabolism, the HIF-1 signaling pathway, and glycolysis/gluconeogenesis. The “SCNA” module analysis indicated that the copy number alterations of ALDOA were correlated with three immune cell infiltration levels, including B cells, CD8+ T cells, and CD4+ T cells. The “Gene” module analysis indicated that ALDOA gene expression was negatively correlated with infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, and macrophages.

Conclusion: Our study suggested that upregulated ALDOA was significantly correlated with tumor progression, poor survival, and immune infiltrations in lung adenocarcinoma. These results suggest that ALDOA is a potential prognostic biomarker and therapeutic target in lung adenocarcinoma.
Review: Balancing Selection for Deleterious Alleles in Livestock
Authors: Derks Martijn F. L. , Steensma Marije
Published: December 2021

Harmful alleles can be under balancing selection due to an interplay of artificial selection for the variant in heterozygotes and purifying selection against the variant in homozygotes. These pleiotropic variants can remain at moderate to high frequency expressing an advantage for favorable traits in heterozygotes, while harmful in homozygotes. The impact on the population and selection strength depends on the consequence of the variant both in heterozygotes and homozygotes. The deleterious phenotype expressed in homozygotes can range from early lethality to a slightly lower fitness in the population. In this review, we explore a range of causative variants under balancing selection including loss-of-function variation (i.e., frameshift, stop-gained variants) and regulatory variation (affecting gene expression). We report that harmful alleles often affect orthologous genes in different species, often influencing analogous traits. The recent discoveries are mainly driven by the increasing genomic and phenotypic resources in livestock populations. However, the low frequency and sometimes subtle effects in homozygotes prevent accurate mapping of such pleiotropic variants, which requires novel strategies to discover. After discovery, the selection strategy for deleterious variants under balancing selection is under debate, as variants can contribute to the heterosis effect in crossbred animals in various livestock species, compensating for the loss in purebred animals. Nevertheless, gene-assisted selection is a useful tool to decrease the frequency of the harmful allele in the population, if desired. Together, this review marks various deleterious variants under balancing selection and describing the functional consequences at the molecular, phenotypic, and population level, providing a resource for further study.
Transcriptome-Wide Analyses Identify Dominant as the Predominantly Non-Conservative Alternative Splicing Inheritance Patterns in F1 Chickens
Authors: Qi Xin , Gu Hongchang , Qu Lujiang
Published: December 2021

Transcriptome analysis has been used to investigate many economically traits in chickens; however, alternative splicing still lacks a systematic method of study that is able to promote proteome diversity, and fine-tune expression dynamics. Hybridization has been widely utilized in chicken breeding due to the resulting heterosis, but the dynamic changes in alternative splicing during this process are significant yet unclear. In this study, we performed a reciprocal crossing experiment involving the White Leghorn and Cornish Game chicken breeds which exhibit major differences in body size and reproductive traits, and conducted RNA sequencing of the brain, muscle, and liver tissues to identify the inheritance patterns. A total of 40 515 and 42 612 events were respectively detected in the brain and muscle tissues, with 39 843 observed in the liver; 2807, 4242, and 4538 events significantly different between two breeds were identified in the brain, muscle, and liver tissues, respectively. The hierarchical cluster of tissues from different tissues from all crosses, based on the alternative splicing profiles, suggests high tissue and strain specificity. Furthermore, a comparison between parental strains and hybrid crosses indicated that over one third of alternative splicing genes showed conserved patterns in all three tissues, while the second prevalent pattern was non-additive, which included both dominant and transgressive patterns; this meant that the dominant pattern plays a more important role than suppression. Our study provides an overview of the inheritance patterns of alternative splicing in layer and broiler chickens, to better understand post-transcriptional regulation during hybridization.
Transcriptomic Response to Perkinsus marinus in Two Crassostrea Oysters Reveals Evolutionary Dynamics of Host-Parasite Interactions
Authors: Chan Jiulin , Wang Lu , Li Li , Mu Kang , Bushek David , Xu Yue , Guo Ximing , Zhang Guofan , Zhang Linlin
Published: December 2021

Infectious disease outbreaks are causing widespread declines of marine invertebrates including corals, sea stars, shrimps, and molluscs. Dermo is a lethal infectious disease of the eastern oysterCrassostrea virginicacaused by the protistPerkinsus marinus. The Pacific oysterCrassostrea gigasis resistant to Dermo due to differences in the host-parasite interaction that is not well understood. We compared transcriptomic responses toP. marinuschallenge in the two oysters at early and late infection stages. Dynamic and orchestrated regulation of large sets of innate immune response genes were observed in both species with remarkably similar patterns for most orthologs, although responses inC. virginicawere stronger, suggesting strong or over-reacting immune response could be a cause of host mortality. Between the two species, several key immune response gene families differed in their expansion, sequence variation and/or transcriptional response toP. marinus, reflecting evolutionary divergence in host-parasite interaction. Of note, significant upregulation ofinhibitors of apoptosis(IAPs) was observed in resistantC. gigasbut not in susceptibleC. virginica, suggesting upregulation ofIAPsis an active defense mechanism, not a passive response orchestrated byP. marinus. Compared withC. gigas,C. virginicaexhibited greater expansion oftoll-like receptors(TLRs) and positive selection inP. marinusresponsiveTLRs. The C1q domain containing proteins (C1qDCs) with the galactose-binding lectin domain that is involved inP. marinusrecognition, were only present and significantly upregulated inC. virginica. These results point to previously undescribed differences in host defense genes between the two oyster species that may account for the difference in susceptibility, providing an expanded portrait of the evolutionary dynamics of host-parasite interaction in lophotrochozoans that lack adaptive immunity. Our findings suggest thatC. virginicaandP. marinushave a history of coevolution and the recent outbreaks may be due to increased virulence of the parasite.
Women, Administered Insecurity, and Multiple Alignments to Assuage Gender Inequalities in the Brazilian Zika Epidemic
Authors: Scott Parry
Published: December 2021

This article deals with the Brazilian Zika epidemic that started in 2015 and became an important event for understanding Gender and Power in health treatment contexts. It discusses a combination of reinforcement of gender normed care and therapeutic itineraries overburdening mothers and the construction of political awareness and practice associated with demands for state services. Working with a concept of administered insecurity elaborated to understand people displaced during the implementation of planned government development policies, it argues that the planned nature of health systems, despite their explicit emphasis on the objective of treating the health of the population, also generate administered insecurity as planned administrators of scarcity. It uses data from a 4-year research project entitled “Doing Ethnography on Care” in Recife, Brazil, to show the multiplicity of contexts that are brought out through the practice of mothers in providing care for their Zika-syndrome stricken children, and how they reflect varying power relations that constantly re-dimension maternity along lines of gender relations in different institutional domains of treatment and research. The severe gender inequality in caring for infants was partially assuaged by multiple alignments made by the mothers and infants promoting dialogue and practice in varied contexts, including interaction with the research team. Family and Community Relations, Mediation, Favors, Accusations, Judicialization, Collective Action, formation of Associations, and learning to produce videos are seen as constructors of complex meaning and practice of mothering in a way in which gender goes beyond the limits of an overburdening practice of care. Gender provides a significant difference for mothers whose knowledge and familiarity of domains of health and health-related provision of services and knowledge, forged in their search for treatment for their child, create and legitimate spaces for the exercise of informed citizenship and a sharp awareness and resistance to practices by the state and other agents who administer insecurity. The final remarks synthesize some of the more important reconfigurations of gender relations and power in the context of the Zika epidemic and alerts to the challenge of the transitory nature of an epidemic and the gradual, and not so gradual, exhaustion of institutional interest for the dilemma of the mothers and also shows the role of anthropological research in promoting gender equality in epidemic contexts.
Multiepitope Dendrimeric Antigen-Silica Particle Composites as Nano-Based Platforms for Specific Recognition of IgEs
Authors: Gil-Ocaña Violeta , Jimenez Isabel M. , Mayorga Cristobalina , Doña Inmaculada , Céspedes Jose Antonio , Montañez Maria I. , Vida Yolanda , Torres Maria J. , Perez-Inestrosa Ezequiel
Published: December 2021

β-lactam antibiotics (BLs) are the drugs most frequently involved in drug hypersensitivity reactions. However, current in vitro diagnostic tests have limited sensitivity, partly due to a poor understanding of in vivo drug–protein conjugates that both induce the reactions and are immunologically recognized. Dendrimeric Antigen-Silica particle composites (DeAn@SiO2), consisting on nanoparticles decorated with BL-DeAns are promising candidates for improving the in vitro clinical diagnostic practice. In this nano-inspired system biology, the synthetic dendrimer plays the role of the natural carrier protein, emulating its haptenation by drugs and amplifying the multivalence. Herein, we present the design and synthesis of new multivalent mono- and bi-epitope DeAn@SiO2, using amoxicillin and/or benzylpenicillin allergenic determinants as ligands. The homogeneous composition of nanoparticles provides high reproducibility and quality, which is critical for in vitro applications. The suitable functionalization of nanoparticles allows the anchoring of DeAn, minimizing the nonspecific interactions and facilitating the effective exposure to specific IgE; while the larger interaction area increments the likelihood of capturing specific IgE. This achievement is particularly important for improving sensitivity of current immunoassays since IgE levels in BL allergic patients are very low. Our data suggest that these new nano-based platforms provide a suitable tool for testing IgE recognition to more than one BL simultaneously. Immunochemical studies evidence that mono and bi-epitope DeAn@SiO2 composites could potentially allow the diagnosis of patients allergic to any of these drugs with a single test. These organic–inorganic hybrid materials represent the basis for the development of a single screening for BL-allergies.
A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer
Authors: Yan Yi-Dan , Cui Jiu-Jie , Fu Jie , Su Ying-Jie , Chen Xiao-Yu , Gu Zhi-Chun , Lin Hou-Wen
Published: December 2021

Background

Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer.

Methods

We systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer.

Results

Overall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity.

Conclusions

In consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero, identifier CRD42021268650
The Role of Interferons in Driving Susceptibility to Asthma Following Bronchiolitis: Controversies and Research Gaps
Authors: Makrinioti Heidi , Bush Andrew , Gern James , Johnston Sebastian Lennox , Papadopoulos Nikolaos , Feleszko Wojciech , Camargo Carlos A. , Hasegawa Kohei , Jartti Tuomas
Published: December 2021

Bronchiolitis is the most common cause of hospitalization in infancy and is associated with a higher risk for the development of childhood asthma. However, not all children hospitalized with bronchiolitis will develop asthma. The mechanisms underlying asthma development following bronchiolitis hospitalization are complex. Immune responses to respiratory viruses may underlie both bronchiolitis severity and long-term sequela (such as asthma). Interferons (IFNs) are important components of innate immune responses to respiratory viruses and could influence both asthma development and asthma exacerbations. However, the nature of the relationship between interferon production and wheezing illnesses is controversial. For example, low peripheral blood IFN responses at birth have been linked with recurrent wheeze and asthma development. In contrast, there is evidence that severe illnesses (e.g., hospitalization for bronchiolitis) are associated with increased IFN responses during acute infection (bronchiolitis hospitalization) and a higher risk for subsequent asthma diagnosis. Furthermore, mechanistic studies suggest that bronchial epithelial cells from asthmatic children have impaired IFN responses to respiratory viruses, which may enable increased viral replication followed by exaggerated secondary IFN responses. This review aims to discuss controversies around the role of IFNs as drivers of susceptibility to asthma development following bronchiolitis hospitalization. Past evidence from both mechanistic and cohort studies are discussed. We will highlight knowledge gaps that can inform future research study design.
Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2hi Osteoclast Progenitors to the Affected Bone
Authors: Flegar Darja , Filipović Maša , Šućur Alan , Markotić Antonio , Lukač Nina , Šisl Dino , Ikić Matijašević Marina , Jajić Zrinka , Kelava Tomislav , Katavić Vedran , Kovačić Nataša , Grčević Danka
Published: December 2021

Detailed characterization of medullary and extramedullary reservoirs of osteoclast progenitors (OCPs) is required to understand the pathophysiology of increased periarticular and systemic bone resorption in arthritis. In this study, we focused on identifying the OCP population specifically induced by arthritis and the role of circulatory OCPs in inflammatory bone loss. In addition, we determined the relevant chemokine axis responsible for their migration, and targeted the attraction signal to reduce bone resorption in murine collagen-induced arthritis (CIA). OCPs were expanded in periarticular as well as circulatory compartment of arthritic mice, particularly the CCR2hi subset. This subset demonstrated enhanced osteoclastogenic activity in arthritis, whereas its migratory potential was susceptible to CCR2 blockade in vitro. Intravascular compartment of the periarticular area contained increased frequency of OCPs with the ability to home to the arthritic bone, as demonstrated in vivo by intravascular staining and adoptive transfer of splenic LysMcre/Ai9 tdTomato-expressing cells. Simultaneously, CCL2 levels were increased locally and systemically in arthritic mice. Mouse cohorts were treated with the small-molecule inhibitor (SMI) of CCR2 alone or in combination with methotrexate (MTX). Preventive CCR2/CCL2 axis blockade in vivo reduced bone resorption and OCP frequency, whereas combining with MTX treatment also decreased disease clinical score, number of active osteoclasts, and OCP differentiation potential. In conclusion, our study characterized the functional properties of two distinct OCP subsets in CIA, based on their CCR2 expression levels, implying that the CCR2hi circulatory-like subset is specifically induced by arthritis. Signaling through the CCL2/CCR2 axis contributes to OCP homing in the inflamed joints and to their increased osteoclastogenic potential. Therefore, addition of CCL2/CCR2 blockade early in the course of arthritis is a promising approach to reduce bone pathology.
Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies
Authors: Pan Quanren , Guo Fengbiao , Huang Yanyan , Li Aifen , Chen Shuxian , Chen Jiaxuan , Liu Hua-feng , Pan Qingjun
Published: December 2021

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that was traditionally thought to be closely related to genetic and environmental risk factors. Although treatment options for SLE with hormones, immunosuppressants, and biologic drugs are now available, the rates of clinical response and functional remission of these drugs are still not satisfactory. Currently, emerging evidence suggests that gut microbiota dysbiosis may play crucial roles in the occurrence and development of SLE, and manipulation of targeting the gut microbiota holds great promises for the successful treatment of SLE. The possible mechanisms of gut microbiota dysbiosis in SLE have not yet been well identified to date, although they may include molecular mimicry, impaired intestinal barrier function and leaky gut, bacterial biofilms, intestinal specific pathogen infection, gender bias, intestinal epithelial cells autophagy, and extracellular vesicles and microRNAs. Potential therapies for modulating gut microbiota in SLE include oral antibiotic therapy, fecal microbiota transplantation, glucocorticoid therapy, regulation of intestinal epithelial cells autophagy, extracellular vesicle-derived miRNA therapy, mesenchymal stem cell therapy, and vaccination. This review summarizes novel insights into the mechanisms of microbiota dysbiosis in SLE and promising therapeutic strategies, which may help improve our understanding of the pathogenesis of SLE and provide novel therapies for SLE.
Haplotype Analysis of Varroa destructor and Deformed Wing Virus Using Long Reads
Authors: Bai Wen Feng , Lin Zhe Guang , Yan Wei Yu , Zhang Li Zhen , Evans Jay D. , Huang Qiang
Published: December 2021

As a phoretic parasite and virus vector, the mite Varroa destructor and the associated Deformed wing virus (DWV) form a lethal combination to the honey bee, Apis mellifera. Routine acaricide treatment has been reported to reduce the diversity of mites and select for tolerance against these treatments. Further, different DWV strains face selective pressures when transmitted via mites. In this study, the haplotypes of Varroa mites and associated DWV variants were quantified using long reads. A single haplotype dominated the mite mitochondrial gene cytochrome oxidase subunit I, reflecting an ancient bottleneck. However, highly polymorphic genes were present across the mite genome, suggesting the diversity of mites could be actively maintained at a regional level. DWV detected in both mites and honey bees show a dominant variant with only a few low-frequency alternate haplotypes. The relative abundances of DWV haplotypes isolated from honey bees and mites were highly consistent, suggesting that some variants are favored by ongoing selection.
High-Velocity Shear and Soft Friction at the Nanometer Scale
Authors: Thorén Per-Anders , Borgani Riccardo , Forchheimer Daniel , Haviland David B.
Published: December 2021

We study high-speed friction on soft polymer materials by measuring the amplitude dependence of cyclic lateral forces on the atomic force microscope (AFM) tip as it slides on the surface with fixed contact force. The resulting dynamic force quadrature curves separate the elastic and viscous contributions to the lateral force, revealing a transition from stick-slip to free-sliding motion as the velocity increases. We explain force quadratures and describe how they are measured, and we show results for a variety of soft materials. The results differ substantially from the measurements on hard materials, showing hysteresis in the force quadrature curves that we attribute to the finite relaxation time of viscoelastic surface deformation.
A Deep-Learning Pipeline for TSS Coverage Imputation From Shallow Cell-Free DNA Sequencing
Authors: Han Bo-Wei , Yang Xu , Qu Shou-Fang , Guo Zhi-Wei , Huang Li-Min , Li Kun , Ouyang Guo-Jun , Cai Geng-Xi , Xiao Wei-Wei , Weng Rong-Tao , Xu Shun , Huang Jie , Yang Xue-Xi , Wu Ying-Song
Published: December 2021

Cell-free DNA (cfDNA) serves as a footprint of the nucleosome occupancy status of transcription start sites (TSSs), and has been subject to wide development for use in noninvasive health monitoring and disease detection. However, the requirement for high sequencing depth limits its clinical use. Here, we introduce a deep-learning pipeline designed for TSS coverage profiles generated from shallow cfDNA sequencing called the Autoencoder of cfDNA TSS (AECT) coverage profile. AECT outperformed existing single-cell sequencing imputation algorithms in terms of improvements to TSS coverage accuracy and the capture of latent biological features that distinguish sex or tumor status. We built classifiers for the detection of breast and rectal cancer using AECT-imputed shallow sequencing data, and their performance was close to that achieved by high-depth sequencing, suggesting that AECT could provide a broadly applicable noninvasive screening approach with high accuracy and at a moderate cost.
Comparative Proteomics Reveals the Spoilage-Related Factors of Shewanella putrefaciens Under Refrigerated Condition
Authors: Yi Zhengkai , Xie Jing
Published: December 2021

Shewanella putrefaciens is a microorganism with strong spoilage potential for aquatic products. This study aimed to investigate the potential spoilage factors of S. putrefaciens by comparative proteomic analysis. The spoilage potential of two strains of S. putrefaciens (00A and 00B) isolated from chilled spoiled bigeye tuna was investigated. The results of total volatile basic nitrogen (TVB-N), trimethylamine (TMA) in fish inoculated with S. putrefaciens, extracellular protease activity of S. putrefaciens, and degradation of fish proteins indicated that the spoilage potential of S. putrefaciens 00A was much higher than that of 00B. Fish proteins are usually degraded by spoilage microorganism proteases into small molecular peptides and amino acids, which are subsequently degraded into spoilage metabolites in bacterial cells, leading to deterioration of fish quality. Thus, proteomic analysis of the extracellular and intracellular proteins of 00A vs. 00B was performed. The results indicated that the intracellular differentially expressed protein (IDEP) contained 243 upregulated proteins and 308 downregulated proteins, while 78 upregulated proteins and 4 downregulated proteins were found in the extracellular differentially expressed protein (EDEP). GO annotation revealed that IDEP and EDEP were mainly involved in cellular and metabolic processes. KEGG annotation results showed that the upregulated proteins in IDEP were mainly involved in sulfur metabolism, amino acid metabolism, and aminoacyl-tRNA biosynthesis, while downregulated proteins were related to propanoate metabolism. In contrast, EDEP of KEGG annotation was mainly involved in ribosomes, quorum sensing, and carbohydrate metabolism. Proteins associated with spoilage containing sulfur metabolism (sulfite reductase, sulfate adenylyltransferase, adenylyl-sulfate kinase), amino acid metabolism (biosynthetic arginine decarboxylase, histidine ammonia-lyase), trimethylamine metabolism (trimethylamine-N-oxide reductase), and extracellular proteins (ATP-dependent Clp protease proteolytic subunit) were identified as upregulated. These proteins may play a key role in the spoilage potential of S. putrefaciens. These findings would contribute to the identification of key spoilage factors and understanding of the spoilage mechanism of microorganisms.
Durability of Antibody Responses to SARS-CoV-2 Infection and Its Relationship to Disease Severity Assessed Using a Commercially Available Assay
Authors: Alshami Alanoud , Al Attas Rabab , Anan Hadeel , Al Maghrabi Aroub , Ghandorah Salim , Mohammed Amani , Alhalimi Abdulbary , Al-Jishi Jumana , Alqahtani Hadi
Published: December 2021

Background: Assessing the humoral immune response to SARS-CoV-2 is crucial for inferring protective immunity from reinfection and for assessing vaccine efficacy. Data regarding the durability and sustainability of SARS-CoV-2 antibodies are conflicting. In this study, we aimed to determine the seroconversion rate of SARS-CoV-2 infection in a cohort of reverse-transcriptase polymerase chain reaction (RT–PCR)-confirmed SARS-CoV-2 infections and the antibody dynamics, durability, and the correlation of antibody titers with disease severity using the commercially available SARS-CoV-2 anti-spike (S1/S2) protein.

Methods: A total of 342 subjects with PCR-confirmed COVID-19 were enrolled. A total of 395 samples were collected at different time points (0–204) after the onset of symptoms or from the day of positive PCR in asymptomatic patients. Demographics, clinical presentation and the date of PCR were collected. All samples were tested using the automated commercial chemiluminescent system (DiaSorin SARS-CoV-2 S1/S2 IgG) on the LIAISONXL® platform (LIAISON).

Results: The seroconversion rate for samples collected 14 days after the onset of infection was much higher than that for samples collected before 14 days (79.4% vs. 39.4%). The rate of seroconversion in symptomatic participants (62.1%) was similar to that of asymptomatic participants (56.1%) (p = 0.496). The IgG titer distribution was also similar across both groups (p = 0.142), with a median IgG level of 27.86 AU/ml (3.8–85.5) and 15 AU/ml (3.8–58.85) in symptomatic and asymptomatic participants, respectively. However, IgG titers were significantly higher in ICU patients, with a median of 104 AU/ml (3.8–179) compared to 34 AU/ml (3.8–70) in the non-ICU participants (p < 0.0001). Furthermore, the median time to seroconversion occurred significantly faster in ICU patients than in non-ICU participants (19 versus 47 days) (P < 0.0001). IgG titers were also higher in subjects ≥50 years compared to those <50 years (p < 0.009), male compared to female (p < 0.054) and non-Saudi compared to Saudi (p < 0.003). Approximately 74% of all samples tested beyond 120 days were positive.

Conclusion: Antibodies can persist in circulation for longer than 4 months after COVID-19 infection. The majority of patients with COVID-19 mounted humoral immune responses to SARS-CoV-2 infection that strongly correlated with disease severity, older age and male gender. However, the population of individuals who tested negative should be further evaluated.