bluuebunny/crossref_metadata_2025 huggingface dataset:
ESSENTIAL PROBLEMS OF FODDER QUALITY EVALUATION AND STANDARDIZATION
Authors: Popov Vladimir
Published: February 2022

The subroutine «Development of fodder production and feed additives» (further – the subroutine), included in the Federal scientific and technical program of development of agriculture for 2017–2025, provides cardinal measures on production of forages only the higher classes of quality. The principle of standardization and unification scientific and (or) scientific and technical results and production simultaneously are introduced. Present article also is devoted questions of perfection and standardization of national system of a fodder quality evaluation. Examples of unjustified abolition of All-Union State Standards (on sampling, in vitro digestibility, quality of pressed forages, etc.) are presented. The question on hardware of laboratories of the physical and chemical analysis, a zootechnical estimation and technology of use of forages by the modern equipment and devices is discussed. Examples of the human factor influences in the field of a fodder quality evaluation and standardization are presented. Absence of uniform ways of sampling, methods of the analysis, fodder quality indicators; nutrients norms of requirement depending on a physiological condition of animals, the uniform approach to balancing of rations, and the main thing - absence of the international standard system of an estimation of energy value of forages and rations - complicates mutual understanding of scientists and experts of the different countries and integration of scientific achievements into a farm-production
ACE2 and TMPRSS2 SNPs as Determinants of Susceptibility to, and Severity of, a COVID-19 Infection
Authors: Abdelsattar S. , Kasemy Z. A. , Ewida S. F. , Abo-Elsoud R. A. A. , Zytoon A. A. , Abdelaal G. A. , Abdelgawad A. S. , Khalil F. O. , Kamel H. F. M.
Published: February 2022

Background: Genetic risk factors may be related to the infectivity and severity of SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2) and host transmembrane serine protease (TMPRSS2) have key role in viral cell entrance and priming.

Methods: This case-control study on 147 healthy controls and 299 COVID-19 patients identified potential determinants and risk factors, including gene polymorphism involved in the severity (mild, moderate, severe) of COVID-19 disease defined by CORAD radiological criteria.

Results: The ACE2 s2285666 and TMPRSS2 rs12329760 SNPs were significantly linked with COVID-19 disease severity, as were certain co-morbidities (hypertension, heart disease) and laboratory parameters. Both SNPs were amongst the highest predictors of disease severity: TMPRSS2 rs12329760 CT + TT [odds ratio (95% CI) 17.6 (5.1–61.10), ACE2 rs2285666 CT + TT 9.9 (3.2–30.9), both p < 0.001]. There was an increase in the expression of genotype frequencies of ACE2 rs2285666 and TMPRSS2 rs1232976 (TT), (CT + TT), and (T) allele in severe COVID-19 group compared to control and mild groups. Disease severity was also linked to elevated CRP, ferritin and D-dimer, and lower lymphocytes and platelet count (all p < 0.001).

Conclusion: ACE2 rs2285666 and TMPRSS2 rs12329760 SNPs, in addition to lymphocyte count, CRP, D-dimers, ferritin, and hypertension, are predictors of COVID-19 disease severity.
Masked Delivery of Allergen in Nanoparticles Safely Attenuates Anaphylactic Response in Murine Models of Peanut Allergy
Authors: Hughes Kevin R. , Saunders Michael N. , Landers Jeffrey J. , Janczak Katarzyna W. , Turkistani Hamza , Rad Laila M. , Miller Stephen D. , Podojil Joseph R. , Shea Lonnie D. , O'Konek Jessica J.
Published: February 2022

Food allergy is a growing health concern worldwide. Current allergen-specific immunotherapy (AIT) approaches require frequent dosing over extended periods of time and may induce anaphylaxis due to allergen-effector cell interactions. A critical need remains to develop novel approaches that refine AIT for the treatment of food allergies. Previous studies show that poly(lactide-co-glycolide) (PLG) nanoscale particles (NP) effectively suppress Th1- and Th17-driven immune pathologies. However, their ability to suppress the distinct Th2-polarized immune responses driving food allergy are unknown. Herein, we describe the safety and efficacy of NPs containing encapsulated peanut allergen in desensitizing murine models of peanut allergy. Peanut extract encapsulation allowed for the safe intravenous delivery of allergen relative to non-encapsulated approaches. Application of 2–3 doses, without the need for dose escalation, was sufficient to achieve prophylactic and therapeutic efficacy, which correlated with suppression of Th2-mediated disease and reduced mast cell degranulation. Efficacy was associated with strong reductions in a broad panel of Th1, Th2, and Th17 cytokines. These results demonstrate the ability of PLG NPs to suppress allergen-specific immune responses to induce a more tolerogenic phenotype, conferring protection from intragastric allergen challenge. These promising studies represent a step forward in the development of improved immunotherapies for food allergy.
Host-Dependent Producibility of Recombinant Cypridina noctiluca Luciferase With Glycosylation Defects
Authors: Mitani Yasuo , Yasuno Rie , Kihira Kiyohito , Chung KwiMi , Mitsuda Nobutaka , Kanie Shusei , Tomioka Azusa , Kaji Hiroyuki , Ohmiya Yoshihiro
Published: February 2022

Cypridina noctiluca luciferase (CLuc) is a secreted luminescent protein that reacts with its substrate (Cypridina luciferin) to emit light. CLuc is known to be a thermostable protein and has been used for various research applications, including in vivo imaging and high-throughput reporter assays. Previously, we produced a large amount of recombinant CLuc for crystallographic analysis. However, this recombinant protein did not crystallize, probably due to heterogeneous N-glycan modifications. In this study, we produced recombinant CLuc without glycan modifications by introducing mutations at the N-glycan modification residues using mammalian Expi293F cells, silkworms, and tobacco Bright Yellow-2 cells. Interestingly, recombinant CLuc production depended heavily on the expression hosts. Among these selected hosts, we found that Expi293F cells efficiently produced the recombinant mutant CLuc without significant effects on its luciferase activity. We confirmed the lack of N-glycan modifications for this mutant protein by mass spectrometry analysis but found slight O-glycan modifications that we estimated were about 2% of the ion chromatogram peak area for the detected peptide fragments. Moreover, by using CLuc deletion mutants during the investigation of O-glycan modifications, we identified amino acid residues important to the luciferase activity of CLuc. Our results provide invaluable information related to CLuc function and pave the way for its crystallographic analysis.
m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Cell-Infiltration Characterization in Head and Neck Cancer
Authors: Yang Qinghui , Xu Feng , Jian Aiwen , Yu Hongmei , Ye Tao , Hu Weiqi
Published: February 2022

Background: Recently, RNA modifications have emerged as essential epigenetic regulators of gene expression. However, the mechanism of how RNA N6-methyladenosine (m6A) modification interacts with tumor microenvironment (TME) infiltration remains obscure.

Methods: A total of 876 head and neck cancer samples considering 21 m6A regulators were included and analyzed to determine the m6A modification patterns. These modification patterns were then correlated with TME immune cell-infiltrating characteristics. A scoring system, the m6Ascore, was constructed using principal component analysis algorithms to quantify m6A modification of tumors.

Results: Three m6A modification patterns were identified, with TME infiltrating characteristics highly consistent with tumors with three distinct immune phenotypes, including immune-inflamed, immune-exclude, and immune-desert phenotypes. It was demonstrated that the identification of the m6A modification patterns via m6Ascore could predict tumor progression, subtypes, TME stromal activity, variation of relevant genes, and patient prognosis. Low m6Ascore, identified to be an inflamed phenotype, is found to be associated with low stroma activity and tumor mutation burden, high survival probability, increased tumor neoantigen burden, and enhanced response to anti-PD-1/L1 immunotherapy. The therapeutic advantages and clinical benefits of patients with low m6Ascore were further verified in two immunotherapy cohorts.

Conclusion: This study identified the significant role that the m6A modification played in the formation of TME characteristics. A more comprehensive understanding of the m6A modification patterns and their correlation with TME infiltration will contribute to the discovery of immunotherapy strategies with better efficacy.
The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective
Authors: Garg Vaishali , Chandanala Shashank , David-Luther M. , Govind M. , Prasad Roshni Ravi , Kumar Anujith , Prasanna S. Jyothi
Published: February 2022

The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field.
Lipoprotein(a) and Pulmonary Embolism Severity-A Retrospective Data Analysis
Authors: Gressenberger Paul , Posch Florian , Pechtold Moritz , Gütl Katharina , Muster Viktoria , Jud Philipp , Riedl Jakob , Silbernagel Günther , Kolesnik Ewald , Schmid Johannes , Raggam Reinhard B. , Brodmann Marianne , Gary Thomas
Published: February 2022

Aim

We aimed to investigate a correlation between PE severity and Lp(a) levels.

Methods

We performed a retrospective data analysis from our medical records of PE patients admitted to the University Hospital Graz, Austria. Patients with an Lp(a) reading within a 1-year interval before and after PE diagnosis were included. In accordance with the 2019 ESC guidelines for the diagnosis and management of acute PE, severity assessment was carried out classifying patients into four groups: low risk (LR), intermediate low risk (IML), intermediate high risk (IMH) and high risk (HR). The study period of interest was between January 1, 2002 and August 1, 2020.

Results

We analyzed 811 patients with PE, of whom 323 (40%) had low-risk PE, 343 (42%) had intermediate-low-risk PE, 64 (8%) had intermediate-high-risk PE, and 81 (10%) had high-risk PE, respectively. We did not observe an association between PE severity and Lp(a) concentrations. In detail, median Lp(a) concentrations were 17 mg/dL [25–75th percentile: 10-37] in low-risk PE patients, 16 mg/dL [10–37] in intermediate-low-risk PE patients, 15mg/dL [10–48] in intermediate-high-risk PE patients, and 13mg/dL [10–27] in high-risk PE patients, respectively (Kruskal-Wallis p = 0.658, p for linear trend = 0.358).

Conclusion

The current findings suggest no correlation between PE severity and Lp(a) levels.
Women Specific Characteristics and 1-Year Outcome Among Patients Hospitalized for Peripheral Artery Disease: A Monocentric Cohort Analysis in a Tertiary Center
Authors: Détriché Grégoire , Guédon Alexis , Mohamedi Nassim , Sellami Olfa , Cheng Charles , Galloula Alexandre , Goudot Guillaume , Khider Lina , Mortelette Hélène , Sitruk Jonas , Gendron Nicolas , Sapoval Marc , Julia Pierre , Smadja David M. , Mirault Tristan , Messas Emmanuel
Published: February 2022

Although women have lower age-standardized cardiovascular disease incidence, prevalence, and death-related rates than men, there are also reports indicating that women with cardiovascular disease receive less care, fewer investigations, and have poorer outcomes after a coronary event. The aims of this study were to compare the characteristics of men and women hospitalized for peripheral artery disease (PAD), their cardiovascular and limb outcomes, and their 1-year mortality. The study is a prospective registry collecting data about all consecutive patients hospitalized for PAD within the vascular department of the tertiary center Georges-Pompidou European Hospital (Paris, France). Patients were required to have one of three inclusion criteria: previous revascularization of the lower limb or any lower limb artery occlusion due to an atherosclerotic vascular disease or hemodynamic evidence of PAD. Exclusion criteria were patients with lower extremity arterial occlusion due to another cause. All patients were followed-up for at least 12 months after the initial hospitalization. Among the 235 patients included, there were 61 women (26%), older than men with a median age of 75.6 and 68.3 years, respectively. Main cardiovascular risk factors and comorbidities were similar for men and women except more former or current smokers [145 (83.4%) vs. 33 (54.1%)] and more history of coronary heart disease [42 (24.1%) vs. 7 (11.5%)] in men. Most patients [138 (58.8%)] had critical limb ischemia and 97 (41.3%) had claudication, with no difference for sex. After discharge, 218 patients received an antithrombotic therapy (93.2%), 195 a lipid-lowering drug (83.3%), 185 an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker (78.9%), similarly between sex. At 1-year, overall mortality, major adverse cardiovascular events, major adverse limb events did not differ with 23 (13.2%), 11 (6.3%) and 32 (18.4%) in men, and 8 (13.1%), 3 (4.9%), 15 (24.6%) in women, respectively, despite the difference in age. Overall mortality, cardiovascular outcomes, limb revascularization or amputation did not differ between men and women, 1-year after hospitalization for PAD although the latter were older, less smoker and had less coronary artery disease. Due to the small size of this cohort, larger studies and future research are needed to better understand sex-specific mechanisms in the pathophysiology and natural history of PAD.
Experimental Study on Permeability and Stress Sensitivity of Different Lithological Surrounding Rock Combinations
Authors: Lv Runsheng , Xue Jiao , Zhang Zhen , Ma Xinyu , Li Bing , Zhu Yuchen , Li Yunbo
Published: February 2022

The different lithological combinations of the surrounding rock of coal seams play a key role in controlling the enrichment and migration of coalbed methane (gas), and their permeability and stress sensitivity have important theoretical guiding significance for the regional election and evaluation of coalbed methane development. In this paper, the HB-2 type coal rock sample pore permeability adsorption simulation measurement device is used to carry out the sensitivity experiment of the permeability of different surrounding rock combinations on the effective stress of the No. 3 coal seam roof in the Daping coal mine area, Luan, Shanxi. The sensitivity coefficient of permeability to effective stress, the maximum damage rate of permeability, and other parameters are defined to characterize the response mode of permeability to effective stress and the dynamic change rule of permeability, and reveal the control mechanism of effective stress on permeability change of different surrounding rock combinations. The results show that the permeability of the roof of No. 3 coal seam is highly sensitive to the effective stress, and the permeability of different surrounding rock combinations decreases with the increase of the effective stress, and there is a strong negative exponential correlation between the permeability and the effective stress; the stress sensitivity coefficients of different surrounding rock combinations under unloading stress are higher than those under loading; the permeability changes of specimens with different combinations of surrounding rock under the same experimental conditions are varied and the differentiation phenomenon is significant; the permeability is affected by lithology, pore fissure degree, and different combinations of surrounding rock, among which different combinations of surrounding rock are the main controlling factors for the dynamic change of permeability.
Middle Eocene Paleoenvironmental Reconstruction in the Gonjo Basin, Eastern Tibetan Plateau: Evidence From Palynological and Evaporite Records
Authors: Wang Licheng , Yuan Qin , Shen Lijian , Ding Lin
Published: February 2022

The early uplift of the Tibetan Plateau (TP) had a profound influence on the paleoenvironment and paleoclimate. However, we still have little information about the link between the paleoclimatic changes and flora ecosystem caused by the uplift. The Eocene fluvial-lacustrine sequences in the Gonjo Basin, eastern TP, provide excellent archives of the paleoecological and paleoclimatic responses to the surface uplift of the TP. In this study, we investigated a section of the middle Eocene Ranmugou Formation (47.8–>44 Ma) and used the sporomorphs assemblages, sedimentology, and geochemistry of the evaporites to reconstruct the paleoclimate and paleovegetation. The palynological assemblages and coexistence analysis reveal that the middle Eocene ecosystem in the Gonjo Basin was dominated by warm and humid temperate deciduous broad-leaved forests. The 87Sr/86Sr ratios (0.709942–0.710062) of all of the gypsum samples are higher than those of contemporaneous seawater, while the δ34S values (10.3–11.0%) are much lower, indicating a lacustrine environment. Combined with published palynological and paleoelevation data for eastern Tibetan lacustrine basins, we infer that the paleoenvironment changed from warm and humid deciduous broad-leaved forests during 47.8–>44 Ma, to cool and arid temperate forest during 44–40 Ma in the Gonjo Basin, and to arid and cool steppe-desert vegetation in the late Eocene Nangqian Basin. The changes in the paleoclimate and vegetation were primarily driven by the surface uplift of the Central Watershed Mountain, the high topography of which blocked the moisture from the Asian Eocene monsoon.
Modulation of Pacific Sea Surface Temperatures on the Late-Season Tropical Cyclone Tracks Over the Western North Pacific and its Implication for Seasonal Forecasting
Authors: Yu Hua , Wang Chao , Ge Xuyang
Published: February 2022

In this study, two leading modes of the late season (October–December) TC track frequency are identified with the empirical orthogonal function analysis. It is found that circulation anomalies associated with the two modes are linked to the concurrent El Niño-Southern Oscillation (ENSO), but with distinct locations of maximum sea surface temperature (SST). For the first mode, the maximum SST warming and the resulted heating can extend to the equatorial central Pacific, which emanates a cyclonic circulation extending to the east of the Philippines, and then generates an anti-cyclonic circulation to the west of the Philippines by dry advection and local air–sea interaction. In contrast, for the second mode, the maximum SST warming and the corresponding heating shift eastward to the equatorial eastern Pacific, the related cyclonic circulation, and the compensation descending motion migrate eastward and are confined to the east of 150°E. The associated suppressed heating then emanates an anti-cyclonic circulation to the west of 150°E. These anomalous circulations can modulate TC genesis and steering flow and thus contribute to variations in the two modes. A set of physics-based empirical models is further built, which shows a promising pathway for the seasonal forecasting of the two modes and the basin-wide total TC track frequency. The results highlight the importance of the location of ENSO maximum SST in understanding and seasonal prediction of the late-season TC tracks over the WNP.
The Complex Quest of Preventing Obesity in Early Childhood: Describing Challenges and Solutions Through Collaboration and Innovation
Authors: Seidler Anna Lene , Johnson Brittany J. , Golley Rebecca K. , Hunter Kylie E.
Published: February 2022

Childhood obesity remains a major public health issue and priority area for action. Promisingly, obesity prevention interventions in the first 2000 days of life have shown modest effectiveness in improving health behaviours and healthy weight status in children. Yet, researchers in this field face several challenges. This can lead to research waste and impede progress towards delivering effective, scalable solutions. In this perspective article, we describe some of the key challenges in early childhood obesity prevention and outline innovative and collaborative solutions to overcome these. Combining these solutions will accelerate the generation of high-quality evidence that can be implemented into policy and practice.
The Risk Stratification of Papillary Thyroid Cancer With Bethesda Category III (Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance) by Thyroid Fine‐Needle Aspiration Could Be Assisted by Tumor Size for Precision Treatment
Authors: Zha Xiaojuan , Miao Zhenchun , Huang Xiu , Wang Xingchun , Xie Ruting , Jin Jiaoying , Zou Dajin , Yang Peng , Huang Yueye
Published: February 2022

Purpose

To investigate the clinical characteristics of papillary thyroid cancer (PTC) classified as Bethesda category III [atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)] by fine-needle aspiration (FNA) for precision treatment.

Methods

A total of 1,739 patients diagnosed with Bethesda category III (AUS/FLUS) by FNA were investigated, and 290 patients diagnosed with PTC were analyzed.

Results

The rate of papillary thyroid microcarcinoma (PTMC) was 82.1% (238/290). The rates of lymph node metastases were 44.9% (22/49) and 25.2% (56/222) for PTC and PTMC, respectively (p = 0.006). The rates of extra-thyroid extension were 46.2% (24/52) and 19.8% (47/237) (p < 0.001). Compared with PTMC, PTC had significantly higher odds ratios (ORs) of 3.41 (1.81–6.44, p < 0.001), 2.19 (1.16–4.13, p = 0.016), and 2.51 (1.29–4.88, p = 0.007) for extra-thyroid extension, multifocality, and lymph node metastases, respectively, after adjustment for age and gender. The larger size and BRAF V600E mutation had a robust synergistic effect for invasive features. The rates of lymph node metastases, multifocality, and extra-thyroid extension were significantly increased with larger sizes harboring BRAF V600E mutation. Compared with PTMC harboring wild type (WT)-BRAF, PTC harboring BRAF V600E mutation had adjusted higher ORs of 3.01 (1.26–8.68, p = 0.015), 3.20 (1.22–8.42, p = 0.018), and 5.62 (2.25–14.01, p < 0.001) for lymph node metastases, multifocality, and extra-thyroid extension, respectively.

Conclusions

In this study, risk stratification was recommended for patients with Bethesda category III (AUS/FLUS) nodules with a size under 1 cm harboring WT-BRAF being regarded as low risk and should be recommended for active surveillance. Nodules with a size over 1 cm harboring WT-BRAF or those under 1 cm harboring BRAF V600E mutation could be regarded as moderate risk, and molecular testing should be recommended. However, those with a size over 1 cm harboring BRAF V600E mutation should be regarded as high risk, and a diagnostic surgery should be recommended.
Umbilical Cord Blood Leptin and IL-6 in the Presence of Maternal Diabetes or Chorioamnionitis
Authors: Vasilakos Lauren K. , Steinbrekera Baiba , Santillan Donna A. , Santillan Mark K. , Brandt Debra S. , Dagle Daniel , Roghair Robert D.
Published: February 2022

Diabetes during pregnancy is associated with elevated maternal insulin, leptin and IL-6. Within the placenta, IL-6 can further stimulate leptin production. Despite structural similarities and shared roles in inflammation, leptin and IL-6 have contrasting effects on neurodevelopment, and the relative importance of maternal diabetes or chorioamnionitis on fetal hormone exposure has not been defined. We hypothesized that there would be a positive correlation between IL-6 and leptin with progressively increased levels in pregnancies complicated by maternal diabetes and chorioamnionitis. To test this hypothesis, cord blood samples were obtained from 104 term infants, including 47 exposed to maternal diabetes. Leptin, insulin, and IL-6 were quantified by multiplex assay. Factors independently associated with hormone levels were identified by univariate and multivariate linear regression. Unlike IL-6, leptin and insulin were significantly increased by maternal diabetes. Maternal BMI and birth weight were independent predictors of leptin and insulin with birth weight the strongest predictor of leptin. Clinically diagnosed chorioamnionitis and neonatal sepsis were associated with increased IL-6 but not leptin. Among appropriate for gestational age infants without sepsis, IL-6 and leptin were strongly correlated (R=0.6, P<0.001). In summary, maternal diabetes and birth weight are associated with leptin while chorioamnionitis is associated with IL-6. The constraint of the positive association between leptin and IL-6 to infants without sepsis suggests that the term infant and placenta may have a limited capacity to increase cord blood levels of the neuroprotective hormone leptin in the presence of increased cord blood levels of the potential neurotoxin IL-6.
Genetic Influence Underlying Brain Connectivity Phenotype: A Study on Two Age-Specific Cohorts
Authors: Cong Shan , Yao Xiaohui , Xie Linhui , Yan Jingwen , Shen Li ,   and the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2022

Background: Human brain structural connectivity is an important imaging quantitative trait for brain development and aging. Mapping the network connectivity to the phenotypic variation provides fundamental insights in understanding the relationship between detailed brain topological architecture, function, and dysfunction. However, the underlying neurobiological mechanism from gene to brain connectome, and to phenotypic outcomes, and whether this mechanism changes over time, remain unclear.

Methods: This study analyzes diffusion-weighted imaging data from two age-specific neuroimaging cohorts, extracts structural connectome topological network measures, performs genome-wide association studies of the measures, and examines the causality of genetic influences on phenotypic outcomes mediated via connectivity measures.

Results: Our empirical study has yielded several significant findings: 1) It identified genetic makeup underlying structural connectivity changes in the human brain connectome for both age groups. Specifically, it revealed a novel association between the minor allele (G) of rs7937515 and the decreased network segregation measures of the left middle temporal gyrus across young and elderly adults, indicating a consistent genetic effect on brain connectivity across the lifespan. 2) It revealed rs7937515 as a genetic marker for body mass index in young adults but not in elderly adults. 3) It discovered brain network segregation alterations as a potential neuroimaging biomarker for obesity. 4) It demonstrated the hemispheric asymmetry of structural network organization in genetic association analyses and outcome-relevant studies.

Discussion: These imaging genetic findings underlying brain connectome warrant further investigation for exploring their potential influences on brain-related complex diseases, given the significant involvement of altered connectivity in neurological, psychiatric and physical disorders.
Low Intelligence Predicts Higher Risks of Coronary Artery Disease and Myocardial Infarction: Evidence From Mendelian Randomization Study
Authors: Yang Fangkun , Hu Teng , Chen Songzan , Wang Kai , Qu Zihao , Cui Hanbin
Published: February 2022

Background: Low intelligence has been shown to be associated with a high risk of cardiovascular disease in observational studies. It remains unclear whether the association is causal. This study aimed to explore the causal association of intelligence with coronary artery disease (CAD) and myocardial infarction (MI).

Methods: A two-sample Mendelian randomization study was designed to infer the causality. A total of 121 single nucleotide polymorphisms were selected as a genetic instrumental variable for intelligence. Summary data on CAD (n = 184,305) and MI (n = 171,875) were obtained from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium and the FinnGen study. Inverse variance weighting method was used to calculate the effect estimates. Sensitivity analyses including other statistical models and leave-one-out analysis were conducted to verify the robustness of results. MR-Egger test was performed to assess the pleiotropy.

Results: Genetically predicted higher intelligence was significantly associated with lower risk of CAD (OR, .76; 95%CI, .69–.85; p = 1.5 × 10–7) and MI (OR, .78; 95%CI, .70–.87; p = 7.9 × 10–6). The results remained consistent in the majority of the sensitivity analyses and were repeated in the FinnGen datasets. MR-Egger test suggested no evidence of directional pleiotropy for the association with coronary artery disease (intercept = −.01, p = .19) and myocardial infarction (intercept = −.01, p = .06).

Conclusion: This Mendelian randomization analysis provided genetic evidence for the causal association between low intelligence and increased risks of CAD and MI.
A Novel Risk Model Identified Based on Pyroptosis-Related lncRNA Predicts Overall Survival and Associates With the Immune Landscape of GC Patients
Authors: Xu Tingting , Gu Hanxin , Zhang Changsong , Zhang Wushuang , Liang Xiaolong , Cheng Xiaoxia
Published: February 2022

Gastric cancer (GC) is one of the most common malignant gastrointestinal tumors worldwide. Pyroptosis was widely reported to exert a crucial function in tumor development. In addition, pyroptosis was also proved to be associated with the immune landscape. However, whether pyroptosis-related lncRNAs are associated with the prognosis and the immune landscape of GC remains unclear. In the present study, we first constructed a novel risk model by using pyroptosis-related lncRNAs. We identified 11 pyroptosis-related lncRNAs for the establishment of the risk model. The risk model could be used to predict the survival outcome and immune landscape of GC patients. The results of survival analysis and AUC value of a time-related ROC curve proved that our risk model has an elevated efficiency and accuracy in predicting the survival outcome of patients. We also found that the risk model was also associated with the immune landscape, drug sensitivity, and tumor mutation burden of GC patients. In conclusion, our risk model plays a crucial role in the tumor immune microenvironment and could be used to predict survival outcomes of GC patients.
Increased Fibrosis in a Mouse Model of Anti-Laminin 332 Mucous Membrane Pemphigoid Remains Unaltered by Inhibition of Aldehyde Dehydrogenase
Authors: Patzelt Sabrina , Pigors Manuela , Steenbock Heiko , Diel Leonard , Boch Katharina , Chakievska Lenche , Künzel Sven , Busch Hauke , Fähnrich Anke , Brinckmann Jürgen , Schmidt Enno
Published: February 2022

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions. The oral cavity and conjunctivae are most frequently affected, albeit clinical manifestations can also occur on the skin. MMP-associated lesions outside the oral cavity typically lead to scarring. Mechanisms underlying scarring are largely unknown in MMP and effective treatment options are limited. Herein, we assessed the collagen architecture in tissue samples of an antibody-transfer mouse model of anti-laminin-332 MMP. In MMP mice, increased collagen fibril density was observed in skin and conjunctival lesions compared to mice injected with normal rabbit IgG. The extracellular matrix of MMP skin samples also showed altered post-translational collagen cross-linking with increased levels of both lysine- and hydroxylysine-derived collagen crosslinks supporting the fibrotic phenotype in experimental MMP compared to control animals. In addition, we evaluated a potential anti-fibrotic therapy in experimental anti-laminin-332 MMP using disulfiram, an inhibitor of the aldehyde dehydrogenase (ALDH), which has been implicated in immune-mediated mucosal scarring. In addition, disulfiram also acts as a copper chelator that was shown to block lysyl oxidase activity, an enzyme involved in formation of collagen crosslinks. Topical use of disulfiram (300 μM in 2% [w/v] methocel) did not improve ocular lesions in experimental MMP over the 12-day treatment period in disulfiram-treated mice compared to vehicle-treated mice (n=8/group). Furthermore, C57BL6/J mice (n=8/group) were treated prophylactically with 200 mg/kg p.o. disulfiram or the solvent once daily over a period of 12 days. Systemic treatment did not show any reduction in the severity of oral and ocular lesions in MMP mice, albeit some improvement in skin lesions was observed in disulfiram- vs. vehicle-treated mice (p=0.052). No reduction in fibrosis was seen, as assessed by immunohistochemistry. Whilst blocking of ALDH failed to significantly ameliorate disease activity, our data provide new insight into fibrotic processes highlighting changes in the collagenous matrix and cross-linking patterns in IgG-mediated MMP.
Rapamycin Attenuated Zinc-Induced Tau Phosphorylation and Oxidative Stress in Rats: Involvement of Dual mTOR/p70S6K and Nrf2/HO-1 Pathways
Authors: Lai Chencen , Chen Zhuyi , Ding Yuanting , Chen Qian , Su Songbai , Liu Heng , Ni Ruiqing , Tang Zhi
Published: February 2022

Alzheimer’s disease is pathologically characterized by abnormal accumulation of amyloid-beta plaques, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation, including excessive zinc released by presynaptic neurons, plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer’s disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of the mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, and synaptic and cognitive impairment has not been fully elucidated in vivo. Here, we assessed the effect of pathological zinc concentrations in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were laterally ventricularly injected with zinc, treated with rapamycin (intraperitoneal injection) for 1 week, and assessed using the Morris water maze. Evaluation of oxidative stress, tau phosphorylation, and synaptic impairment was performed using the hippocampal tissue of the rats by biochemical assays and immunofluorescence staining. The results from the Morris water maze showed that the capacity of spatial memory was impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356 and decreased the levels of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in SH-SY5Y cells and in zinc-treated rats compared with the control groups. Increased expression of reactive oxygen species was observed in zinc sulfate-induced SH-SY5Y cells and in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued zinc-induced increases in mTOR/p70S6K activation, tau phosphorylation, and oxidative stress, and Nrf2/HO-1 inactivation, cognitive impairment, and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress, and synaptic impairment by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity.
Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence
Authors: Fuentes-Villalobos Francisco , Garrido Jose L. , Medina Matías A. , Zambrano Nicole , Ross Natalia , Bravo Felipe , Gaete-Argel Aracelly , Oyarzún-Arrau Aarón , Amanat Fatima , Soto-Rifo Ricardo , Valiente-Echeverría Fernando , Ocampo Renato , Esveile Christian , Ferreira Leonila , Cabrera Johanna , Torres Vivianne , Rioseco Maria L. , Riquelme Raúl , Barría Sebastián , Alvarez Raymond , Pinos Yazmín , Krammer Florian , Calvo Mario , Barria Maria I. ,   COVID-19 South Chile Group
Published: February 2022

The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.
Children and Adults With Mild COVID-19: Dynamics of the Memory T Cell Response up to 10 Months
Authors: Kaaijk Patricia , Olivo Pimentel Verónica , Emmelot Maarten E. , Poelen Martien C. M. , Cevirgel Alper , Schepp Rutger M. , den Hartog Gerco , Reukers Daphne F.M. , Beckers Lisa , van Beek Josine , van Els Cécile A. C. M. , Meijer Adam , Rots Nynke Y. , de Wit Jelle
Published: February 2022

Background

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory.

Methods

To determine whether a memory T cell response is being developed, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker analyses of peripheral blood samples from unvaccinated children and adults with mild-to-moderate COVID-19.

Results

Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-γ T cell responses in infected children (83%) and adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially several cases with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-γ T cell response correlated with S1-SARS-CoV-2-specific serum antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens. Frequencies of SARS-CoV-2-specific T cells were significantly reduced at 10 months after symptom onset, while S1-SARS-CoV-2-specific IgG concentrations were still detectable in 90% of all children and adults.

Conclusions

Our data indicate that an antigen-specific T cell and antibody response is developed after mild SARS-CoV-2 infection in children and adults. It remains to be elucidated to what extent this SARS-CoV-2-specific response can contribute to an effective recall response after reinfection.
Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis
Authors: Maity Shreyasi , Chakraborty Arijit , Mahata Sushil Kumar , Roy Syamal , Das Anjan Kumar , Sen Malini
Published: February 2022

Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.
Th17 CD4+ T-Cell as a Preferential Target for HIV Reservoirs
Authors: Renault Constance , Veyrenche Nicolas , Mennechet Franck , Bedin Anne-Sophie , Routy Jean-Pierre , Van de Perre Philippe , Reynes Jacques , Tuaillon Edouard
Published: February 2022

Among CD4+ T-cells, T helper 17 (Th17) cells play a sentinel role in the defense against bacterial/fungal pathogens at mucosal barriers. However, Th17 cells are also highly susceptible to HIV-1 infection and are rapidly depleted from gut mucosal sites, causing an imbalance of the Th17/Treg ratio and impairing cytokines production. Consequently, damage to the gut mucosal barrier leads to an enhanced microbial translocation and systemic inflammation, a hallmark of HIV-1 disease progression. Th17 cells’ expression of mucosal homing receptors (CCR6 and α4β7), as well as HIV receptors and co-receptors (CD4, α4β7, CCR5, and CXCR4), contributes to susceptibility to HIV infection. The up-regulation of numerous intracellular factors facilitating HIV production, alongside the downregulation of factors inhibiting HIV, helps to explain the frequency of HIV DNA within Th17 cells. Th17 cells harbor long-lived viral reservoirs in people living with HIV (PLWH) receiving antiretroviral therapy (ART). Moreover, cell longevity and the proliferation of a fraction of Th17 CD4 T cells allow HIV reservoirs to be maintained in ART patients.
Impact of Ocean Warming, Overfishing and Mercury on European Fisheries: A Risk Assessment and Policy Solution Framework
Authors: Issifu Ibrahim , Alava Juan José , Lam Vicky W. Y. , Sumaila U. Rashid
Published: February 2022

Previous studies have shown that multiple-environmental stressors are expected to have significant and geographically differential impacts on the health and abundance of marine species. In this paper, we analyze the combined impacts of ocean warming, overfishing and mercury pollution in European waters by projecting the impacts of climatic and non-climate drivers on marine species in European waters. Our findings suggest that the impacts vary widely depending on different species and their mean temperature tolerance (MTT). We find for instance, that more than 5 temperate benthopelagic species including, bobtail squids (Sepiida) frogfishes (Lophius) great Atlantic scallop (Pecten maximus) red mullet (Mullus barbatus barbatus) and common octopus (Octopus vulgaris) are affected (i.e., weakens their resilience to climate change) by the increase in sea surface temperature (SST) under RCP 8.5 in 2050 and 2100. Mercury contamination was estimated to increase in some species (e.g., ∼50% in swordfish), exceeding mercury consumption guideline thresholds (>1 mg/kg). This negative impact may limit the capacity of fisheries and marine ecosystem to respond to the current climate induced pollution sensitivity. An implication of our study is that the international community should strengthen a global ban on mercury emissions under the mandate of the Minamata Convention, comparable to the United Nations framework for persistent organic pollutant emission sources. Ongoing global efforts aimed at minimizing carbon footprint and mercury emissions need to be enhanced in concert with a reduction in fishing intensity to maintain effective conservation measures that promote increased resilience of fisheries to climate change and other stressors.
Sediment Resuspension as a Major Contributor to Sinking Particles in the Northwestern South China Sea: Evidence From Observations and Modeling
Authors: Ran Lihua , Ma Wentao , Wiesner Martin G. , Wang Yuntao , Chen Jianfang , Zhang Lanlan , Yang Zhi , Zhang Jingjing , Li Hongliang , Ren Jian , Xiang Rong , Fredj Erick
Published: February 2022

The lateral advection of sinking particles is a well-known phenomenon in the South China Sea (SCS) and has a significant impact on the estimation of the efficiency of the biological carbon pump. However, little is known about the sources and pathways of sinking particles. Here, we present benthic and freshwater diatom fluxes and relative abundances collected by a sediment trap deployed at a water depth of 1,000 m and more than 500 m above the seafloor in the northwestern SCS, indicating that laterally transported resuspended sediment accounts for a significant part of the particle flux to the deep sea. A Lagrangian particle tracking model (LPTM) revealed that the resuspended particles likely originated from the neighboring continental slope, approximately 12–145 km to the west of the study site. Sediment trap observations and the LPTM together indicated that the impact of resuspended sediment occurred mainly in the deep water, and especially strong sediment resuspension was related to summer monsoon-induced coastal upwelling. The results suggest that particle resuspension has an important impact on the biological pump as well as on paleoenvironmental reconstructions of the SCS.