bluuebunny/crossref_metadata_2025 huggingface dataset:
No Casual Relationship Between T2DM and the Risk of Infectious Diseases: A Two-Sample Mendelian Randomization Study
Authors: Wang Huachen , Guo Zheng , Zheng Yulu , Yu Chunyan , Hou Haifeng , Chen Bing
Published: September 2021

Background

In epidemiological studies, it has been proven that the occurrence of type 2 diabetes mellitus (T2DM) is related to an increased risk of infectious diseases. However, it is still unclear whether the relationship is casual.

Methods

We employed a two-sample Mendelian randomization (MR) to clarify the causal effect of T2DM on high-frequency infectious diseases: sepsis, skin and soft tissue infections (SSTIs), urinary tract infections (UTIs), pneumonia, and genito-urinary infection (GUI) in pregnancy. And then, we analyzed the genome-wide association study (GWAS) meta-analysis of European-descent individuals and conducted T2DM-related single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) that were associated with genome-wide significance (p < 5 × 10–8). MR estimates were obtained using the inverse variance-weighted (IVW), the MR-Egger regression, the simple mode (SM), weighted median, and weighted mode.

Results

The UK Biobank (UKB) cohort (n > 500,000) provided data for GWASs on infectious diseases. MR analysis showed little evidence of a causal relationship of T2DM with five mentioned infections’ (sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy) susceptibility [odds ratio (OR) = 0.99999, p = 0.916; OR = 0.99986, p = 0.233; OR = 0.99973, p = 0.224; OR = 0.99997, p = 0.686; OR, 1.00002, p = 0.766]. Sensitivity analysis showed similar results, indicating the robustness of causality. There were no heterogeneity and pleiotropic bias.

Conclusion

T2DM would not be causally associated with high-frequency infectious diseases (including sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy).
Mitochondrial Sequence Variation, Haplotype Diversity, and Relationships Among Dromedary Camel-Types
Authors: Alaqeely Randa , Alhajeri Bader H. , Almathen Faisal , Alhaddad Hasan
Published: September 2021

Dromedary camels are outstanding livestock that developed efficient abilities to tolerate desert conditions. Many dromedary camel-types (i.e., named populations) exist but lack defined specific breed standards, registries, and breeders’ governing organizations. The breed status of dromedary camel-types can partly be assessed by exploring mitochondrial DNA (mtDNA) variation. Accordingly, this study aimed to examine the breed status and the inter-population relationships of dromedary camel-types by analyzing sequence variation in the mtDNA control region and in three coding genes [cytochrome b, threonine, and proline tRNA, and part of the displacement loop (D-loop)] (867 bp region). Tail hair samples (n = 119) that represent six camel-types from Kuwait were collected, extracted, sequenced, and compared to other publicly available sequences (n = 853). Within the sequenced mitochondrial region, 48 polymorphic sites were identified that contributed to 82 unique haplotypes across 37 camel-types. Haplotype names and identities were updated to avoid previous discrepancies. When all sequences were combined (n = 972), a nucleotide diversity of 0.0026 and a haplotype diversity of 0.725 was observed across the dromedary-types. Two major haplogroups (A and B) were identified and the B1 haplotype was predominant and found in almost all dromedary-types whereas the A haplotypes were more abundant in African regions. Non-metric multidimensional scaling revealed an increased similarity among Arabian Peninsula “Mezayen” camel-types, despite their defining coat colors. The relationships among dromedary camel-types can partly be explained by mtDNA. Future work aimed at a deeper understanding of camel-type breed status should focus on a high number of nuclear markers.
Rapid CRISPR/Cas9 Editing of Genotype IX African Swine Fever Virus Circulating in Eastern and Central Africa
Authors: Abkallo Hussein M. , Svitek Nicholas , Oduor Bernard , Awino Elias , Henson Sonal P. , Oyola Samuel O. , Mwalimu Stephen , Assad-Garcia Nacrya , Fuchs Walter , Vashee Sanjay , Steinaa Lucilla
Published: September 2021

African swine fever virus (ASFV) is the etiological agent of a contagious and fatal disease of domestic pigs that has significant economic consequences for the global swine industry. Due to the lack of effective treatment and vaccines against African swine fever, there is an urgent need to leverage cutting-edge technologies and cost-effective approaches for generating and purifying recombinant virus to fast-track the development of live-attenuated ASFV vaccines. Here, we describe the use of the CRISPR/Cas9 gene editing and a cost-effective cloning system to produce recombinant ASFVs. Combining these approaches, we developed a recombinant virus lacking the non-essential gene A238L (5EL) in the highly virulent genotype IX ASFV (ASFV-Kenya-IX-1033) genome in less than 2 months as opposed to the standard homologous recombination with conventional purification techniques which takes up to 6 months on average. Our approach could therefore be a method of choice for less resourced laboratories in developing nations.
Soluble B7-CD28 Family Inhibitory Immune Checkpoint Proteins and Anti-Cancer Immunotherapy
Authors: Khan Muhammad , Arooj Sumbal , Wang Hua
Published: September 2021

Co-inhibitory B7-CD28 family member proteins negatively regulate T cell responses and are extensively involved in tumor immune evasion. Blockade of classical CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein-1) checkpoint pathways have become the cornerstone of anti-cancer immunotherapy. New inhibitory checkpoint proteins such as B7-H3, B7-H4, and BTLA (B and T lymphocyte attenuator) are being discovered and investigated for their potential in anti-cancer immunotherapy. In addition, soluble forms of these molecules also exist in sera of healthy individuals and elevated levels are found in chronic infections, autoimmune diseases, and cancers. Soluble forms are generated by proteolytic shedding or alternative splicing. Elevated circulating levels of these inhibitory soluble checkpoint molecules in cancer have been correlated with advance stage, metastatic status, and prognosis which underscore their broader involvement in immune regulation. In addition to their potential as biomarker, understanding their mechanism of production, biological activity, and pathological interactions may also pave the way for their clinical use as a therapeutic target. Here we review these aspects of soluble checkpoint molecules and elucidate on their potential for anti-cancer immunotherapy.
Influenza Viruses: Innate Immunity and mRNA Vaccines
Authors: Lee SangJoon , Ryu Jin-Hyeob
Published: September 2021

The innate immune system represents the first line of defense against influenza viruses, which cause severe inflammation of the respiratory tract and are responsible for more than 650,000 deaths annually worldwide. mRNA vaccines are promising alternatives to traditional vaccine approaches due to their safe dosing, low-cost manufacturing, rapid development capability, and high efficacy. In this review, we provide our current understanding of the innate immune response that uses pattern recognition receptors to detect and respond to mRNA vaccination. We also provide an overview of mRNA vaccines, and discuss the future directions and challenges in advancing this promising therapeutic approach.
Eubacterium rectale Attenuates HSV-1 Induced Systemic Inflammation in Mice by Inhibiting CD83
Authors: Islam S. M. Shamsul , Ryu Hye-Myung , Sayeed Hasan M. , Byun Hae-Ok , Jung Ju-Yang , Kim Hyoun-Ah , Suh Chang-Hee , Sohn Seonghyang
Published: September 2021

The purpose of this study was to determine whether administration of the microorganism Eubacterium rectale (E. rectale) could regulate dendritic cell (DC) activation and systemic inflammation in herpes simplex virus type 1-induced Behçet’s disease (BD). E. rectale, butyrate-producing bacteria, was administered to BD mice. Peripheral blood leukocytes (PBL) and lymph node cells were isolated and analyzed by flow cytometry. 16S rRNA metagenomic analysis was performed in the feces of mice to determine the differences in the composition of the microbial population between normal and BD mice. Serum cytokine levels were measured by enzyme-linked immunosorbent assay. The frequency of DC activation marker CD83 positive cells was significantly increased in PBL of BD mice. Frequencies of CD83+ cells were also significantly increased in patients with active BD. 16S rRNA metagenomic analysis revealed different gut microbiota composition between normal and BD mice. The administration of E. rectale to BD mice reduced the frequency of CD83+ cells and significantly increased the frequency of NK1.1+ cells with the improvement of symptoms. The co-administration of colchicine and E. rectale also significantly reduced the frequency of CD83+ cells. Differences in gut microbiota were observed between normal mice and BD mice, and the administration of E. rectale downregulated the frequency of CD83, which was associated with BD deterioration. These data indicate that E. rectale could be a new therapeutic adjuvant for BD management.
Systemic Inflammation Associates With a Myeloid Inflamed Tumor Microenvironment in Primary Resected Colon Cancer—May Cold Tumors Simply Be Too Hot?
Authors: Køstner Anne Helene , Nielsen Patricia Switten , Georgsen Jeanette Baehr , Parner Erik Thorlund , Nielsen Mette Bak , Kersten Christian , Steiniche Torben
Published: September 2021

Systemic inflammation measured by the acute-phase protein CRP associates with poor outcome across cancer types. In contrast, local tumor-associated inflammation, primarily evaluated by T-lymphocytes, correlates with favorable prognosis. Yet, little is known whether these two responses are related or opposing processes and why elevated CRP in relation to cancer is detrimental for clinical outcome. As proof of concept, we developed a platform combining multiplexed IHC and digital imaging, enabling a virtual readout of both lymphoid and myeloid immune markers and their spatial patterns in the primary tumors of resected stage II and III colon cancer (CC) patients with and without accompanying systemic inflammation. Twenty-one patients with elevated CRP (>30 mg/l) and 15 patients with low CRP (<10 mg/l) were included in the analyses. Whole slides from the primary tumors were stained for markers of adaptive (CD8+, CD4+, foxp3 regulatory T cells, CD20+ B cells) and innate (CD68+ macrophages, CD66b+ neutrophils) immunity and the immune checkpoint molecule PD-L1. Associations between individual immune markers, preoperative CRP values, mismatch repair status (MMR), and risk of recurrence or death were assessed. Unsupervised hierarchical clustering was used to explore whether distinct immune phenotypes were present. Tumors from systemically inflamed patients (CRP >30 mg/l) displayed significantly more myeloid features in terms of higher densities of CD66b+neutrophils (p = 0.001) and CD68+macrophages (p = 0.04) and less lymphoid features (lower CD8 T cell, p = 0.03, and foxp3 regulatory T cell densities, p = 0.03) regardless of MMR status. Additionally, systemically inflamed patients harbored lower mean distances between neutrophils and tumor cells within the TME. Intriguingly, microsatellite instable (MSI) tumor status correlated with systemic inflammation. However, using a combinatorial approach, we found that regardless of an adaptive composite score (compounded CD4+ and CD8+ T cells), a high innate score (CD66b+ neutrophils and CD68+ macrophages) associated significantly with elevated CRP. In conclusion, tumor-associated systemic inflammation correlated with a myeloid-dominated TME in a small cohort of resectable CC patients. Our data highlight the importance of a comprehensive immune classification of tumors including players of innate immunity and support a role for CRP as an informative biomarker of the immune response taking place at the tumor site.
Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death
Authors: Yang Lingtao , Chen Wei , Li Li , Xiao Yueyue , Fan Shilin , Zhang Quan , Xia Tian , Li Mengjie , Hong Yazhen , Zhao Tongjin , Li Qiyuan , Liu Wen-Hsien , Xiao Nengming
Published: September 2021

Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4+ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4+ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4+ helper T cells.
Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain
Authors: Goddery Emma N. , Fain Cori E. , Lipovsky Chloe G. , Ayasoufi Katayoun , Yokanovich Lila T. , Malo Courtney S. , Khadka Roman H. , Tritz Zachariah P. , Jin Fang , Hansen Michael J. , Johnson Aaron J.
Published: September 2021

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigenviamajor histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kband H-2Dbupon infection. Conditional ablation of H-2Kband H-2Dbfrom CNS-myeloid cells allowed us to determine that antigen presentationviaH-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler’s murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.
Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies
Authors: Grammatikos Alexandros , Donati Matthew , Johnston Sarah L. , Gompels Mark M.
Published: September 2021

In the era of COVID-19, understanding how our immune system responds to viral infections is more pertinent than ever. Immunodeficiencies with very low or absent B cells offer a valuable model to study the role of humoral immunity against these types of infection. This review looks at the available evidence on viral infections in patients with B cell alymphocytosis, in particular those with X-linked agammaglobulinemia (XLA), Good’s syndrome, post monoclonal-antibody therapy and certain patients with Common Variable Immune Deficiency (CVID). Viral infections are not as infrequent as previously thought in these conditions and individuals with very low circulating B cells seem to be predisposed to an adverse outcome. Particularly in the case of SARS-CoV2 infection, mounting evidence suggests that peripheral B cell alymphocytosis is linked to a poor prognosis.
PD-1 Blockade on Tumor Microenvironment-Resident ILC2s Promotes TNF-α Production and Restricts Progression of Metastatic Melanoma
Authors: Howard Emily , Hurrell Benjamin P. , Helou Doumet Georges , Quach Christine , Painter Jacob D. , Shafiei-Jahani Pedram , Fung Marshall , Gill Parkash S. , Soroosh Pejman , Sharpe Arlene H. , Akbari Omid
Published: September 2021

While pulmonary ILC2s represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigate the specific effect of PD-1 inhibition on ILC2s during pulmonary B16 melanoma cancer metastasis. We demonstrate that PD-1 inhibition on ILC2s suppresses B16 tumor growth. Further, PD-1 inhibition upregulates pulmonary ILC2-derived TNF-α production, a cytotoxic cytokine that directly induces cell death in B16 cells, independent of adaptive immunity. Together, these results highlight the importance of ILC2s and their anti-tumor role in pulmonary B16 cancer progression during PD-1 inhibitory immunotherapy.
Janus Kinase Inhibitors and Cell Therapy
Authors: Assal Amer , Mapara Markus Y.
Published: September 2021

Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.
Brugia malayi Glycoproteins Detected by the Filariasis Test Strip Antibody AD12.1
Authors: Hertz Marla I. , Hamlin Irene , Rush Amy , Budge Philip J.
Published: September 2021

Background

Rapid and accurate prevalence mapping of lymphatic filariasis (LF) is necessary to eliminate this disfiguring and disabling neglected tropical disease. Unfortunately, rapid tests such as the filariasis test strip (FTS) forWuchereria bancrofti, the causative agent of LF in Africa, can cross-react with antigens circulating in some persons infected by the African eye worm,Loa loa, rendering the test unreliable in eleven co-endemic nations. The intended target of the FTS is a heavily glycosylatedW. bancrofticirculating filarial antigen (Wb-CFA). Previously, we determined that the FTS monoclonal antibody, AD12.1, which detects a carbohydrate epitope on Wb-CFA, also detects multipleL. loaproteins in cross-reactive sera from persons with loiasis. Since the carbohydrate epitope recognized by AD12.1 is present on glycoproteins of other parasitic nematodes, includingBrugiaspecies, it is unclear why reactive glycoproteins are not detected in infections with other filarial parasites.

Methods

To gain a better understanding of the proteins recognized by the FTS diagnostic antibody, we used proteomics and lectin array technology to characterize filarial glycoproteins that are bound by the AD12.1 antibody usingBrugia malayias a model.

Results

Distinct but overlapping sets of AD12 glycoproteins were identified from somatic and excretory/secretory worm products. One of the identified proteins, Bm18019 was confirmed as a secreted AD12-reactive glycoprotein by in-gel proteomics and immunoassays. Based on lectin binding patterns,BrugiaAD12-reactive glycoproteins express glycans including core fucose, galactose, N-acetylglucosamine and galactose(β1-3)N-acetylgalactosamine in addition to the epitope recognized by AD12.1. None of the lectins that boundB. malayiAD12 glycoproteins had affinity for the Wb-CFA, highlighting a key difference between it and other AD12 glycoproteins.

Conclusions

B. malayisomatic and excretory/secretory proteins are similar toL. loaantigens found in FTS-positive human sera, bolstering the hypothesis that circulatingL. loaAD12 antigens result from worm tissue damage or death. The difference in glycan and protein composition between the Wb-CFA and other AD12 glycoproteins can be used to differentiate LF from cross-reactive loiasis.
Diversity, Composition, and Activities of Nano- and Pico-Eukaryotes in the Northern South China Sea With Influences of Kuroshio Intrusion
Authors: Wang Feipeng , Huang Bangqin , Xie Yuyuan , Cai Shujie , Wang Xiuxiu , Mu Jingli
Published: September 2021

Nano- and pico-eukaryotes play important roles in the diversity and functions of marine ecosystems. Warm, saline, and nutrient-depleted water that originates in the Kuroshio Current seasonally intrudes into the northern South China Sea (NSCS) from autumn to spring. To clarify the mechanisms in shaping the community structure of nano- and pico-eukaryotes as well as impacts of the Kuroshio intrusion on the NSCS ecosystem, genomic DNA and RNA were co-extracted from samples collected at two depths from nine stations, and then the V9 region of 18S rDNA and rRNA was sequenced with high-throughput sequencing. Our results showed that Dinophyceae was the most diverse and abundant nanoeukaryotic group during the study period revealed by both DNA and RNA surveys. In contrast, the relative read abundance of MAST, Pelagophyceae, and Dinophyceae in the size fraction of picoeukaryotes might be largely underestimated by the DNA survey. The RNA survey was the more reliable method to investigate the eukaryotic community structure. Environmental filtering played an important role in shaping the community structure, and the sampling depth became the governing factor of the beta diversity under the environmental setting of stratification during the study period. The spatial variations in the diversity of nanoeukaryotes were subject to the dispersal limitation under the size rule. The effects of the Kuroshio intrusion on the nanoeukaryotic community structure might also be explained by the dispersal limitation. Overall, neutral processes are critical in shaping the community structure of nanoeukaryotes. The relative metabolic activities of nanoeukaryotes were relatively stable in accordance with the high similarity of community structure between sampling sites. The responses of the relative metabolic activities of picoeukaryotes to environmental factors displayed two distinct patterns: positive correlations with salinity and nutrients and negative with temperature for Dinophyceae, MAST, and Pelagophyceae, while reversed patterns for Mamiellophyceae and Radiolaria. Our findings improve the understanding of the nano- and pico-eukaryotic communities in the NSCS and the mechanisms of their assembly.
Contrasting Proteomic Responses of Adult and Larval Coral to High Temperatures
Authors: McRae Crystal J. , Mayfield Anderson B. , Huang Wen-Bin , Côté Isabelle M. , Fan Tung-Yung
Published: September 2021

Climate change-induced increases in seawater temperature continue to impact coral reef ecosystems globally. There is a consequent need to characterize the responses of corals to thermal stress to understand the molecular processes underpinning these responses and identify hallmarks of resilience. Here we used an iTRAQ approach to compare the proteomes of adult corals (Pocillopora acuta) that had been thermally conditioned at a control (26°C) or elevated temperature (29.5°C) for three reproductive cycles, as well as the larvae released by these corals. We found that larvae responded more to high-temperature exposure at the protein level than their parents and that different proteins were affected between life stages; a single protein was up-regulated at high temperatures in both adults and their offspring, and its identity is currently unknown. Similarly, different cellular pathways were affected by high-temperature exposure between the coral hosts and their dinoflagellate endosymbionts; proteins involved in translation and protein trafficking were most likely to be affected by high-temperature exposure in the former, with photosynthesis being the most thermo-sensitive process in the latter. Collectively, these findings highlight the importance of considering both life stage and the composition of the coral holobiont when using molecular-scale data to model cellular processes associated with responses to future ocean warming.
2-Arachidonoylglycerol as an Endogenous Cue Negatively Regulates Attachment of the Mussel Perna viridis
Authors: Dai Qi , Wang Zhi-Xuan , Sheng Yan-Qing , Wu Zhi-Wen , Qiu Yan , Su Pei , Ke Cai-Huan , Feng Dan-Qing
Published: September 2021

Endocannabinoids play important roles in the functioning of various physiological systems in humans and non-mammalian animals, including invertebrates. However, information concerning their roles in physiological functions in members of the phylum Mollusca is scarce. Here the hypothesis that the endocannabinoids are involved in mediating settlement of marine invertebrates was tested. Two endocannabinoids [N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG)], and two endocannabinoid-like lipids [N-Oleoylethanolamide (OEA) and N-Palmitoylethanolamide (PEA)] were detected in the green musselPerna viridis. In particular, 2-AG was present at significantly higher levels in unattachedP. viridiscompared with attached mussels. Thein vivolevel of 2-AG was inversely correlated with the attachment activity ofP. viridis. Furthermore, exposure to synthetic 2-AG inhibited attachment ofP. viridisin a reversible manner. Transcriptomic analysis suggested that up-regulation of 2-AG synthase (Phospholipase C-β, PLC-β) and down-regulation of its degrading enzyme (Monoacylglycerol lipase, MAGL) resulted in higher levels of 2-AG in unattached mussels. A putative mechanism for the negative regulation of mussel attachment by 2-AG is proposed that involves a Ca2+- Nitric oxide (NO)- cyclic guanosine monophosphate (cGMP) pathway. This study broadens our understanding of the evolution and roles of the endocannabinoid system in animals, and reveals an endogenous regulatory cue for mussel attachment.
Fleshy Red Algae Mats Influence Their Environment in the Mediterranean Sea
Authors: Schmidt Neele , El-Khaled Yusuf C. , Roßbach Felix I. , Wild Christian
Published: September 2021

In the Mediterranean Sea, the fleshy red alga Phyllophora crispa forms dense mats of up to 15 cm thickness, mainly located on rocky substrates in water depths below 20 m. Because of the observed density of these mats and some first observations, we hypothesize that P. crispa is a yet undescribed ecosystem engineer that provides a multitude of ecological niches for associated organisms along small-scale environmental gradients. Therefore, we conducted an in-situ pilot study in the Western Mediterranean Sea to assess potential influence of the algae mats on the key environmental factors water movement, temperature and light intensity. We comparatively and simultaneously measured in P. crispa mats, in neighboring Posidonia oceanica seagrass meadows, on neighboring bare rocky substrates without algae mats, and in the directly overlying water column. We used several underwater logging sensors and gypsum clod cards. Findings revealed that P. crispa significantly reduced water movement by 41% compared to the overlying water column, whereas water movement was not affected by P. oceanica meadows and bare rocky substrates. Surprisingly, P. crispa increased the water temperature by 0.3°C relative to the water column, while the water temperature in P. oceanica and on bare rocky substrates was reduced by 0.5°C. Light intensity inside the red algae mats was reduced significantly by 69% compared to the water column. This was similar to measured light reduction of 77% by P. oceanica. These findings highlight the strong influence of the dense red algae mats on some key environmental factors. Their influence is obviously similar or even higher than for the well-known seagrass ecosystem engineer. This may be a factor that facilitates associated biodiversity similarly as described for P. oceanica.
Missing the Reef for the Corals: Unexpected Trends Between Coral Reef Condition and the Environment at the Ecosystem Scale
Authors: Hochberg Eric J. , Gierach Michelle M.
Published: September 2021

It is incontrovertible that many coral reefs are in various stages of decline and may be unable to withstand the effects of global climate change, jeopardizing vital ecosystem goods and services to hundreds of millions of people around the world. An estimated 50% of the world's corals have already been lost, and those remaining may be lost by 2030 under the “business as usual” CO2 emissions scenario. However, the foundation of these predictions is a surprisingly sparse dataset, wherein ~0.01–0.1% of the world's reef area has been quantitatively surveyed. Further, the available data comprise observations at the 1–10 m scale, which are not evenly spaced across reefs, but often clustered in areas representing focused survey effort. This impedes modeling and predicting the impact of a changing environment at the ecosystem scale. Here we highlight deficiencies in our current understanding of the relationship between coral reefs and their environments. Specifically, we conduct a meta-analysis using estimates of coral cover from a variety of local surveys, quantitatively relating reef condition to a suite of biogeophysical forcing parameters. We find that readily available public data for coral cover exhibit unexpected trends (e.g., a positive correlation between coral cover and multi-year cumulative thermal stress), contrary to prevailing scientific expectations. We illustrate a significant gap in our current understanding, and thereby prediction, of coral reefs at the ecosystem scale that can only be remedied with uniform, high-density data across vast coral reef regions, such as that from remote sensing.
Gradient Nonlocal Enhanced Microprestress-Solidification Theory and Its Finite Element Implementation
Authors: Tong Teng , Du Changqing , Liu Xiaofan , Yuan Siqi , Liu Zhao
Published: September 2021

Time-dependent responses of cracked concrete structures are complex, due to the intertwined effects between creep, shrinkage, and cracking. There still lacks an effective numerical model to accurately predict their nonlinear long-term deflections. To this end, a computational framework is constructed, of which the aforementioned intertwined effects are properly treated. The model inherits merits of gradient-enhanced damage (GED) model and microprestress-solidification (MPS) theory. By incorporating higher order deformation gradient, the proposed GED-MPS model circumvents damage localization and mesh-sensitive problems encountered in classical continuum damage theory. Moreover, the model reflects creep and shrinkage of concrete with respect to underlying moisture transport and heat transfer. Residing on the Kelvin chain model, rate-type creep formulation works fully compatible with the gradient nonlocal damage model. 1-D illustration of the model reveals that the model could regularize mesh-sensitivity of nonlinear concrete creep affected by cracking. Furthermore, the model depicts long-term deflections and cracking evolutions of simply-supported reinforced concrete beams in an agreed manner. It is noteworthy that the gradient nonlocal enhanced microprestress-solidification theory is implemented in the general finite element software Abaqus/Standard with the implicit solver, which renders the model suitable for large-scale creep-sensitive structures.
Surface Reactivity of Carbonaceous Nanoparticles: The Importance of Surface Pocket
Authors: Wang Hongyu , Chang Xiaoya , Chen Dongping
Published: September 2021

The surface reactivity of carbonaceous nanoparticles is revealed from the barrier height and reaction enthalpy of hydrogen abstraction reaction by H radicals computed at the M06-2X/6–311g(d,p)//B3LYP/6-311G(d,p) level of theory. Small polycyclic aromatic hydrocarbon (PAH) clusters are selected as the model system of carbonaceous nanoparticles. The PAHs considered are naphthalene, pyrene, coronene, ovalene and circumcoronene. Cluster sizes range from dimer to tetramer with a parallel or crossed configuration. All results show similar values as that of monomers, but naphthalene dimers with a crossed configuration yield a lower barrier height and reaction enthalpy by ∼2 kcal/mol. A minor size dependence is noticed in the series of naphthalene clusters where a larger cluster exhibits a smaller barrier height. Larger homogeneous PAH clusters in a size range of 1.1–1.9 nm are later generated to mimic nascent soot surface. It is found that the barrier height decreases with the increase in particle size, and the averaged values are ∼2 kcal/mol lower than that of monomers. More importantly, a larger particle shows a wider spread in barrier heights, and low barrier heights are seen in the surface shallow regions (e.g., surface pockets). The lowest barrier height of ∼8.5 kcal/mol is observed at a C-H site locating in a surface pocket. A set of model systems are built to reveal the underlying mechanism of reduction in barrier height. It is shown that the reduction is caused by local interactions between the neighboring atoms and the local curvature. Further analysis on the average localized ionization potential shows that larger particles have higher reactivity, further supporting our findings from the barrier height of hydrogen abstraction reactions. Therefore, it is concluded that the surface reactivity depends on the particle size and the most reactive sites always locate at the surface pockets.
PRAgmatic Clinical Trial Design of Integrative MediCinE (PRACTICE): A Focus Group Series and Systematic Review on Trials of Diabetes and Kidney Disease
Authors: Chan Kam Wa , Lee Pak Wing , Leung Crystal Pui-sha , Law Yee Kwan , Gao Lucy , Chan Gary Chi-wang , Yiu Wai Han , Lam Tai Pong , Tang Sydney Chi-wai
Published: September 2021

Background: Pragmatic trials inform clinical decision with better generalizability and can bridge different streams of medicine. This study collated the expectations regarding pragmatic trial design of integrative medicine (IM) for diabetes and kidney diseases among patients and physicians. Dissonance between users' perspective and existing pragmatic trial design was identified. The association between risk of bias and pragmatism of study design was assessed.

Method: A 10-group semi-structured focus group interview series [21 patients, 14 conventional medicine (ConM) and 15 Chinese medicine (CM) physicians] were purposively sampled from private and public clinics in Hong Kong. Perspectives were qualitatively analyzed by constant comparative method. A systematic search of four databases was performed to identify existing IM pragmatic clinical trials in diabetes or kidney disease. Primary outcomes were the pragmatism, risk of bias, and rationale of the study design. Risk of bias and pragmatism were assessed based on Cochrane risk-of-bias tool and PRECIS-2, respectively. The correlation between risk of bias and pragmatism was assessed by regression models with sensitivity analyses.

Results: The subtheme on the motivation to seek IM service was analyzed, covering the perceived limitation of ConM effect, perceived benefits of IM service, and assessment of IM effectiveness. Patients expected IM service to retard disease progression, stabilize concomitant drug dosage, and reduce potential side effects associated with ConM. In the systematic review, 25 studies from six countries were included covering CM, Korean medicine, Ayurvedic medicine, and western herbal medicine. Existing study designs did not include a detailed assessment of concomitant drug change and adverse events. Majority of studies either recruited a non-representative proportion of patients as traditional, complementary, and integrative medicine (TCIM) diagnosis was used as inclusion criteria, or not reflecting the real-world practice of TCIM by completely dropping TCIM diagnosis in the trial design. Consultation follow-up frequency is the least pragmatic domain. Increase in pragmatism did not associate with a higher risk of bias.

Conclusion: Existing IM pragmatic trial design does not match the patients' expectation in the analysis of incident concomitant drug change and adverse events. A two-layer design incorporating TCIM diagnosis as a stratification factor maximizes the generalizability of evidence and real-world translation of both ConM and TCIM.
Depression and Endothelial Dysfunction in Psoriatic Arthritis: Is There Any Possible Relationship?
Authors: De Lorenzis Enrico , Di Giorgio Angela , Natalello Gerlando , Nesci Antonio , Tanti Giacomo , Rubortone Pietro , Lucchetti Donatella , Magurano Maria Rosaria , Di Mario Clara , Tolusso Barbara , Peluso Giusy , Santoliquido Angelo , Gremese Elisa
Published: September 2021

Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA.

Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed.

Results: In PsA patients (age 50.7 ± 10.2 years, male 42%, disease duration 5.9 ± 3.3 years, Disease Activity in PSoriatic Arthritis (DAPSA) score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS (ρ = −0.339, p = 0.016), age (ρ = −0.507, p = 0.001), aFRS (rs = −0.453, p < 0.001), duration of PsA (ρ = −0.507, p = 0.001), intensity of pain (ρ = −0.507, p = 0.001), and DAPSA (ρ = −0.507, p = 0.001). No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity (β = −0.271, p = 0.008), with depressive symptoms contributing directly to 6.4% of the variance.

Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients.
The Risk Factors for Weaning Failure of Mechanically Ventilated Patients With COVID-19: A Retrospective Study in National Medical Team Work
Authors: Zhao Hua , Su Longxiang , Ding Xin , Chen Huan , Zhang Hongmin , Wang Jinglan , Long Yun , Zhou Xiang , Zhang Shuyang
Published: September 2021

Purpose: This study aimed to describe the clinical and laboratory characteristics and the parameters of the respiratory mechanics of mechanically ventilated patients with confirmed COVID-19 pneumonia and to clarify the risk or protective factors for weaning failure.

Methods: Patients diagnosed with COVID-19 pneumonia were selected from the special intensive care unit (ICU) of the Sino-French New City Branch of Tong Ji Hospital, Wuhan, and treated by the National Medical Team Work. They were divided into successful weaning (SW) group (N = 15) and unsuccessful weaning (USW) group (N = 18) according to the prognosis. Information of these patients was analyzed.

Results: There were 33 patients included in this study. Patients in the USW group were associated with a poor outcome; the 28-day mortality rate was higher than in the SW group (86.7 vs. 16.7% p < 0.001). By comparison, we found that the initial plateau pressure (Pplat) and driving pressure (DP) of the USW group were higher and that compliance was lower than that of the SW group, but there was no difference between positive end-expiratory pressure (PEEP), partial pressure of carbon dioxide (PCO2), and the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio). Comparing the worst respiratory mechanics parameters of the two groups, the results of the Pplat, DP, compliance, and PEEP were the same as the initial data. The PCO2 of the USW group was higher, while the P/F ratio was lower. A logistic regression analysis suggested that higher Pplat might be an independent risk factor and that higher compliance and lower DP might be protective factors for weaning failure of invasive mechanically ventilated patients with COVID-19 pneumonia.

Conclusions: Patients with USW were associated with a poor outcome, higher Pplat might be a risk factor, and a higher compliance and a lower DP might be protective factors for the weaning failure of ventilated COVID-19 patients. Mechanical ventilation settings will affect the patient's prognosis.
Pathophysiology of COVID-19: Everywhere You Look You Will See ACE2!
Authors: Cousin Vladimir L. , Giraud Raphael , Bendjelid Karim
Published: September 2021

Angiotensin converting enzyme 2 (ACE2) seems to be a central actor in the pathophysiology of SARS-Cov-2 infection. First, it acts as the receptor for the virus and permits its attachment to cells expressing ACE2. Second, the relative deficiency of ACE2 during infection could be linked to several clinical features encountered during the disease, like ARDS and coagulation abnormalities. This study explores the strong link between ACE2 and the majority of risk factors for the severe evolution of COVID-19. It seems that all these risks factors are linked to an increased level of ACE2 and/or imbalance in ACE/ACE2.
Beyond the Visual Acuity: Assessing the Visual Function in mCNV Patients After Anti-VEGF Treatment
Authors: Li Songshan , Sun Limei , Zhao Xiujuan , Zhang Zhaotian , Luo Xiaoling , Ding Xiaoyan
Published: September 2021

Purpose: To investigate visual function and vision-related quality of life (VR-QoL) changes in patients with myopic choroidal neovascularization (mCNV) after ranibizumab treatment.

Methods: Quantitatively evaluate the objective tests of visual function (visual acuity, microperimetry, and metamorphopsia by m-Charts) before and after 3+prn (pro re neta) ranibizumab treatment for 1 year. The National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25) was performed to evaluate the VR-QoL.

Results: A total of 57 eyes of 57 patients were included in this study. The median average metamorphopsia score was 0.65 before treatment and improved to 0.45 after treatment (p = 0.0003). There was also a significant difference in the average threshold, macular integrity, and proportion of patients with stable fixation by the microperimetry (p < 0.000, p < 0.0001, and p = 0.03, respectively). After treatment, the VR-QoL composite, general vision subscale, and vision-related mental health subscale score were increased with borderline or statistical significance (p = 0.088, p = 0.0038, and p = 0.012, respectively). Subgroup analysis demonstrated parallel improvement of the VR-QoL score, metamorphopsia, average macular threshold, and fixation stability in patients with or without visual acuity increase. By multiple linear regression analysis, the VFQ-25 score after anti-VEGF treatment was only associated with the baseline VFQ-25 score and macular integrity. Improvements in the VFQ-25 score were only associated with changes in the metamorphopsia score.

Conclusions: Integral lifting in several aspects of visual function was observed in mCNV after ranibizumab treatment. Macular integrity and metamorphopsia, but not visual acuity, were associated with VR-QoL.
Safety and Efficacy of Roxadustat for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis
Authors: Liu Chao , Fu Zhangning , Jiang Jiawei , Chi Kun , Geng Xiaodong , Mao Zhi , Song Chengcheng , Sun Guannan , Hong Quan , Cai Guangyan , Chen Xiangmei , Sun Xuefeng
Published: September 2021

Background: Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial.

Methods: The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis.

Results: Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, P = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, P = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat.

Conclusion: Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.