bluuebunny/crossref_metadata_2025 huggingface dataset:
Green Supply Chain Coordination During the COVID-19 Pandemic Based on Consignment Contract
Authors: Wang Yi , Reivan Ortiz Geovanny Genaro , Dextre-Martinez William , Zhang Liandi
Published: June 2022

COVID-19 has further strengthened consumers’ online consumption habits and brought a new boom in which enterprises can use online transactions and green products to avoid risk and gain profits in the pandemic. A green supply chain model is established containing one e-commerce platform and one manufacturer. The Nash bargaining contract and Rubinstein bargaining contract are applied to mitigate conflicts of profits in the model. From the coordination analysis, we show that both Nash and Rubinstein bargaining contracts can achieve coordination and mitigate conflict of profits through the adjustment of platform usage rates. According to each member’s bargaining power and patience, the optimal platform usage rate is determined, the supply chain profits of both sides are allocated, the green production’s research and development are promoted, and a win-win situation is realized. Specifically, in the Nash bargaining contract, the excess profit of each member depends on their bargaining power. The stronger the bargaining power, the more excess profits will go to the e-commerce platform, and the less excess profits will go to the manufacturer. In the Rubinstein bargaining contract, the excess profit of each member depends on the lowest profit bound and bargaining patience. The higher the manufacturer’s (or e-commerce platform’s) patience, the higher his profit. When the patience of both is high (or low), the e-commerce platform (or the manufacturer) plays a leading role and obtains more profits.
Modifying the SWAT Model to Simulate Eco-Hydrological Processes in an Arid Grassland Dominated Watershed
Authors: Jin Xin , Jin Yanxiang , Fu Di , Mao Xufeng
Published: June 2022

Grasslands are the main land cover type and one of the most important ecosystems in arid and alpine endorheic basins. The vegetation coverage of grasslands is spatially heterogeneous in arid and alpine areas and it may lead to variations in water allocation. The Soil and Water Assessment Tool (SWAT) is one of the most widely used semi-distributed catchment-scale eco-hydrological models. The leaf area index (LAI) is one of the vegetation coverage indexes and is incorporated in the SWAT model. However, in SWAT, the LAI accumulation is controlled by heat, and neglects other relevant factors such as precipitation and terrain. To address the drawbacks of the SWAT in simulating vegetation coverage and plant patterns, several studies have focused on improving LAI estimation. However, they still have been limited to arid and alpine grasslands with different vegetation coverages. In this study, we modified the SWAT model using remotely sensed LAI data with high temporal and spatial resolution. We used this to better simulate eco-hydrological processes in grassland basins with different vegetation coverages in the upper reaches of the Bayin River Basin. Results showed that for the original SWAT model, the simulated LAI was homogeneous within each land use/cover type, whereas the remotely sensed LAI was spatially heterogeneous and better captured the vegetation coverage of the entire basin. The proper estimation of the LAI was reflected in the improved simulation of the monthly streamflow and sediment yield at the basin outlet and the monthly ET. These findings indicate that the modified SWAT could better simulate hydrological processes in arid and alpine grasslands with different vegetation coverages.
Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review
Authors: Zhang Wei , Mao Jiangfeng , Wang Xi , Sun Bang , Zhao Zhiyuan , Zhang Xiaoxia , Nie Min , Wu Xueyan
Published: June 2022

Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases.

Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords “PPP2R3C” or “G5PR” and “46,XY disorders of sex development”.

Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient.

Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system abnormalities, muscle abnormalities, impaired nervous system, impaired hearing and vision, heart and kidney anomalies, and gastrointestinal dysfunction.
Argonaute1 and Gawky Are Required for the Development and Reproduction of Melon fly, Zeugodacus cucurbitae
Authors: Jamil Momana , Ahmad Shakil , Ran Yingqiao , Ma Siya , Cao Fengqin , Lin Xianwu , Yan Rihui
Published: June 2022

Argonaute family genes encode a highly conserved group of proteins that have been associated with RNA silencing in both animals and plants. This study investigates the importance of microRNA biogenesis key regulatorsArgonaute1(Ago1) andGawkygenes in the post-embryonic and ovarian development of the melon fly,Zeugodacus cucurbitae. The expression levels of these genes were mapped in all developmental stages and different adult tissues. Their roles in development were investigated using RNA interference (RNAi)viatwo different dsRNA delivery techniques. Embryo microinjection and oral feeding of third instar larvae successfully knocked down and greatly reduced the expression level of the target genes. Additionally, ex vivo essays revealed the stability of dsRNA in food was sufficient for gene silencing, although its integrity was affected in midgut. A wide range of phenotypes were observed on pupation, segmentation, pigmentation, and ovarian development. RNAi-mediated silencing ofGawkycaused high mortality and loss of body segmentation, whileAgo1knockdown affected ovarian development and pigmentation. Developmental abnormalities and ovarian malformations caused by silencing these genes suggest that these genes are crucial for viability and reproductive capacity ofZ. cucurbitae, and may be used as potential target genes in pest management.
Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder
Authors: Beaman Glenda M. , Lopes Filipa M. , Hofmann Aybike , Roesch Wolfgang , Promm Martin , Bijlsma Emilia K. , Patel Chirag , Akinci Aykut , Burgu Berk , Knijnenburg Jeroen , Ho Gladys , Aufschlaeger Christina , Dathe Sylvia , Voelckel Marie Antoinette , Cohen Monika , Yue Wyatt W. , Stuart Helen M. , Mckenzie Edward A. , Elvin Mark , Roberts Neil A. , Woolf Adrian S. , Newman William G.
Published: June 2022

Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology.
Features of Hemophagocytic Lymphohistiocytosis in Infants With Severe Combined Immunodeficiency: Our Experience From Chandigarh, North India
Authors: Vignesh Pandiarajan , Anjani Gummadi , Kumrah Rajni , Singh Ankita , Mondal Sanjib , Nameirakpam Johnson , Jindal Ankur , Suri Deepti , Sharma Madhubala , Kaur Gurjit , Sharma Sathish , Gupta Kirti , Sreedharanunni Sreejesh , Rawat Amit , Singh Surjit
Published: June 2022

Background

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive inflammation leading to high mortality. Aetiology of HLH can be primarily due to genetic causes or secondarily due to infections or rheumatological illness. However, rarely T-cell deficiencies like severe combined immunodeficiency (SCID) can develop HLH.

Objective

To describe clinical and laboratory features of SCID cases who developed HLH.

Methods

We collected clinical, laboratory, and molecular details of patients with SCID who developed HLH at our center at Chandigarh, North India.

Results

Of the 94 cases with SCID, 6 were noted to have developed HLH-like manifestations. Male-female ratio was 5:1. Median (inter-quartile range) age of onset of clinical symptoms was 4.25 months (2-5 months). Median (inter-quartile range) delay in diagnosis was 1 month (1-3.5 months). Family history of deaths was seen in 4 cases. Molecular defects inIL2RGwere seen in 5 out of 6 cases. Documented infections include disseminated bacillus calmette-guerin (BCG) infection (n=2), blood stream infections (n=3) withStaphylococcal aureus(n=1),Klebsiella pneumonia(n=1), andPseudomonas aeruginosa(n=1), pneumonia (influenza H1N1 strain, and K.pneumoniae(n=1).

Conclusion

Children with SCID can present with HLH-like manifestations secondary to fulminant infections. A high index of suspicion of SCID is needed in infants who present with HLH who have an associated infection or a suggestive family history. Occurrence of HLH-like manifestations in SCID suggests that T-lymphocytes may not have a significant role in immunopathogenesis of HLH.
Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma
Authors: Peng Shun-Li , Wang Rong , Zhou Yu-Ling , Wei Wei , Zhong Gui-Hua , Huang Xiao-Tao , Yang Shuai , Liu Qiao-Dan , Liu Zhi-Gang
Published: June 2022

Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients’ prognosis.
Fecal Microbiota Transplantation Reshapes the Physiological Function of the Intestine in Antibiotic-Treated Specific Pathogen-Free Birds
Authors: Li Peng , Gao Mingkun , Song Bochen , Liu Yan , Yan Shaojia , Lei Jiaqi , Zhao Yizhu , Li Guang , Mahmood Tahir , Lv Zengpeng , Hu Yongfei , Guo Yuming
Published: June 2022

The topic about the interactions between host and intestinal microbiota has already caught the attention of many scholars. However, there is still a lack of systematic reports on the relationship between the intestinal flora and intestinal physiology of birds. Thus, this study was designed to investigate it. Antibiotic-treated specific pathogen-free (SPF) bird were used to construct an intestinal bacteria-free bird (IBF) model, and then, the differences in intestinal absorption, barrier, immune, antioxidant and metabolic functions between IBF and bacteria-bearing birds were studied. To gain further insight, the whole intestinal flora of bacteria-bearing birds was transplanted into the intestines of IBF birds to study the remodeling effect of fecal microbiota transplantation (FMT) on the intestinal physiology of IBF birds. The results showed that compared with bacteria-bearing birds, IBF birds had a lighter body weight and weaker intestinal absorption, antioxidant, barrier, immune and metabolic functions. Interestingly, FMT contributed to reshaping the abovementioned physiological functions of the intestines of IBF birds. In conclusion, the intestinal flora plays an important role in regulating the physiological functions of the intestine.
Natural Exposure- and Vaccination-Induced Profiles of Ex Vivo Whole Blood Cytokine Responses to Coxiella burnetii
Authors: Raju Paul Susan , Scholzen Anja , Mukhtar Ghazel , Wilkinson Stephanie , Hobson Peter , Dzeng Richard K. , Evans Jennifer , Robson Jennifer , Cobbold Rowland , Graves Stephen , Poznansky Mark C. , Garritsen Anja , Sluder Ann E.
Published: June 2022

Q fever is a zoonotic disease caused by the highly infectious Gram-negative coccobacillus, Coxiella burnetii (C. burnetii). The Q fever vaccine Q-VAX® is characterised by high reactogenicity, requiring individuals to be pre-screened for prior exposure before vaccination. To date it remains unclear whether vaccine side effects in pre-exposed individuals are associated with pre-existing adaptive immune responses to C. burnetii or are also a function of innate responses to Q-VAX®. In the current study, we measured innate and adaptive cytokine responses to C. burnetii and compared these among individuals with different pre-exposure status. Three groups were included: n=98 Dutch blood bank donors with unknown exposure status, n=95 Dutch village inhabitants with known natural exposure status to C. burnetii during the Dutch Q fever outbreak of 2007-2010, and n=96 Australian students receiving Q-VAX® vaccination in 2021. Whole blood cytokine responses following ex vivo stimulation with heat-killed C. burnetii were assessed for IFNγ, IL-2, IL-6, IL-10, TNFα, IL-1β, IP-10, MIP-1α and IL-8. Serological data were collected for all three cohorts, as well as data on skin test and self-reported vaccine side effects and clinical symptoms during past infection. IFNγ, IP-10 and IL-2 responses were strongly elevated in individuals with prior C. burnetii antigen exposure, whether through infection or vaccination, while IL-1β, IL-6 and TNFα responses were slightly increased in naturally exposed individuals only. High dimensional analysis of the cytokine data identified four clusters of individuals with distinct cytokine response signatures. The cluster with the highest levels of adaptive cytokines and antibodies comprised solely individuals with prior exposure to C. burnetii, while another cluster was characterized by high innate cytokine production and an absence of C. burnetii-induced IP-10 production paired with high baseline IP-10 levels. Prior exposure status was partially associated with these signatures, but could not be clearly assigned to a single cytokine response signature. Overall, Q-VAX® vaccination and natural C. burnetii infection were associated with comparable cytokine response signatures, largely driven by adaptive cytokine responses. Neither individual innate and adaptive cytokine responses nor response signatures were associated retrospectively with clinical symptoms during infection or prospectively with side effects post-vaccination.
Research Advances for Virus-vectored Tuberculosis Vaccines and Latest Findings on Tuberculosis Vaccine Development
Authors: Hu Zhidong , Lu Shui-Hua , Lowrie Douglas B. , Fan Xiao-Yong
Published: June 2022

Tuberculosis (TB), caused by respiratory infection with Mycobacterium tuberculosis, remains a major global health threat. The only licensed TB vaccine, the one-hundred-year-old Bacille Calmette-Guérin has variable efficacy and often provides poor protection against adult pulmonary TB, the transmissible form of the disease. Thus, the lack of an optimal TB vaccine is one of the key barriers to TB control. Recently, the development of highly efficacious COVID-19 vaccines within one year accelerated the vaccine development process in human use, with the notable example of mRNA vaccines and adenovirus-vectored vaccines, and increased the public acceptance of the concept of the controlled human challenge model. In the TB vaccine field, recent progress also facilitated the deployment of an effective TB vaccine. In this review, we provide an update on the current virus-vectored TB vaccine pipeline and summarize the latest findings that might facilitate TB vaccine development. In detail, on the one hand, we provide a systematic literature review of the virus-vectored TB vaccines are in clinical trials, and other promising candidate vaccines at an earlier stage of development are being evaluated in preclinical animal models. These research sharply increase the likelihood of finding a more effective TB vaccine in the near future. On the other hand, we provide an update on the latest tools and concept that facilitating TB vaccine research development. We propose that a pre-requisite for successful development may be a better understanding of both the lung-resident memory T cell-mediated mucosal immunity and the trained immunity of phagocytic cells. Such knowledge could reveal novel targets and result in the innovative vaccine designs that may be needed for a quantum leap forward in vaccine efficacy. We also summarized the research on controlled human infection and ultra-low-dose aerosol infection murine models, which may provide more realistic assessments of vaccine utility at earlier stages. In addition, we believe that the success in the ongoing efforts to identify correlates of protection would be a game-changer for streamlining the triage of multiple next-generation TB vaccine candidates. Thus, with more advanced knowledge of TB vaccine research, we remain hopeful that a more effective TB vaccine will eventually be developed in the near future.
IGFBP7 and the Tumor Immune Landscape: A Novel Target for Immunotherapy in Bladder Cancer
Authors: Yi Xianyanling , Zheng Xiaonan , Xu Hang , Li Jin , Zhang Tianyi , Ge Peng , Liao Dazhou , Li Hong , Lyu Xiaoyan , Ai Jianzhong
Published: June 2022

Insulin-like growth factor binding protein-7 (IGFBP7) was recently reported to be a ligand of CD93, a potential target to normalize vasculature and attenuate immunotherapy. However, its role in the tumor microenvironment (TME) and immunotherapy response of bladder cancer (BLCA) remains unclear. We comprehensively evaluated the correlation between IGFBP7 and multiple immunological characteristics of BLCA across The Cancer Genome Atlas (TCGA) and two external cohorts. Importantly, the response of IGFBP7-grouped BLCA patients to immunotherapy was predicted and validated by five real-word immunotherapy cohorts. Finally, we developed an IGFBP7-based immune risk model validated by five independent cohorts. IGFBP7 modulated the TME across pan-caners. In BLCA, high expression of IGFBP7 was correlated with more aggressive clinical features. IGFBP7 was positively associated with immunomodulators and promoted tumor-infiltrating lymphocyte trafficking into the tumor microenvironment. However, T cells recognition and tumor cell killing were lower in the high-IGFBP7 group. In addition, high expression of IGFBP7 displayed lower enrichment scores for most pro-immunotherapy pathways. Clinical data from IMvigor210 and GSE176307 indicated that IGFBP7 negatively correlated with the BLCA immunotherapy response. The same trend was also observed in a renal cell carcinoma (RCC) cohort and two melanoma cohorts. Notably, urothelial and luminal differentiation were less frequently observed in the high-IGFBP7 group, while neuroendocrine differentiation was more frequently observed. Mechanistically, high IGFBP7 was associated with an enriched hypoxia pathway and higher expression of key genes in ERBB therapy and antiangiogenic therapy. Furthermore, our IGFBP7-based immune risk model was able to predict the prognosis and response to immunotherapy with good accuracy (5-year AUC = 0.734). Overall, IGFBP7 plays a critical role in the immunoregulation and TME of BLCA and may serve as a novel potential target for combination treatment with immunotherapy for BLCA.
Screening Novel Vaccine Candidates for Leishmania Donovani by Combining Differential Proteomics and Immunoinformatics Analysis
Authors: Zhang Jianhui , Li Jiao , Hu Kaifeng , Zhou Qi , Chen Xiaoxiao , He Jinlei , Yin Shuangshuang , Chi Yangjian , Liao Xuechun , Xiao Yuying , Qin Hanxiao , Zheng Zhiwan , Chen Jianping
Published: June 2022

Visceral leishmaniasis (VL), also known as kala-azar, is the most dangerous form of leishmaniasis. Currently no effective vaccine is available for clinical use. Since the pathogenicity of differentLeishmaniastrains is inconsistent, the differentially expressed proteins inLeishmaniastrains may play an important role as virulence factors in pathogenesis. Therefore, effective vaccine candidate targets may exist in the differentially expressed proteins. In this study, we used differential proteomics analysis to find the differentially expressed proteins in twoLeishmania donovanistrains, and combined with immunoinformatics analysis to find new vaccine candidates. The differentially expressed proteins fromL. DD8 (low virulent) andL. 9044 (virulent) strains were analyzed by LC-MS/MS, and preliminarily screened by antigenicity, allergenicity and homology evaluation. The binding peptides of MHC II, IFN-γ and MHC I from differentially expressed proteins were then predicted and calculated for the second screening. IFN-γ/IL-10 ratios and conserved domain prediction were performed to choose more desirable differentially expressed proteins. Finally, the 3D structures of three vaccine candidate proteins were produced and submitted for molecular dynamics simulation and molecular docking interaction with TLR4/MD2. The results showed that 396 differentially expressed proteins were identified by LC-MS/MS, and 155 differentially expressed proteins were selected through antigenicity, allergenicity and homology evaluation. Finally, 16 proteins whose percentages of MHC II, IFN-γ and MHC I binding peptides were greater than those of control groups (TSA, LmSTI1, LeIF, Leish-111f) were considered to be suitable vaccine candidates. Among the 16 candidates, amino acid permease, amastin-like protein and the hypothetical protein (XP_003865405.1) simultaneously had the large ratios of IFN-γ/IL-10 and high percentages of MHC II, IFN-γ and MHC I, which should be focused on. In conclusion, our comprehensive work provided a methodological basis to screen new vaccine candidates for a better intervention against VL and associated diseases.
Exosomally Targeting microRNA23a Ameliorates Microvascular Endothelial Barrier Dysfunction Following Rickettsial Infection
Authors: Zhou Changcheng , Bei Jiani , Qiu Yuan , Chang Qing , Nyong Emmanuel , Vasilakis Nikos , Yang Jun , Krishnan Balaji , Khanipov Kamil , Jin Yang , Fang Xiang , Gaitas Angelo , Gong Bin
Published: June 2022

Spotted fever group rickettsioses caused by Rickettsia (R) are devastating human infections, which mainly target microvascular endothelial cells (ECs) and can induce lethal EC barrier dysfunction in the brain and lungs. Our previous evidence reveals that exosomes (Exos) derived from rickettsial-infected ECs, namely R-ECExos, can induce disruption of the tight junctional (TJ) protein ZO-1 and barrier dysfunction of human normal recipient brain microvascular endothelial cells (BMECs). However, the underlying mechanism remains elusive. Given that we have observed that microRNA23a (miR23a), a negative regulator of endothelial ZO-1 mRNA, is selectively sorted into R-ECExos, the aim of the present study was to characterize the potential functional role of exosomal miR23a delivered by R-ECExos in normal recipient BMECs. We demonstrated that EC-derived Exos (ECExos) have the capacity to deliver oligonucleotide RNAs to normal recipient BMECs in an RNase-abundant environment. miR23a in ECExos impairs normal recipient BMEC barrier function, directly targeting TJ protein ZO-1 mRNAs. In separate studies using a traditional in vitro model and a novel single living-cell biomechanical assay, our group demonstrated that miR23a anti-sense oligonucleotide-enriched ECExos ameliorate R-ECExo-provoked recipient BMEC dysfunction in association with stabilization of ZO-1 in a dose-dependent manner. These results suggest that Exo-based therapy could potentially prove to be a promising strategy to improve vascular barrier function during bacterial infection and concomitant inflammation.
Baicalin Induces a Potent Innate Immune Response to Inhibit Respiratory Syncytial Virus Replication via Regulating Viral Non-Structural 1 and Matrix RNA
Authors: Qin Sheng , Huang Xianzhang , Qu Shaogang
Published: June 2022

Respiratory syncytial virus (RSV) infection is the most frequent cause of hospitalization in pediatric patients. Current systemic treatment and vaccines are not curative and re-infection is often associated with a more drastic incidence of the disease. Baicalin is a flavonoid isolated from Scutellaria baicalensis with potent anti-viral characteristics, namely against RSV. However, its precise mechanism of action remains unclear. Here, using in vitro methods and an in vivo murine model of RSV infection, we showed that baicalin inhibits RSV replication induces translational upregulation of type I interferons (IFNs), IFN-α and IFN-β, and reverses epithelial thickening in lung tissues. Moreover, baicalin inhibits transcription of the RSV non-structural proteins NS1 and NS2. Molecular docking and surface plasmon resonance-based affinity analysis showed that baicalin also binds to the α3 helix of the NS1 protein with an affinity constant of 1.119 × 10−5 M. Polysome profiling showed that baicalin inhibits translation of the RSV matrix protein (M) RNA. Baicalin mediates increased release of the ribosomal protein L13a from the large ribosomal subunit, where the extra ribosomal subunit L13a inhibits M RNA translation. These results comprehensively establish the multiple mechanisms by which baicalin induces a potent innate immune response against RSV infection.
Comparison of Haploidentical Hematopoietic Stem Cell Transplant With or Without Unrelated Cord Blood Infusion in Severe Aplastic Anemia: Outcomes of a Multicenter Study
Authors: Lei Meiqing , Zhang Yanming , Jiao Wenjing , Li Xiaoli , Zhou Huifen , Wang Qingyuan , Qiu Huiying , Tang Xiaowen , Han Yue , Fu Chengcheng , Jin Zhengming , Chen Suning , Sun Aining , Miao Miao , Liu Limin , Wu Depei
Published: June 2022

The purpose of this study in severe aplastic anemia (SAA) patients was to compare the feasibility and efficacy of haploidentical hematological stem cell transplantation combined with a single unrelated cord blood (UCB) infusion (Haplo-cord-HSCT) or haplo-identical HSCT (Haplo-HSCT) alone. The five-year graft-versus-host disease (GVHD)-free or failure-free survival (GFFS) was similar between the two groups (72.4 ± 3.4% vs. 65.4 ± 5.2%, P = 0.178); however, the five-year overall survival (OS) was more favorable in the Haplo-cord-HSCT group than that in the Haplo-HSCT group (84.0 ± 2.8% vs. 72.6 ± 4.9%, P = 0.022), as was transplantation-related mortality (16.4% vs. 27.4%, P = 0.039). Multivariate analysis showed that Haplo-cord HSCT was the only independent determinant of increased OS (P = 0.013). Explorative subgroup analysis showed that only an Human leukocyte antigen-A (HLA-A) allele match between UCB and the recipient was a beneficial factor for GFFS in the Haplo-cord-HSCT group (P = 0.011). In the haplo-cord with an HLA-A match (n = 139) or mismatch (n = 32) or Haplo-HSCT groups, a haplo-cord HLA-A allele match was associated with lower I–IV and III–IV acute GVHD. The haplo-cord with an HLA-A match subgroup also had higher five-year OS than the Haplo-HSCT group (85.4 ± 3.0% vs. 72.6 ± 4.9%, P = 0.013), and higher five-year GFFS than the Haplo-cord HLA-A allele mismatch subgroup (76.2 ± 3.6% vs. 56.3 ± 8.8%, P = 0.011). These findings suggest that the coinfusion of a single UCB potentially improves survival of Haplo-HSCT in SAA patients and that an HLA-A allele-matched UCB is the preferred option.
Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism
Authors: Shi Jia , Cai Cheng
Published: June 2022

The field of immunology is undergoing rapid and dramatic changes. Immunometabolism, a change in metabolic pathways within immune cells, is a key determinant in the activation of immune cells, and intermediates of immunometabolic processes which can influence inflammatory gene expression and play a role in inflammation. Itaconate is one of the most representative metabolites, produced in the tricarboxylic acid cycle (TCA cycle), which links macrophage metabolism, oxidative stress response and immune response to regulate macrophage activity, playing an important role in the function of macrophages. In this paper, we review the mechanisms of the metabolite itaconate and its derivatives in the regulation of macrophage immune metabolism, intending to gain further insight into the role and mechanisms of this metabolite in macrophages and provide new ideas for the mechanisms and treatment of clinical diseases.
Nucleic Acid Sensing by Toll-Like Receptors in the Endosomal Compartment
Authors: Miyake Kensuke , Shibata Takuma , Fukui Ryutaro , Sato Ryota , Saitoh Shin-Ichiroh , Murakami Yusuke
Published: June 2022

Toll-like receptors (TLRs) respond to pathogen constituents, such as microbial lipids and nucleic acids (NAs). TLRs recognize NAs in endosomal compartments. Structural and functional studies have shown that recognition of NAs by TLRs depends on NA processing by RNases and DNases. DNase II-dependent DNA degradation is required for TLR9 responses to single-stranded DNAs, whereas RNase T2-dependent RNA degradation enables TLR7 and TLR8 to respond to nucleosides and oligoribonucleotides. In contrast, RNases and DNases negatively regulate TLR responses by degrading their ligands. RNase T2 negatively regulates TLR3 responses to degrading the TLR3 ligand double-stranded RNAs. Therefore, NA metabolism in the endosomal compartments affects the endosomal TLR responses. Dysregulation of NA metabolism in the endosomal compartment drives the TLR-dependent pathologies in human diseases.
An Observation-Based Study of Gulf Stream Meander Kinematics Offshore of Cape Hatteras
Authors: Muglia Mike , Seim Harvey , Bane John , Taylor Patterson
Published: June 2022

Gulf Stream (GS) meander structure and propagation offshore of Cape Hatteras are investigated by integrating current measurements from a bottom-moored Acoustic Doppler Current Profiler (ADCP) with high-frequency radar (HFR) surface current measurements and satellite Sea Surface Temperature (SST) images during November 2014. The ADCP measurements provide well-resolved current observations throughout most of the water column, while hourly surface current measurements from HF radars and available satellite SST images provide spatial context to the GS orientation, meander propagation, circulation, and shear structure in the region of the ADCP mooring. The observations provide new insights about meander propagation and evolution in this important transition region. ADCP measurements observed that the increase and deepening intervals of the downstream current with approaching meander crests were typically longer than those for the decrease and shoaling of downstream current, consistent with prominent skewed crests near the surface. The transition time from trough to crest is much greater than that from crest to trough, reflecting the asymmetry in the downstream velocity structure. Vertical shears in the downstream and cross-stream velocity components are indicative of a cold dome centered downslope and offshore of the ADCP. Local maxima in downstream current and bottom temperature at the ADCP occur simultaneously, are accompanied by large vertical velocities, and are led by offshore currents in the upper water column. The mean meander phase speed estimated with HFRs is 48 km/day. Meander periods during the month are about 5-6 days. Where the maxima are seen in the water column, downstream currents reach 2.5 m/s, with current reversals sometimes in excess of 0.5 m/s. Downstream currents occupy an increasing portion of the water column as a crest approaches, and a decreasing fraction as a trough approaches. The deepening increase in downstream velocities with approaching crests is often accompanied by an increase in upstream velocities near the bottom.
A Contrast of Criteria for Special Places Important for Biodiversity Outcomes
Authors: Rice Jake , Friedman Kim , Garcia Serge , Govan Hugh , Himes-Cornell Amber
Published: June 2022

This paper contrasts seven spatial biodiversity conservation area designations by six different bodies: Other Effective Area-Based Conservation Measures (OECMs), and the Ecologically and Biologically Significant Areas (EBSAs) of the Convention on Biological Diversity (CBD); the Vulnerable Marine Ecosystems (VMEs) of the Food And Agriculture Organization (FAO); the Key Biodiversity Areas (KBAs) under criteria developed by the IUCN; the Areas of Particular Environmental Interest (APEIs) of the International Seabed Authority (ISA); the Particularly Sensitive Sea Areas (PSSAs) of the International Maritime Organization (IMO); and the Locally Managed Marine Areas (LMMAs) used by small island States in the Pacific Ocean; on five themes: biological and ecological features, functions served by areas receiving these labels, governance, threats and pressures, and other considerations. The seven different labels for such areas were generally similar in the biologically and ecological criteria to be met, and the functions typically served by these areas. Differences among the labels increased when considering governance, threat and pressures, and other considerations. Implications of these similarities and differences for policy development and outcomes are discussed. Performance reviews of the various labels under these themes could provide insight into both the effectiveness of the provisions in the Agreements and Decisions and how evidence is acquired and used to inform their application, allowing improvements to each approach to learn from experiences with other labels.
Plastic Filtration and Decomposition According to Ricochet Filtering Mechanism Using Ideonella sakaiensis
Authors: Sankrityayan Prakhar , Biswas Sumit
Published: June 2022

Our oceans have been under immense stress due to the deposition and accumulation of marine debris, of which 80% are plastics. Of these, microplastics which are small plastic fragments measuring less than five mm, have been a real bane to the marine fauna, especially the ornamental fishes inhabiting coral reef regions. The multibillion-dollar marine ornamental fish trade depends on these fishes caught from coral reefs. It has often been found that these small fishes are severely affected due to the choking of their gills with microplastics as they are natural filter feeders. To curb the load of plastics in the oceans, and especially in the waters around coral reefs, this study aims to develop a small-scale solution, which could later be scaled up by increasing the size and number of each unit as required. The system has been inspired by the filter-feeding mechanism of manta rays as a basic model for the filtration module. The use of a bacteria named Ideonella sakaiensis, which has been known to decompose plastics inherently is the second level of ideation that has gone into the design. The whole system has been envisaged as a floating system, where the filtration units would be submerged under water and the design of the platform over water would have a provision for self-sustenance, apart from the obvious role in maintaining buoyancy. Each filtration unit has been designed to possess multiple layers of sieving, vortexing and cross-flow filtration with a batch of I. sakaiensis at the end of the unit. To maintain a unidirectional flow of water, a fan would be placed at the end of these filtration units. This system can be a solution to the accumulation of plastics in a localized environment and can be scaled up in terms of size and the number of units to cover a greater area and volume to reduce the menace of plastic pollution. This could be a unique and cost-effective answer to the loss of marine fauna, more specifically ornamental fishes to the curse of microplastics.
Novel Insight of CircRNAs in Cervical Cancer: Potential Biomarkers and Therapeutic Target
Authors: Wu Maomao , Han Yanxun , Gong Xiangfei , Wan Ke , Liu Yuchen , Zhou Yi , Zhang Lizhi , Tang Guozheng , Fang Hui , Chen Bangjie , Yang Fan , Zhao Qing , Wang Genbao , Zhanghuang Chenghao , Zhang Yunling
Published: June 2022

Cervical cancer (CC) is a prominent cancer around the globe, with a high incidence, and fatality rate. Numerous recent investigations have shown that various non-coding RNAs are associated with the progression of CC. Circular RNAs, a novel class of non-coding RNAs, have a single chain covalent closed-loop structure and are involved in cell growth and other physiological processes. These dysregulated circRNAs seem to have environment-specific functions. They have been demonstrated in certain studies to have a dual involvement in oncogene production and tumor inhibition in different cell settings. Simultaneously, some evidence indicates that circRNAs are abnormally expressed in CC and contributes to its progression. Thus, the distinctive expression profile of circRNAs is associated with the diagnosis, prognosis, and treatment outcomes of CC. We summarized numerous CC-specific circles and their function in revealing the molecular processes of carcinogenesis and progression in CC in this review. Taken together, these data suggest that circRNA may be used as an early detection biomarker and potential therapeutic target in patients with CC.
The Armadillo as a Model for Leprosy Nerve Function Impairment: Preventative and Therapeutic Interventions
Authors: Pena Maria Teresa , Lahiri Ramanuj , Ebenezer Gigi J. , Wheat Stephen W. , Figarola John , Truman Richard W. , Adams Linda B.
Published: June 2022

Mycobacterium lepraeinfection of peripheral nerves and the subsequent nerve function impairment (NFI), especially in response to reactional episodes, are hallmarks of leprosy. Improved treatments forM. leprae-induced nerve injury are needed, as most if not all of the disability and stigma associated with leprosy arises from the direct or indirect effects of NFI. Nine-banded armadillos (Dasypus novemcinctus), like humans, exhibit the full clinical spectrum of leprosy and extensive involvement of the peripheral nerves. In this study, state-of-the-art technology was used to compare nerve function between uninfected andM. leprae-infected armadillos. Motor nerve conduction velocity (MNCV) and compound muscle action potential (cMAP), which measure changes in the rate of impulse conduction velocity and amplitude, revealed a progression of impairment that was directly correlated with the duration ofM. lepraeinfection and enabled development of an objective nerve impairment scoring system. Ultrasonography accompanied by color Doppler imaging detected enlargement of theM. leprae-infected nerves and increased vascularity, possibly due to inflammation. Assessment of epidermal nerve fiber density (ENFD), which shows a length-dependent innervation in armadillos that is similar to humans, identified small fiber degeneration early afterM. lepraeinfection. Staining for neuromuscular junction (NMJ) integrity, which is an indicator of signal transduction efficiency into skeletal muscle, discerned a markedly lower number and structural integrity of NMJ inM. leprae-infected armadillo footpads. These tools for assessing nerve injury were used to monitor the effects of intervention therapy. Two potential neuro-protective drugs, ethoxyquin (EQ) and 4-aminopyridine (4-AP), were tested for their ability to ameliorate peripheral nerve injury inM. leprae-infected armadillos. 4-AP treatment improved MNCV, cMAP, and EFND compared to untreated animals, while EQ had less effect. These results support the armadillo as a model forM. leprae-induced peripheral nerve injury that can provide insights toward the understanding of NFI progression and contribute to the preclinical investigation of the safety and efficacy of neuro-preventive and neuro-therapeutic interventions for leprosy.
The Burden of Osteoarthritis in the Middle East and North Africa Region From 1990 to 2019
Authors: Shamekh Ali , Alizadeh Mahasti , Nejadghaderi Seyed Aria , Sullman Mark J. M. , Kaufman Jay S. , Collins Gary S. , Kolahi Ali-Asghar , Safiri Saeid
Published: June 2022

Objective

We aimed to report the most current data on the prevalence, incidence, and years lived with disability (YLDs) associated with osteoarthritis (OA) for the 21 countries and territories located in the Middle East and North Africa (MENA) region from 1990 to 2019 by age, sex, cause, and sociodemographic index (SDI).

Methods

Publicly available data from the Global Burden of Disease 2019 study were used to report the OA-related burden. Estimates are reported as counts and age-standardized rates, along with their corresponding 95% uncertainty intervals (UIs).

Results

In 2019, the age-standardized prevalence of OA in MENA was 5,342.8 per 100,000 (95% UI: 4,815.9–5,907.8), which is 9.3% higher than in 1990 (8.1–10.5%). Similarly, the age-standardized annual incidence of OA per 100,000 was 430.4 (382.2–481.9), demonstrating a 9.4% increase since 1990 (8.3–10.5). OA was the cause of 185.4 (92.8–370.2) age-standardized YLDs per 100,000 in 2019, which was 10% higher than in 1990 (8.7–11.4). Saudi Arabia, Kuwait, and Iran had the highest OA burden in MENA, while Yemen, Afghanistan, and Sudan had the lowest burden. In all MENA countries, OA affected more women than men, had an increasing burden with increased age, and had the highest impact on the knee, hip, and hand joints, respectively. OA was also positively associated with the SDI.

Conclusion

The burden of OA increased over 1990–2019 in the MENA region. The study emphasizes the importance of early preventative approaches in order to control any future health, economic, and quality of life crises imposed by OA in this region.
Genome-Wide Association Study and Gene-Based Analysis of Participants With Hemophilia A and Inhibitors in the My Life, Our Future Research Repository
Authors: Lessard Samuel , He Chunla , Rajpal Deepak K. , Klinger Katherine , Loh Christine , Harris Tim , Dumont Jennifer
Published: June 2022

Introduction

Up to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered F8 and F9 mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.

Aim and Methods

Here, we performed a genome-wide association study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.

Results

We identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with F8 intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB1*15:01) and major histocompatibility complex, class II, DQ beta 1 (DQB1*03:03). Variant aggregation tests further identified low-frequency variants within GRID2IP (glutamate receptor, ionotropic, delta 2 [GRID2] interacting protein 1) significantly associated with inhibitors.

Conclusion

Overall, our study confirms the association of DRB1*15:01 with FVIII inhibitors and identifies a novel association of DQB1*03:03 in individuals with HA carrying intronic inversions of F8. In addition, our results implicate GRID2IP, encoding GRID2-interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.