bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches
Authors: Kuo Mickey J. M. , Nazari Matthew A. , Jha Abhishek , Pacak Karel
Published: July 2022

Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient’s tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.
Optimization of the Electrocoagulation Process with Aluminum Electrodes for Rainwater Treatment
Authors: Morales-Figueroa Alejandra , Teutli-Sequeira Elia Alejandra , Linares-Hernández Ivonne , Martínez-Miranda Verónica , García-Morales Marco A. , Roa-Morales Gabriela
Published: July 2022

Rainwater collected in the Toluca region of Mexico with a pH of 6.25 was treated with an electrochemical process, and the efficiency of two supporting electrolytes were compared, one food grade (sea salt) and the other reagent grade (sodium sulfate). In the first stage, rainwater was characterized to detect the COD content, turbidity, metals such as zinc, iron, aluminum, and lead. Electrocoagulation treatment was performed with an electrochemical cell using aluminum electrodes to study the effect on COD and turbidity, as well as the removal of heavy metals present. The results obtained with response surface methodology and a central composite design reveal that the optimal conditions of the electrocoagulation treatment were a current density of 3.26 mA/cm2 and a time of 11.38 min. Using sodium sulfate, the percentage of turbidity removal is 99.27% and COD 70.83%. The use of sea salt as a support electrolyte in these conditions allowed the removal of COD at 100%, turbidity at 100%, and Al 100%, Mn 84.29%, Zn 97.97%, Pb 46%, Fe 21%. Energy costs that are low lead to proven savings when using this system, indicating that this treatment is an option to both improve rainwater conditions and be able to make use of it safely.
Microbial Community Compositional Stability in Agricultural Soils During Freeze-Thaw and Fertilizer Stress
Authors: Jensen Grant , Krogstad Konrad , Rezanezhad Fereidoun , Hug Laura A.
Published: July 2022

Microbial activity persists in cold region agricultural soils during the fall, winter, and spring (i.e., non-growing season) and frozen condition, with peak activity during thaw events. Climate change is expected to change the frequency of freeze-thaw cycles (FTC) and extreme temperature events (i.e, altered timing, extreme heat/cold events) in temperate cold regions, which may hasten microbial consumption of fall-amended fertilizers, decreasing potency come the growing season. We conducted a high-resolution temporal examination of the impacts of freeze-thaw and nutrient stress on microbial communities in agricultural soils across both soil depth and time. Four soil columns were incubated under a climate model of a non-growing season including precipitation, temperature, and thermal gradient with depth over 60 days. Two columns were amended with fertilizer, and two incubated as unamended soil. The impacts of repeated FTC and nutrient stress on bacterial, archaeal, and fungal soil community members were determined, providing a deeply sampled longitudinal view of soil microbial response to non-growing season conditions. Geochemical changes from flow-through leachate and amplicon sequencing of 16S and ITS rRNA genes were used to assess community response. Despite nitrification observed in fertilized columns, there were no significant microbial diversity, core community, or nitrogen cycling population trends in response to nutrient stress. FTC impacts were observable as an increase in alpha diversity during FTC. Community compositions shifted across a longer time frame than individual FTC, with bulk changes to the community in each phase of the experiment. Our results demonstrate microbial community composition remains relatively stable for archaea, bacteria, and fungi through a non-growing season, independent of nutrient availability. This observation contrasts canonical thinking that FTC have significant and prolonged effects on microbial communities. In contrast to permafrost and other soils experiencing rare FTC, in temperate agricultural soils regularly experiencing such perturbations, the response to freeze-thaw and fertilizer stress may be muted by a more resilient community or be controlled at the level of gene expression rather than population turn-over. These results clarify the impacts of winter FTC on fertilizer consumption, with implications for agricultural best practices and modeling of biogeochemical cycling in agroecosystems.
Arctic Migratory Raptor Selects Nesting Area During the Previous Breeding Season
Authors: Curk Teja , Kulikova Olga , Fufachev Ivan , Wikelski Martin , Safi Kamran , Pokrovsky Ivan
Published: July 2022

Migratory species have a limited time for habitat selection upon arrival at the breeding grounds. This is especially evident in arctic migrants, which are restricted by a narrow window of opportunity when environmental conditions are favorable for breeding. This general time constraint is amplified in rough-legged buzzards (Buteo lagopus) who, as many other arctic predators, rely on rodent (lemming) cycles during the breeding season, a 3–5 year period of waxing and waning local food abundance. It remains unclear how arctic predators, especially migrants, can find nesting areas where rodents are numerous when their selection time is so limited. We hypothesized that rough-legged buzzards select nesting areas during the previous breeding season. We tracked 43 rough-legged buzzards using GPS telemetry and assessed their movements post-breeding prospecting behavior to test our hypothesis. Here we show that rough-legged buzzards search for a nesting location during the previous breeding season in a post-breeding period. In the following year, individuals return to and attempt to breed in the area they inspected the year before. Rough-legged buzzards, regardless of breeding success, remained in the Arctic all breeding season until the end of September. Failed breeders prospected more than successful ones. At the same time, buzzards that bred in the rodent-free ecosystem prospected less and showed a high level of philopatry. Therefore, as rodent cycles have been predicted to collapse in the warming Arctic, we can expect arctic predators to change their movement patterns in the future with serious potential consequences for their conservation. We anticipate our study provides a step forward toward understanding movement and settlement decisions in animals experiencing high inter-annual environmental variation.
The Role of ERBB Signaling Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma and Establishing a Prognostic Risk Assessment Model for Patients
Authors: Wang Zicheng , Li Jiayi , Zhang Peizhi , Zhao Leizuo , Huang Bingyin , Xu Yingkun , Wu Guangzhen , Xia Qinghua
Published: July 2022

Objective: We aimed to investigate the potential role of ERBB signaling pathway–related genes in kidney renal clear cell carcinoma (KIRC) and establish a new predictive risk model using various bioinformatics methods.

Methods: We downloaded the KIRC dataset and clinicopathological information from The Cancer Genome Atlas database. Univariate Cox analysis was used to identify essential genes significantly associated with KIRC progression. Next, we used the STRING website to construct a protein–protein interaction network of ERBB signaling pathway–related molecules. We then used the least the absolute shrinkage and selection operator (LASSO) regression analysis to build a predictive risk model for KIRC patients. Next, we used multiple bioinformatics methods to analyze the copy number variation, single-nucleotide variation, and overall survival of these risk model genes in pan-cancer. At last, we used the Genomics of Drug Sensitivity in Cancer to investigate the correlation between the mRNA expression of genes associated with this risk model gene and drug sensitivity.

Results: Through the LASSO regression analysis, we constructed a novel KIRC prognosis–related risk model using 12 genes: SHC1, GAB1, SOS2, SRC, AKT3, EREG, EIF4EBP1, ERBB3, MAPK3, transforming growth factor-alpha, CDKN1A, and PIK3CD. Based on this risk model, the overall survival rate of KIRC patients in the low-risk group was significantly higher than that in the high-risk group (p = 1.221 × 10−15). Furthermore, this risk model was associated with cancer metastasis, tumor size, node, stage, grade, sex, and fustat in KIRC patients. The receiver operating characteristic curve results showed that the model had better prediction accuracy. Multivariate Cox regression analysis showed that the model’s risk score was an independent risk factor for KIRC. The Human Protein Atlas database was used to validate the protein expression of risk model–associated molecules in tumors and adjacent normal tissues. The validation results were consistent with our previous findings.

Conclusions: We successfully established a prognostic-related risk model for KIRC, which will provide clinicians with a helpful reference for future disease diagnosis and treatment.
Exploring Potential Causal Genes for Uterine Leiomyomas: A Summary Data-Based Mendelian Randomization and FUMA Analysis
Authors: Dai Yuxin , Liu Xudong , Zhu Yining , Mao Su , Yang Jingyun , Zhu Lan
Published: July 2022

Objective: To explore potential causal genetic variants and genes underlying the pathogenesis of uterine leiomyomas (ULs).

Methods: We conducted the summary data-based Mendelian randomization (SMR) analyses and performed functional mapping and annotation using FUMA to examine genetic variants and genes that are potentially involved in the pathogenies of ULs. Both analyses used summarized data of a recent genome-wide association study (GWAS) on ULs, which has a total sample size of 244,324 (20,406 cases and 223,918 controls). We performed separate SMR analysis using CAGE and GTEx eQTL data.

Results: Using the CAGE eQTL data, our SMR analysis identified 13 probes tagging 10 unique genes that were pleiotropically/potentially causally associated with ULs, with the top three probes being ILMN_1675156 (tagging CDC42, PSMR = 8.03 × 10−9), ILMN_1705330 (tagging CDC42, PSMR = 1.02 × 10−7) and ILMN_2343048 (tagging ABCB9, PSMR = 9.37 × 10−7). Using GTEx eQTL data, our SMR analysis did not identify any significant genes after correction for multiple testing. FUMA analysis identified 106 independent SNPs, 24 genomic loci and 137 genes that are potentially involved in the pathogenesis of ULs, seven of which were also identified by the SMR analysis.

Conclusions: We identified many genetic variants, genes, and genomic loci that are potentially involved in the pathogenesis of ULs. More studies are needed to explore the exact underlying mechanisms in the etiology of ULs.
Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media
Authors: Kurabi Arwa , Lee Jasmine , Pak Kwang , Leichtle Anke , Ryan Allen F
Published: July 2022

Intracellular nucleotide binding and oligomerization domain (NOD) and Toll-like (TLR) receptors have emerged as pivotal sensors of infection. Both Nod1 and Nod2 contain a caspase activation and recruitment domain (CARD) that interacts with the adaptor protein RIP2 (receptor-interaction protein-2). This leads to ubiquitination of RIP2 and in turn to the activation of NFκB and MAPK transcription factors, to command the host defensive response against pathogenic infections. RIP2 is also activated by TLRs 2 and 4, although the mechanism of this activation is less. The role of RIP2 in otitis media (OM) pathogenesis has yet to be examined. Herein, we used in vivo animal models including C57BL/6 wild-type (WT) and RIP2−/− knockout mice inoculated in the middle ear (ME) with non-typeable Haemophilus influenzae (NTHi), a common human OM pathogen, to evaluate the expression of RIP2 and its signaling genes at the cellular level to determine the role of RIP2 in OM pathogenesis and recovery. The Nod1, Nod2, and Ripk2 genes are minimally expressed in the normal ME. However, they are strongly upregulated during acute OM, as are many genes related to RIP2 signaling. However, while signaling genes were expressed by various ME cell types, only mucosal epithelial and stromal cells expressed the NODs, RIP2, and signaling genes required for the activation of the host defensive response. Whereas WT mice clear ME bacteria and recover from OM within 5 days after infection, RIP2-deficient mice show persistent ME bacterial carriage and inflammation to at least 15 days. This includes significantly prolonged mucosal hyperplasia and ME leukocytic infiltration. Recruitment of macrophages is also delayed in comparison to WT mice. Thus, RIP2 is required to elicit a robust innate immune response that promotes bacterial clearance and increases host innate resistance. The results also identify the structural cells of the ME mucosa, as opposed to leukocytes, as the primary sites of NOD/RIP2 activity in the infected ME.
Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study
Authors: Hirtz Raphael , Hars Christine , Naaresh Roaa , Laabs Björn-Hergen , Antel Jochen , Grasemann Corinna , Hinney Anke , Hebebrand Johannes , Peters Triinu
Published: July 2022

A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94–0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94–0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.
Identification of 12 OCA Cases in Chinese Population and Two Novel Variants
Authors: Zhong Zilin , Zhou Zheng , Chen Jianjun , Zhang Jun
Published: July 2022

OCA (oculocutaneous albinism) refers to a group of heterogeneous congenital disorders of which the common manifestations are variable degrees of cutaneous hypopigmentation and significant visual impairment, including poor visual acuity, photophobia, and nystagmus. Molecular analysis may elucidate its pathogenesis and be in favor of accurate diagnosis. High-throughput sequencing and Sanger sequencing were performed to detect mutational alleles and in silico analysis was performed for prediction of variant pathogenicity. Ten TYR-related and two OCA2-related patients were identified with 16 different variants with potential pathogenicity. Two novel missense variants [TYR: c.623T > G, p(Leu208Arg) and OCA2: c.1325A > G, p(Asn442Ser)] are identified in this study, and three OCA cases are reported for the first time in Chinese population based on their associated variants. Analysis of crystal structures of TYR ortholog and its paralog TYRP1 suggests that the substitution of Leu208 may have an impact on protein stability. This study may facilitate OCA diagnosis by expanding the mutational spectrum of TYR and OCA2 as well as further basic studies about these two genes.
Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families
Authors: Guo Ting , Lu Chenyang , Yang Danhui , Lei Cheng , Liu Ying , Xu Yingjie , Yang Binyi , Wang Rongchun , Luo Hong
Published: July 2022

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge.

Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity.

Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C > T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella.

Conclusion: Our study identified a novel variant c.733C > T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
SmTAL-9, a Member of the Schistosoma mansoni Tegument Allergen-Like Family, Is Important for Parasite Survival and a Putative Target for Drug/Vaccine Development
Authors: Bernardes Wilma Patrícia de Oliveira Santos , Dutra Isabela Thamara Xavier , da Silva-Pereira Rosiane Aparecida , Mourão Marina Moraes , Fonseca Cristina Toscano
Published: July 2022

The tegument of Schistosoma mansoni is involved in essential functions for parasite survival and is known to stimulate immune responses in pre-clinical vaccine trials. Smtal-9, a member of the tegument-allergen-like (TAL) family, is one of the components of the tegument of schistosomula recognized by sera from immunized and protected mice. In this work, we assessed the role of Smtal-9 in parasite survival using the RNAi approach. Also, we cloned and expressed a recombinant form of Smtal-9 and evaluated its ability to induce protection in mice. Smtal-9 knockdown did not impact parasite survival in vitro, but significantly decreased schistosomula size. Additionally, significant reduction in both parasite and egg burdens were observed in mice inoculated with Smtal-9-knockdown schistosomula. Immunization using the Smtal-9 as an antigen conferred partial protection against challenge infection. Overall, our results indicate that Smtal-9 is a candidate target for drug and/or vaccine development due to its important role in parasite biology and survival.
Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough?
Authors: Christen Urs , Hintermann Edith
Published: July 2022

Autoimmune liver diseases like autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related cholangitis are chronic inflammatory diseases of the liver with an autoimmune background. The therapy of autoimmune hepatitis targets the autoreactive immune system and is largely dependent on the use of glucocorticoids and cytostatic drugs. In contrast, the treatment of cholestatic autoimmune liver diseases is restricted to the use of secondary or semi-synthetic bile acids, like ursodeoxycholic acid or obeticholic acid. Although the management of the disease using such drugs works well for the majority of patients, many individuals do not respond to standard therapy. In addition, chronic treatment with glucocorticoids results in well-known side effects. Further, the use of bile acids is a symptomatic therapy that has no direct immunomodulatory effect. Thus, there is still a lot of room for improvement. The use of animal models has facilitated to elucidate the pathogenesis of autoimmune liver diseases and many potential target structures for immunomodulatory therapies have been identified. In this review, we will focus on autoimmune hepatitis for which the first animal models have been established five decades ago, but still a precise treatment for autoimmune hepatitis, as obtainable for other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis has yet to be introduced. Thus, the question arises if our animal models are too far from the patient reality and thus findings from the models cannot be reliably translated to the patient. Several factors might be involved in this discrepancy. There is first and foremost the genetic background and the inbred status of the animals that is different from human patients. Here the use of humanized animals, such as transgenic mice, might reduce some of the differences. However, there are other factors, such as housing conditions, nutrition, and the microbiome that might also play an important role. This review will predominantly focus on the current status of animal models for autoimmune hepatitis and the possible ways to overcome discrepancies between model and patient.
Epstein-Barr Virus Reactivation After Paediatric Haematopoietic Stem Cell Transplantation: Risk Factors and Sensitivity Analysis of Mathematical Model
Authors: Kania Soumya P. , Silva Juliana M. F. , Charles Oscar J. , Booth John , Cheung S. Y. Amy , Yates James W. T. , Worth Austen , Breuer Judith , Klein Nigel , Amrolia Persis J. , Veys Paul , Standing Joseph F.
Published: July 2022

Epstein-Barr virus (EBV) establishes a lifelong latent infection in healthy humans, kept under immune control by cytotoxic T cells (CTLs). Following paediatric haematopoetic stem cell transplantation (HSCT), a loss of immune surveillance leads to opportunistic outgrowth of EBV-infected cells, resulting in EBV reactivation, which can ultimately progress to post-transplant lymphoproliferative disorder (PTLD). The aims of this study were to identify risk factors for EBV reactivation in children in the first 100 days post-HSCT and to assess the suitability of a previously reported mathematical model to mechanistically model EBV reactivation kinetics in this cohort. Retrospective electronic data were collected from 56 children who underwent HSCT at Great Ormond Street Hospital (GOSH) between 2005 and 2016. Using EBV viral load (VL) measurements from weekly quantitative PCR (qPCR) monitoring post-HSCT, a multivariable Cox proportional hazards (Cox-PH) model was developed to assess time to first EBV reactivation event in the first 100 days post-HSCT. Sensitivity analysis of a previously reported mathematical model was performed to identify key parameters affecting EBV VL. Cox-PH modelling revealed EBV seropositivity of the HSCT recipient and administration of anti-thymocyte globulin (ATG) pre-HSCT to be significantly associated with an increased risk of EBV reactivation in the first 100 days post-HSCT (adjusted hazard ratio (AHR) = 2.32, P = 0.02; AHR = 2.55, P = 0.04). Five parameters were found to affect EBV VL in sensitivity analysis of the previously reported mathematical model. In conclusion, we have assessed the effect of multiple covariates on EBV reactivation in the first 100 days post-HSCT in children and have identified key parameters in a previously reported mechanistic mathematical model that affect EBV VL. Future work will aim to fit this model to patient EBV VLs, develop the model to account for interindividual variability and model the effect of clinically relevant covariates such as rituximab therapy and ATG on EBV VL.
Effects of Vaccination Against Influenza, Pertussis, and COVID-19 on Human Milk Antibodies: Current Evidence and Implications for Health Equity
Authors: Hunagund Soumya , Golan Yarden , Asiodu Ifeyinwa V. , Prahl Mary , Gaw Stephanie L.
Published: July 2022

Human milk contains three antibody classes that confer mucosal immunity to the breastfed infant: secretory IgA (SIgA), secretory IgM (SIgM), and IgG. Influenza and pertussis vaccines administered during pregnancy induce pathogen specific SIgA and IgG responses in human milk that have been shown to protect the breastfed infant from these respiratory illnesses. In addition, mRNA vaccines against the SARS-CoV-2 virus administered during pregnancy and lactation induce anti-SARS-CoV-2 IgG and IgA responses in human milk. This review summarizes the immunologic benefits of influenza, pertussis, and COVID-19 vaccines conferred by human milk. Additionally, future research direction in human milk immunity and public health needs to improve lactational support are discussed.
Identification of Immune Microenvironment Changes and the Expression of Immune-Related Genes in Liver Cirrhosis
Authors: Liu Yuwei , Dong Yutong , Wu Xiaojing , Wang Xiaomei , Niu Junqi
Published: July 2022

Liver inflammation and the immune response have been recognized as critical contributors to cirrhosis pathogenesis. Immunity-related genes (IRGs) play an essential role in immune cell infiltration and immune reactions; however, the changes in the immune microenvironment and the expression of IRGs involved in cirrhosis remain unclear. CD45+ liver cell single-cell RNA (scRNA) sequencing data (GSE136103) from patients with cirrhosis were analyzed. The clusters were identified as known cell types through marker genes according to previous studies. GO and KEGG analyses among differentially expressed genes (DEGs) were performed. DEGs were screened to identify IRGs based on the ImmPort database. The protein-protein interaction (PPI) network of IRGs was generated using the STRING database. IRGs activity was calculated using the AUCell package. RNA microarray expression data (GSE45050) of cirrhosis were analyzed to confirm common IRGs and IRGs activity. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. A total of ten clusters were obtained. CD8+ T cells and NK cells were significantly decreased in patients with cirrhosis, while CD4+ T memory cells were increased. Enrichment analyses showed that the DEGs focused on the regulation of immune cell activation and differentiation, NK-cell mediated cytotoxicity, and antigen processing and presentation. Four common TFs, IRF8, NR4A2, IKZF3, and REL were expressed in both the NK cluster and the DEGs of liver tissues. In conclusion, we proposed that the reduction of the CD8+ T cell cluster and NK cells, as well as the infiltration of CD4+ memory T cells, contributed to immune microenvironment changes in cirrhosis. IRF8, NR4A2, IKZF3, and REL may be involved in the transcriptional regulation of NK cells in liver fibrosis. The identified DEGs, IRGs, and pathways may serve critical roles in the development and progression of liver fibrosis.
Donor-Derived CD7 CAR-T Therapy Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Acute T-Lymphocytic Leukemia Associated With Hepatitis B: A Case Report
Authors: Li Zhihui , Meng Fanqiao , Li Jing , Wu Tong
Published: July 2022

The use of chimeric antigen receptor T cells (CAR-Ts) is effective in the treatment of hematological malignancies. It has been reported that HBV is reactivated after CAR-T immunotherapy for refractory/relapsed hematological malignant B-cell tumors. However, there is little literature on donor-derived CAR-T therapy combined with allogeneic hematopoietic stem cell transplantation in hepatitis B patients with acute T-lymphocytic leukemia. We report the case of one patient with hepatitis B associated with relapsed/refractory acute T-lymphocytic leukemia (T-ALL) treated with donor-derived CD7 CAR-T therapy and allogeneic hematopoietic stem cell transplantation. During treatment, the copy number of hepatitis B virus continuously decreased, and AST, ALT, DBIL and TBIL remained within the controllable ranges. CD7-negative MRD recurred 4.5 months after transplantation, and the flow cytometry results became negative after immunosuppressive reduction. Seven months after transplantation, the patient had complete remission, and the copy number of hepatitis B virus decreased to below 102. This is the first study on the safety and effectiveness of donor-derived CD7 CAR-T therapy bridging to allogeneic hematopoietic stem cell transplantation in a patient with relapsed/refractory acute T-lymphocytic leukemia and hepatitis B.
When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells
Authors: Hoeks Cindy , Duran Gayel , Hellings Niels , Broux Bieke
Published: July 2022

Once regarded as an experimental artefact, cytotoxic CD4+T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4+T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies.
Effects of Ocean Chlorophyll on the Mode Water Subduction Rate in the Northwestern and Central Pacific Ocean
Authors: Ma Jinfeng , Yang Qian , Liu Hailong , Lin Pengfei , Liu Juan
Published: July 2022

The effects of ocean chlorophyll on the mode water subduction rate in the subtropical mode water (STMW) and central mode water (CMW) in Pacific Ocean are investigated by performing two ocean-only experiments, using two different solar radiation penetration schemes, one with and one without chlorophyll effects. The biological impacts on mixed layer depth (MLD), upper ocean temperature and density are analyzed. Results show that the subduction rates of both STMW and CMW are increased with the effects of ocean chlorophyll. The increase in the subduction rate is mainly caused by the increased lateral induction term, which is related to larger MLD gradient in early spring in the chlorophyll experiment.
Characterization and Analysis of Retinal Axial Motion at High Spatiotemporal Resolution and Its Implication for Real-Time Correction in Human Retinal Imaging
Authors: Cai Yao , Grieve Kate , Mecê Pedro
Published: July 2022

High-resolution ophthalmic imaging devices including spectral-domain and full-field optical coherence tomography (SDOCT and FFOCT) are adversely affected by the presence of continuous involuntary retinal axial motion. Here, we thoroughly quantify and characterize retinal axial motion with both high temporal resolution (200,000 A-scans/s) and high axial resolution (4.5 μm), recorded over a typical data acquisition duration of 3 s with an SDOCT device over 14 subjects. We demonstrate that although breath-holding can help decrease large-and-slow drifts, it increases small-and-fast fluctuations, which is not ideal when motion compensation is desired. Finally, by simulating the action of an axial motion stabilization control loop, we show that a loop rate of 1.2 kHz is ideal to achieve 100% robust clinical in-vivo retinal imaging.
Bidirectional Relationship Between Tuberculosis and Hypothyroidism: An 18-Year Nationwide Population-Based Longitudinal Cohort Study
Authors: Cheng Li-Ting , Chung Chi-Hsiang , Peng Chung-Kan , Shu Chin-Chung , Wu Shu-Yu , Wang Sheng-Huei , Wu Gwo-Jang , Tsao Chang-Huei , Sun Chien-An , Chien Wu-Chien , Tang Shih-En
Published: July 2022

Some antituberculosis agents may cause hypothyroidism, and thyroid hormones play a vital role in Mycobacterium tuberculosis infection. However, the relationship between tuberculosis (TB) and hypothyroidism has not been clearly established. Therefore, this retrospective, longitudinal cohort study aimed to investigate the association between these two diseases using the 2000–2017 data from the Taiwan's National Health Insurance Research Database. The hypothyroidism and TB cohorts were matched with the control group in a 1:4 ratio. Adjusted hazard ratios (aHRs) were assessed using Cox proportional hazards regression analysis in each cohort. In total, 3,976 individuals with hypothyroidism and 35 120 individuals with TB were included in this study. The risk of developing TB in patients with hypothyroidism was 2.91 times higher than that in those without hypothyroidism (95% confidence interval [CI], 1.50–3.65). The subgroup of thyroxine replacement therapy (TRT) had a 2.40 times higher risk (95% CI, 1.26–3.01), whereas the subgroup of non-TRT had a 3.62 times higher risk of developing TB than those without hypothyroidism (95% CI, 2.19–4.84). On the other hand, the risk of developing hypothyroidism in patients with TB was 2.01 times higher than that in those without TB (95% CI, 1.41–2.38). Our findings provide evidence that TB and hypothyroidism are interrelated. Thus, clinicians and public health authorities should monitor the association between these two diseases to reduce the relevant disease burden.
Humoral Response Following Triple Dose of mRNA Vaccines Against SARS-CoV-2 in Hemodialysis Patients: Results After 1 Year of Follow-Up
Authors: Gallego-Valcarce Eduardo , Shabaka Amir , Leon-Poo Mariana , Gruss Enrique , Acedo-Sanz Juan Manuel , Cordón Alfredo , Cases-Corona Clara , Fernandez-Juarez Gema
Published: July 2022

Introduction

COVID-19 is associated with an increased mortality in hemodialysis patients. Therefore, achieving a long-lasting effective immune response to SARS-CoV-2 vaccines is essential. This study describes the humoral immune response in hemodialysis patients following three doses of mRNA vaccines against SARS-CoV-2, and explores the factors associated with a sustained immune response.

Materials and Methods

We analyzed the monthly serological evolution of SARS-CoV-2 anti-S(RBD) antibodies for 1 year in 178 chronic hemodialysis patients who received three doses of SARS-CoV-2 mRNA vaccines. The primary outcome was sustained effective humoral response defined as anti-S(RBD) levels > 1,000 AU/ml after 4 months from the third dose. Multivariate logistic regression analyses were used to identify features associated with a sustained humoral immune response.

Results

After the initial two SARS-CoV-2 mRNA vaccine doses, 77.8% of patients showed an immediate effective humoral response, decreasing to 52.5% after 4 months. Antibody levels were significantly higher in COVID-exposed patients and HBV vaccine responders. After the third dose, 97% of patients showed an effective humoral response, and remained in 91.7% after 4 months. The mean monthly rate of antibody titer decline decreased from 33 ± 14.5 to 25 ± 16.7%. Multivariate regression analysis showed that previous exposure to COVID-19 and response to HBV vaccines were associated with an effective sustained humoral immune response.

Conclusion

Immunization with SARS-CoV-2 mRNA vaccines elicits an effective immediate humoral immune response in hemodialysis patients, with a progressive waning in antibody levels. A third booster dose enhances the immune response with significantly higher antibody levels and more sustained humoral immune response. COVID-naïve patients and patients without previous response to HBV vaccines are likely to benefit from receiving more booster doses to maintain an effective immune response.
Effects of Normal Reference Range of Phosphorus and Corresponding PTH on Endothelial Function in CKD Patients
Authors: Lee Shina , Kim Seung-Jung
Published: July 2022

Introduction

Endothelial dysfunction commonly occurs in chronic kidney disease (CKD) patients and increases the risk for cardiovascular disease. Among CKD patients, biomarkers involved in the pathogenesis of CKD-mineral bone disorder (CKD-MBD), such as phosphorus, parathyroid hormone, and fibroblast growth factor 23, are associated with endothelial dysfunction. We investigated whether these biomarkers induce endothelial dysfunction in CKD patients with normal phosphorus levels.

Methods

This cross-sectional study examined CKD patients with normal phosphorus levels; patients with an estimated glomerular filtration rate (eGFR) <15 or who were under dialysis were excluded. Iontophoresis with laser doppler flowmetry (ILDF) and peripheral arterial tonometry were performed to assess endothelial function in 85 patients. Pearson's correlation coefficient, multiple regression, and mediation analyses were performed to examine the association between CKD-MBD biomarkers and endothelial dysfunction.

Results

Endothelial dysfunction was observed in all subjects with a low response to ILDF and 27% of subjects according to peripheral arterial tonometry. Acetylcholine (Ach)-induced ILDF was significantly associated with eGFR (r = 0.22, P = 0.04), intact parathyroid hormone (iPTH; r = −0.46, P < 0.01), and VCAM-1 (r = −0.36, P < 0.01). The reactive hyperemia index (RHI) was significantly related to phosphorus levels (r = 0.32, P < 0.01) and iPTH (r = −0.39, P = 0.02). After adjusting for eGFR, iPTH and VCAM-1 remained independent factors for predicting endothelial dysfunction measured using Ach-induced ILDF. In addition, iPTH and phosphorus levels were independent predictors for endothelial dysfunction measured using RHI in the eGFR-adjusted model. Mediation analyses showed that the individual indirect effects of iPTH were significantly affected ILDF and RHI.

Conclusion

Serum levels of phosphorus and iPTH are associated with endothelial dysfunction, even in CKD patients with normal phosphorus levels.
Bacterial Community Dynamics in Kumamoto Oyster Crassostrea sikamea Hatchery During Larval Development
Authors: Dai Wenfang , Ye Jing , Liu Sheng , Chang Guangqiu , Xu Hongqiang , Lin Zhihua , Xue Qinggang
Published: July 2022

Increasing evidence indicates that microbes colonized in early life stages have a long-term effect on animal wellbeing in later life stages. Related research is still limited in aquatic animals, particularly in bivalve mollusks. In this study, we analyzed the dynamics of the bacterial composition of the pelagic larval stages (fertilized egg, trochophore, D-stage, veliger, and pediveliger) and the sessile postlarval stage (spat) of Kumamoto oyster (Crassostrea sikamea) and their relationships with the rearing water bacterioplankton in a hatchery by using Illumina sequencing of bacterial 16S rRNA gene. Both bacterioplankton and larval bacterial communities changed greatly over larval development, and the two communities remarkably differed (r = 0.956, P < 0.001), as highlighted by the differences in the dominant taxa and bacterial diversity. Ecological processes of larval bacterial communities were measured by abundance-unweighted and abundance-weighted standardized effect sizes of the mean nearest taxon distance (ses.MNTD). The unweighted ses.MNTD analysis revealed that the deterministic process constrained the larval bacterial assembly, whereas the weighted ses.MNTD analysis showed that larval bacterial composition was initially governed by stochasticity and then gradually by determinism in the later stages. SourceTracker analysis revealed that the larval bacteria were primarily derived from an internal source, mainly from larvae at the present stage. Additionally, the abundances of larval bacterial-mediated functional pathways that were involved in the amino acid, energy, lipid and carbohydrate metabolisms significantly altered with the larval development. These findings suggest that bacteria assemble into distinct communities in larvae and rearing water in the hatchery system, and the dynamics of bacterial community composition in larvae is likely associated with larval developmental stages.
Multi-Omics Approach in Amelioration of Food Products
Authors: Dutta Bandita , Lahiri Dibyajit , Nag Moupriya , Abukhader Rose , Sarkar Tanmay , Pati Siddhartha , Upadhye Vijay , Pandit Soumya , Amin Mohamad Faiz Mohd , Al Tawaha Abdel Rahman Mohammad Said , Kumar Manoj , Ray Rina Rani
Published: July 2022

Determination of the quality of food products is an essential key factor needed for safe-guarding the quality of food for the interest of the consumers, along with the nutritional and sensory improvements that are necessary for delivering better quality products. Bacteriocins are a group of ribosomally synthesized antimicrobial peptides that help in maintaining the quality of food. The implementation of multi-omics approach has been important for the overall enhancement of the quality of the food. This review uses various recent technologies like proteomics, transcriptomics, and metabolomics for the overall enhancement of the quality of food products. The matrix associated with the food products requires the use of sophisticated technologies that help in the extraction of a large amount of information necessary for the amelioration of the food products. This review would provide a wholesome view of how various recent technologies can be used for improving the quality food products and for enhancing their shelf-life.
Cytotoxic Indolocarbazoles From a Marine-Derived Streptomyces Sp. OUCMDZ-5380
Authors: Cui Tongxu , Lin Simin , Wang Zizhen , Fu Peng , Wang Cong , Zhu Weiming
Published: July 2022

Under the guidance of global natural product social molecular networking, three new indolocarbazoles named streptocarbazoles F–H (1-3), along with staurosporine (4) were isolated from the marine-derived Streptomyces sp. OUCMDZ-5380. Structures of streptocarbazoles F–H were, respectively, determined as N-demethyl-N-hexanoylstaurosporine (1), N-demethyl-N-(2-methyl-3-methoxypyridin-4-yl) staurosporine staurosporine (2), and 4-(N-demethylstaurosporine-N-yl)-1,2-dimethyl-3-methoxypyridinium (3) by spectroscopic analysis and electronic circular dichroism comparison with staurosporine. Compared with staurosporine (4), streptocarbazoles F–H (1-3) showed a selective antiproliferation of the acute myeloid leukemia cell line MV4-11 with the IC50 values of 0.81, 0.55, and 1.88 μM, respectively.
Mapping CAR T-Cell Design Space Using Agent-Based Models
Authors: Prybutok Alexis N. , Yu Jessica S. , Leonard Joshua N. , Bagheri Neda
Published: July 2022

Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating liquid cancers and increasingly for solid tumors as well. While potential design strategies exist to address translational challenges, including the lack of unique tumor antigens and the presence of an immunosuppressive tumor microenvironment, testing all possible design choicesin vitroandin vivois prohibitively expensive, time consuming, and laborious. To address this gap, we extended the modeling framework ARCADE (Agent-based Representation of Cells And Dynamic Environments) to include CAR T-cell agents (CAR T-cell ARCADE, or CARCADE). We conductedin silicoexperiments to investigate how clinically relevant design choices and inherent tumor features—CAR T-cell dose, CD4+:CD8+CAR T-cell ratio, CAR-antigen affinity, cancer and healthy cell antigen expression—individually and collectively impact treatment outcomes. Our analysis revealed that tuning CAR affinity modulates IL-2 production by balancing CAR T-cell proliferation and effector function. It also identified a novel multi-feature tuned treatment strategy for balancing selectivity and efficacy and provided insights into how spatial effects can impact relative treatment performance in different contexts. CARCADE facilitates deeper biological understanding of treatment design and could ultimately enable identification of promising treatment strategies to accelerate solid tumor CAR T-cell design-build-test cycles.