COVID-19 pandemic: Insights into genetic susceptibility to SARS-CoV-2 and host genes implications on virus spread, disease severity and outcomes

The outbreak of the newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) all over the world has caused global public health emergencies, international concern and economic crises. The systemic SARS-CoV-2 disease (COVID-19) can lead to death through causing unrestrained cytokines-storm and subsequent pulmonary shutdown among the elderly and patients with pre-existing comorbidities. Additionally, in comparison with poor nations without primary health care services, in developed countries with advanced healthcare system we can witness higher number of infections per one million people. In this review, we summarize the latest studies on genes associated with SARS-CoV-2 pathogenesis and propose possible mechanisms of the virus replication cycle and its triggered signaling pathways to encourage researchers to investigate genetic and immune profiles of the disease and try strategies for its treatment. Our review shows that immune response in people with different genetic background might vary as African and then Asian populations have lowest number of affected cases compared with European and American nations. Considering SARS-CoV-2 pathogenesis, we put forward some potentially important genetic gateways to COVID-19 infection including genes involved in the entry and replication of SARS-CoV-2 and the regulation of host immune response which might represent explanation for its spread, severity, and morality. Finally, we suggest that genetic alterations within these gateways could be critical factors in influencing geographical discrepancies of the virus, so it is essential to fully study them and design appropriated and reliable therapeutic agents against COVID-19.

Human Organoid and Supporting Technologies for Cancer and Toxicological Research

Recent progress in the field of organoid-based cell culture systems has enabled the use of patient-derived cells in conditions that resemble those in cancer tissue, which are better than two-dimensional (2D) cultured cell lines. In particular, organoids allow human cancer cells to be handled in conditions that resemble those in cancer tissue, resulting in more efficient establishment of cells compared with 2D cultured cell lines, thus enabling the use of multiple patient-derived cells with cells from different genetic background, in keeping with the heterogeneity of the cells. One of the most valuable points of using organoids is that human cells from either healthy or cancerous tissue can be used. Using genome editing technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein, organoid genomes can be modified to, for example, cancer-prone genomes. The normal, cancer, or genome-modified organoids can be used to evaluate whether chemicals have genotoxic or non-genotoxic carcinogenic activity by evaluating the cancer incidence, cancer progression, and cancer metastasis. In this review, the organoid technology and the accompanying technologies were summarized and the advantages of organoid-based toxicology and its application to pancreatic cancer study were discussed.

Integrated Analysis of Cecal Microbiome and Metabolome Revealed Different Inflammatory Reponses to Salmonella Enterica Serovar Enteritidis Between Reciprocal Crosses of Chicken

Background: Salmonella enterica serovar Enteritidis (S. Enteritidis) bacteria can colonize intestinal tract of chicken and transmit to humans, while the intestinal microbiota are resistant to their colonization. Our knowledge of the interplay between host, pathogen and microbiota is scarce, particularly in context of different genetic background of the host, such as the reciprocal cross.Results: Comprehensive analysis of microbiome and metabolome showed that 23.4% of genera and 11.6% of metabolites in the Cross, and 17.2% of genera and 25.1% of metabolites in the Reverse-cross were altered (P<0.05) in response to Salmonella infection. In comparison of the reciprocal crosses, all the co-differential genera and 73.1% of the co-differential metabolites were opposite in alteration trend. Phenylpropanoids and lipids were increased significantly in the Cross and in the Reverse-cross, respectively.Conclusions: A more extensive inflammatory response to S. Enteritidis might be triggered in the Reverse-cross than in the Cross, and the regulatory modes were different. The Reverse-cross upregulated pro- and anti-inflammatory factors simultaneously, while the Cross was aided with the phenylpropanoids produced by intestinal bacteria.

TP53 and NRAS are the Most Frequently Mutated Genes in Stool DNA of CRC Patients from Central Part of Iran

Colorectal cancer (CRC) rated among the three most diagnosed cancers and the fourth main cause of death worldwide. CRC is a curable cancer provided to be diagnosed at its early-stage. Colonoscopy, stool and blood-based tests are in use for CRC diagnosis/screening. Due to low patient compliance, low specificity and high rate of false results, more reliable methods with desired level of detection accuracy and high patients’ compliance are highly demanded. Detecting hotspot mutations in stool DNA emerged as a robust noninvasive alternative, but due to the different genetic background of various populations and hence varied mutation spectrum/prevalence, prior assessment of CRC mutations in the population is essential. Here, we have evaluated stool DNAs from CRC patients and controls using a NGS based 22 genes panel. Hotspot mutations in NRAS, FGFR3, SMAD4 and TP53 genes had higher prevalence among the CRC patients compare to normal controls. Patients were followed up in their post-surgical period. Six of them (12%) with TP53 mutations (2 patients had NRAS mutation as well) were died of cancer. Those harboring mutations in TP53 and/or NRAS would be regarded as high risk and should be provided with special care.

Loss of Function of OsARG Resulted in Pepper-Shaped Husk in Indica Rice

Grain shape is one of the most important and complex traits determining the grain yield in rice. In this study, we discovered two rice mutants with defective shape spikelets, designated as psh1-1/2 (pepper-shaped husk 1-1/2), which were both isolated from the tissue-culture-regenerated plants of indica cultivar Minghui 86. The two mutants showed the same mutant phenotypes, containing pepper-shaped spikelets; shorter, smaller and compact panicles; very low seed-setting rate; high percentage of split grains; and lower grain width. Genetic analysis indicated that the mutant phenotypes were controlled by a recessive gene. Gene mapping indicated that the target gene PSH1 was located on the short arm of chromosome 4. Sequencing analysis revealed that the two mutants each had a different nonsense mutation in OsARG, confirming that the target gene is OsARG. Compared with the previously reported OsARG mutant nglf-1, psh1-1/2 possessed some distinct mutant phenotypes, probably because of the influence of different genetic background, suggesting that OsARG may function differently under different genetic backgrounds.

Disparate Metabolomic Responses to Fructose Consumption between Different Mouse Strains and the Role of Gut Microbiota

High fructose consumption has been linked to metabolic syndrome, yet the fructose-induced phenotypes, gene expression, and gut microbiota alterations are distinct between mouse strains. In this study, we aim to investigate how fructose consumption shapes the metabolomic profiles of mice with different genetic background and microbiome. We used fructose-sensitive DBA/2J (DBA) and fructose-resistant C57BL/6J (B6) mice given 8% fructose or regular water for 12 weeks. Plasma and fecal metabolites were profiled using a liquid chromatography-tandem mass spectrometry based global metabolomic approach. We found that the baseline metabolomic profiles were different between DBA and B6 mice, particularly plasma metabolites involved in lipid metabolism and fecal metabolites related to dipeptide/amino acid metabolism. In response to fructose, DBA mice showed a distinct decrease of plasma branched chain fatty acids with concordantly increased branched chain amino acids, which were correlated with adiposity; B6 mice had significantly increased plasma cholesterol and total bile acids, accompanied by decreased fecal levels of farnesoid X receptor antagonist tauro-β-muricholate, which were correlated with fructose-responsive bacteria Dehalobacterium, Magibacteriaceae, and/or Akkermansia. Our results demonstrate that baseline metabolomic profiles differ and respond differentially to fructose between mice with different genetic background and gut microbiota, which may play a role in individualized risks to fructose-induced metabolic syndrome.

Genetic Basis for Lentil Adaptation to Summer Cropping in Northern Temperate Environments

ABSTRACTThe continued success of lentil (Lens culinaris Medik.) genetic improvement relies on the availability of broad genetic diversity and new alleles need to be identified and incorporated into the cultivated gene pool. Availability of robust and predictive markers greatly enhances the precise transfer of genomic regions from unadapted germplasm. Quantitative trait loci (QTLs) for key phenological traits in lentil were located using a recombinant inbreed line (RIL) population derived from a cross between an Ethiopian landrace (ILL 1704) and a northern temperate cultivar (CDC Robin). Field experiments were conducted at Sutherland research farm in Saskatoon and at Rosthern, Saskatchewan, Canada during 2018 and 2019. A linkage map was constructed using 21,634 SNPs located on seven linkage groups (LGs) which correspond to the seven haploid chromosomes of lentil. Eight QTL were identified for six phenological traits. Flowering related QTL were identified at two regions on LG6. FLOWERING LOCUS T (FT) genes were annotated within the flowering time QTL interval based on the lentil reference genome. Similarly, a major QTL for post-flowering developmental processes was located on LG5 with several senescence-associated genes annotated within the QTL interval. The flowering time QTL was validated in a different genetic background indicating the potential use of the identified markers for marker-assisted selection to precisely transfer genomic regions from exotic germplasm into elite crop cultivars without disrupting adaptation.Core IdeasStable QTL were located for key phenological traits in lentil that lead to regional adaptation.FT genes are candidates for controlling flowering time in lentil grown in temperate environments.A major locus controlling post-flowering developmental processes was located on lentil LG5 with several senescence-associated genes annotated within the QTL interval.Markers identified in this study can be useful for marker-assisted selection to precisely transfer genomic regions from exotic germplasm into elite lentil cultivars without disrupting adaptation.

Cerebrospinal Fluid Oligoclonal Immunoglobulin Gamma Bands and Long-term Disability Progression in Multiple Sclerosis: a Retrospective Cohort Study

Multiple sclerosis (MS) patients with and without the oligoclonal band (OCB) distribution of immunoglobulin gamma (IgG) in the cerebrospinal fluid (CSF) has a different genetic background and brain MRI features. In this study we have aimed to determine whether CSF-OCB status is associated with long-term disability outcomes. We used Swedish MS register data on clinically definite MS patients with known OCB status. Date of birth, MS onset and date at sustained Expanded Disability Status Scale (EDSS) score milestones 3, 4, 6, date at conversion to secondary progressive (SP) MS, sex, and immunomodulatory treatment (IMTs) duration were collected. Multivariate Cox regression models were used to investigate the association between OCB status and risk of reaching each milestone. The OCB-positive group reached disability milestones at earlier time and at younger age. OCB-positivity significantly increased the risk of reaching EDSS score 3.0 (HR=1.29, 95%CI: 1.12 to 1.48, P<0.001) and 4.0 (HR= 1.38, 95%CI: 1.17 to 1.63, P<0.001). The OCB-positive group had a 20 % higher risk to convert to SPMS. CSF-OCBs presence is associated with higher risk to reach EDSS milestones and to convert to SPMS. Our findings suggest higher disease modifying effect of OCB presence in the early inflammatory stages of MS.

Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.

Killing efficiency affected by mutually modulated PD-1 and PD-L1 expression via NKT-hepatoma cell interactions

Aim: To explore the expression of programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1), natural killer T (NKT) and hepatoma cells in coculture system, and the influence of abolishing PD-1 on antitumor efficiency. Materials & methods: CRISPR/Cas9 technology, flow cytometry, ELISA, CCK-8 assay and mouse models were performed to investigate the interactions between PD-1/PD-L1 expression on NKT and hepatoma cells, respectively. Results: The NKT and hepatoma cells mutually affected the expression of PD-1/PD-L1. The killing effect was positively correlated with NKT-mediated PD-L1 expression on hepatoma cells. Conclusion: Hepatoma cells in different genetic background responded differently to NKT-induced PD-L1 stimulation, and those cells with lower PD-L1 expression fail to PD-1 blocking intervention. Additionally, the killing effect was more time-efficient with PD-1 knockout than with monoclonal antibody blockade.