Host Genetic Factors, Comorbidities and the Risk of Severe COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was varied in disease symptoms. We aim to explore the effect of host genetic factors and comorbidities on severe COVID-19 risk. METHODS: A total of 20,320 COVID-19 patients in the UK Biobank cohort were included. Genome-wide association analysis (GWAS) was used to identify host genetic factors in the progression of COVID-19 and a polygenic risk score (PRS) consisted of 86 SNPs was constructed to summarize genetic susceptibility. Colocalization analysis and Logistic regression model were used to assess the association of host genetic factors and comorbidities with COVID-19 severity. All cases were randomly split into training and validation set (1:1). Four algorithms were used to develop predictive models and predict COVID-19 severity. Demographic characteristics, comorbidities and PRS were included in the model to predict the risk of severe COVID-19. The area under the receiver operating characteristic curve (AUROC) was applied to assess the models' performance. RESULTS: We detected an association with rs73064425 at locus 3p21.31 reached the genome-wide level in GWAS (odds ratio: 1.55, 95% confidence interval: 1.36-1.78). Colocalization analysis found that two genes (SLC6A20 and LZTFL1) may affect the progression of COVID-19. In the predictive model, logistic regression models were selected due to simplicity and high performance. Predictive model consisting of demographic characteristics, comorbidities and genetic factors could precisely predict the patient's progression (AUROC = 82.1%, 95% CI 80.6-83.7%). Nearly 20% of severe COVID-19 events could be attributed to genetic risk. CONCLUSION: In this study, we identified two 3p21.31 genes as genetic susceptibility loci in patients with severe COVID-19. The predictive model includes demographic characteristics, comorbidities and genetic factors is useful to identify individuals who are predisposed to develop subsequent critical conditions among COVID-19 patients.

Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

A pharmacokinetic drug-drug interaction study between rosuvastatin and emvododstat, a potent anti-SARS-CoV-2 (COVID-19) DHODH (dihydroorotate dehydrogenase) inhibitor.

A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) management. Emvododstat (PTC299) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by the inhibition of dihydroorotate dehydrogenase (DHODH) to reduce SARS-CoV-2 replication. DHODH is the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction study was performed to determine whether emvododstat was an inhibitor of breast cancer resistance protein (BCRP) transporters in humans. Potential drug-drug interactions (DDIs) between emvododstat and a BCRP transporter substrate (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations before and after emvododstat administration. There was no apparent difference in rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin concentrations (Cmax ) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the concentration-time curve (AUC) from time 0 to the last measurable plasma concentration was 45 616 and 48 975 h·pg/mL when administered alone and after 7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean ratios for Cmax and AUC were approximately equal to 1. Overall, administration of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a single dose of rosuvastatin was safe and well tolerated. Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered.

IFN-stimulated metabolite transporter ENT3 facilitates viral genome release.

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.

Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa.

Antimicrobial resistance is an old and silent pandemic. Resistant organisms emerge in parallel with new antibiotics, leading to a major global public health crisis over time. Antibiotic resistance may be due to different mechanisms and against different classes of drugs. These mechanisms are usually found in the same organism, giving rise to multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. One resistance mechanism that is closely associated with the emergence of MDR and XDR bacteria is the efflux of drugs since the same pump can transport different classes of drugs. In Gram-negative bacteria, efflux pumps are present in two configurations: a transmembrane protein anchored in the inner membrane and a complex formed by three proteins. The tripartite complex has a transmembrane protein present in the inner membrane, a periplasmic protein, and a porin associated with the outer membrane. In Pseudomonas aeruginosa, one of the main pathogens associated with respiratory tract infections, four main sets of efflux pumps have been associated with antibiotic resistance: MexAB-OprM, MexXY, MexCD-OprJ, and MexEF-OprN. In this review, the function, structure, and regulation of these efflux pumps in P. aeruginosa and their actions as resistance mechanisms are discussed. Finally, a brief discussion on the potential of efflux pumps in P. aeruginosa as a target for new drugs is presented.

Therapeutic strategy targeting host lipolysis limits infection by SARS-CoV-2 and influenza A virus.

The biosynthesis of host lipids and/or lipid droplets (LDs) has been studied extensively as a putative therapeutic target in diverse viral infections. However, directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated. Here, we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids (FFAs) at the late stage of diverse RNA viral infections, which represents a broad-spectrum antiviral target. Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection, thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy. The replication of SARS-CoV-2 and influenza A virus (IAV), which is suppressed by the treatment with LD-associated lipases inhibitors, is rescued by supplementation with FFAs. The administration of lipase inhibitors, either individually or in a combination with virus-targeting drugs, protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters. Moreover, the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2- and IAV-challenged animals, a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients. In conclusion, the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19- and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.

Host Genetic Risk Factors Associated with COVID-19 Susceptibility and Severity in Vietnamese.

Since the emergence and rapid transmission of SARS-CoV-2, numerous scientific reports have searched for the association of host genetic variants with COVID-19, but the data are mostly acquired from Europe. In the current work, we explored the link between host genes (SARS-CoV-2 entry and immune system related to COVID-19 sensitivity/severity) and ABO blood types with COVID-19 from whole-exome data of 200 COVID-19 patients and 100 controls in Vietnam. The O blood type was found to be a protective factor that weakens the worst outcomes of infected individuals. For SARS-CoV-2 susceptibility, rs2229207 (TC genotype, allele C) and rs17860118 (allele T) of IFNAR2 increased the risk of infection, but rs139940581 (CT genotype, allele T) of SLC6A20 reduced virus sensitivity. For COVID-19 progress, the frequencies of rs4622692 (TG genotype) and rs1048610 (TC genotype) of ADAM17 were significantly higher in the moderate group than in the severe/fatal group. The variant rs12329760 (AA genotype) of TMPRSS2 was significantly associated with asymptomatic/mild symptoms. Additionally, rs2304255 (CT genotype, allele T) of TYK2 and rs2277735 (AG genotype) of DPP9 were associated with severe/fatal outcomes. Studies on different populations will give better insights into the pathogenesis, which is ethnic-dependent, and thus decipher the genetic factor's contribution to mechanisms that predispose people to being more vulnerable to COVID-19.

The REEP family of proteins: Molecular targets and role in pathophysiology.

Receptor expression-enhancing proteins (REEPs) are an evolutionarily conserved protein family that is pivotal to the structure and function of the endoplasmic reticulum (ER). The REEP family can be classified into two major subfamilies in higher species, the REEP1-4 and REEP5-6 subfamilies. Within the REEP1-4 subfamily, REEP1 and REEP2 are closely related, and REEP3 and REEP4 are similarly related. The REEP family is widely distributed in various tissues. Recent studies indicate that the REEP family is involved in many pathological and physiological processes, such as ER morphogenesis and remodeling, microtubule cytoskeleton regulation, and the trafficking and expression of G protein-coupled receptors (GPCRs). Moreover, the REEP family plays crucial roles in the occurrence and development of many diseases, including neurological diseases, diabetes, retinal diseases, cardiac diseases, infertility, obesity, oligoarticular juvenile idiopathic arthritis (OJIA), COVID-19, and cancer. In the present review, we describe the distribution and structure of the REEP family. Furthermore, we summarize the functions and the associated diseases of this family. Based on the pleiotropic actions of the REEP family, the study of its family members is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.

Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening.

We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure-activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series.

Investigating underlying human immunity genes, implicated diseases and their relationship to COVID-19.

Aim: A human immunogenetics variation study was conducted in samples collected from diverse COVID-19 populations. Materials & methods: Whole-genome and whole-exome sequencing (WGS/WES), data processing, analysis and visualization pipeline were applied to identify variants associated with genes of interest. Results: A total of 2886 mutations were found across the entire set of 13 genomes. Functional annotation of the gene variants revealed mutation type and protein change. Many variants were found to be biologically implicated in COVID-19. The involvement of these genes was also found in multiple other diseases. Conclusion: The analysis determined that ACE2, TMPRSS4, TMPRSS2, SLC6A20 and FYCOI had functional implications and TMPRSS4 was the gene most altered in virally infected patients.

The quest to establish an understanding of the genetics underlying COVID-19 is a central focus of life sciences today. COVID-19 is triggered by SARS-CoV-2, a single-stranded RNA respiratory virus. Several clinical-genomics studies have emerged positing different human gene mutations occurring due to COVID-19. A global analysis of these genes was conducted targeting major components of the immune system to identify possible variations likely to be involved in COVID-19 predisposition. Gene-variant analysis was performed on whole-genome sequencing samples collected from diverse populations. ACE2, TMPRSS4, TMPRSS2, SLC6A20 and FYCOI were found to have functional implications and TMPRSS4 may have a role in the severity of clinical manifestations of COVID-19.

The unfavorable clinical outcome of COVID-19 in smokers is mediated by H3K4me3, H3K9me3 and H3K27me3 histone marks.

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.

Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.

SIT1 transporter as a potential novel target in treatment of COVID-19.

Studies published earlier this year demonstrated the association of the solute carrier SLC6A20 gene with the risk and severity of COVID-19. The SLC6A20 protein product (Sodium-dependent Imino Transporter 1 (SIT1)) is involved in the transport of amino acids, including glycine. Here we summarized the results of recent studies demonstrating the interaction of SIT1 with the ACE2 receptor for SARS-CoV-2 as well as an observed association of SLC6A20 with the risk and traits of Type 2 diabetes (T2D). Recently, it was also proposed that SLC6A20 represents the novel regulator of glycine levels and that glycine has beneficial effects against the proinflammatory cytokine secretion induced by SARS-CoV-2 infection. Ivermectin, as a partial agonist of glycine-gated chloride channels, was also recently suggested to interfere with the COVID-19 cytokine storm by inducing the activation of glycine receptors. Furthermore, plasma glycine levels are found to be decreased in diabetic patients. Thus, further clinical trials are warranted to confirm the potential favorable effects of targeting the SIT1 transporter and glycine levels in the treatment of COVID-19, particularly for the severe case of disease associated with hyperglycemia, inflammation, and T2D. These findings suggest that SIT1 may potentially represent one of the missing pieces in the complex puzzle observed between these two pandemic diseases and the potential novel target for their efficient treatment.

Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease.

The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.

Biotin-thiamine responsive basal ganglia disease in the era of COVID-19 outbreak diagnosis not to be missed: A case report.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTRBGD) is a rare treatable autosomal recessive neurometabolic disorder characterized by progressive encephalopathy that eventually leads to severe disability and death if not treated with biotin and thiamine. BTRBGD is caused by mutations in the SLC19A3 gene on chromosome 2q36.6, encoding human thiamine transporter 2 (hTHTR2). Episodes of BTRBGD are often triggered by febrile illness. CASE REPORT: The patient was 2 years 10 months old male child presented with fever and progressive acute encephalopathy associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus infection. MRI revealed bilateral symmetrical high signal involving both basal ganglia and medial thalami which is swollen with central necrosis, initially diagnosed as acute necrotizing encephalomyelitis with increased severity. Genetic analysis revealed BTRBGD. CONCLUSION: BTRBGD requires high index of suspicion in any patient presenting with acute encephalopathy, characteristic MRI findings (that are difficult to differentiate from necrotizing encephalopathy), regardless of the existence of a proven viral infection.

Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study.

Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors, and NPC1L1 inhibitior) on COVID-19 outcomes using two-sample Mendelian randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL cholesterol from genome-wide association study). Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) were used to calculate the effect estimates. Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.06-1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR = 1.32, 95% CI = 1.00-1.74). No consistent evidence from both analyses was found for other associations. Conclusions: This two-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization. Funding: Start-up Fund for high-level talents of Fujian Medical University.

The virus SARS-CoV-2 has caused millions of infections and deaths during the COVID-19 pandemic, but as of December 2021, no new drugs targeted to SARS-CoV-2 specifically exist. Thus, it is important to identify existing drugs that can reduce the infection and mortality of this virus, since repurposing old drugs is faster and cheaper than developing new ones. Fats, such as cholesterol, can play an important role in viral infections, meaning that drugs intended to lower the levels of fats in the blood could have a protective effect against SARS-CoV-2. To test this hypothesis, Huang, Xiao, et al. carried out a Mendelian randomization study to investigate if there is a link between drugs that lower fats and outcomes of SARS-CoV-2 infection, including susceptibility, hospitalization, and severe disease. This approach consists on grouping people according to their version of a particular gene, which minimizes the effect of variables that can cause spurious associations, something known as confounding bias. Thus, Mendelian randomization studies allow scientists to disentangle cause and effect. Using this method, Huang, Xiao, et al. found an association between statins (a type of drug that decreases the levels of bad cholesterol) and a reduced risk of being hospitalized after being infected with SARS-CoV-2. These findings suggest that statins could benefit patients infected with SARS-CoV-2, and indicate that they should be prioritized in future clinical trials for treating COVID-19.

In vitro metabolism, pharmacokinetics and drug interaction potentials of emvododstat, a DHODH inhibitor.

Emvododstat was identified as a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19. The objective of this paper is to evaluate the metabolism, pharmacokinetics, and drug interaction potentials of emvododstat.Emvododstat showed high binding to plasma protein with minimal distribution into blood cells in mouse, rat, dog, monkey, and human whole blood.O-Demethylation followed by glucuronidation appeared to be the major metabolic pathway in rat, dog, monkey, and human hepatocytes. CYP2C8, 2C19, 2D6, and 3A4 were involved in O-desmethyl emvododstat metabolite formation. Both emvododstat and O-desmethyl emvododstat inhibited CYP2D6 activity and induced CYP expression to different extents in vitro.Emvododstat and O-desmethyl emvododstat inhibited BCRP transporter activity but did not inhibit bile salt transporters and other efflux or uptake transporters. Neither emvododstat nor O-desmethyl emvododstat was a substrate for common efflux or uptake transporters investigated.Emvododstat is bioavailable in mice, rats, dogs, and monkeys following a single oral dose. The absorption was generally slow with the mean plasma Tmax ranging from 2 to 5 h; plasma exposure of O-desmethyl emvododstat was lower in rodents, but relatively higher in dogs and monkeys.

Expression of SARS-CoV-2 entry factors, electrolyte, and mineral transporters in different mouse intestinal epithelial cell types.

Angiotensin-converting enzyme 2 (ACE2) and transmembrane proteases (TMPRSS) are multifunctional proteins required for SARS-CoV-2 infection or for amino acid (AA) transport, and are abundantly expressed in mammalian small intestine, but the identity of the intestinal cell type(s) and sites of expression are unclear. Here we determined expression of SARS-CoV-2 entry factors in different cell types and then compared it to that of representative AA, electrolyte, and mineral transporters. We tested the hypothesis that SARS-CoV-2, AA, electrolyte, and mineral transporters are expressed heterogeneously in different intestinal cell types by making mouse enteroids enriched in enterocytes (ENT), goblet (GOB), Paneth (PAN), or stem (ISC) cells. Interestingly, the expression of ACE2 was apical and modestly greater in ENT, the same pattern observed for its associated AA transporters B0 AT1 and SIT1. TMPRSS2 and TMPRSS4 were more highly expressed in crypt-residing ISC. Expression of electrolyte transporters was dramatically heterogeneous. DRA, NBCe1, and NHE3 were greatest in ENT, while those of CFTR and NKCC1 that play important roles in secretory diarrhea, were mainly expressed in ISC and PAN that also displayed immunohistochemically abundant basolateral NKCC1. Intestinal iron transporters were generally expressed higher in ENT and GOB, while calcium transporters were expressed mainly in PAN. Heterogeneous expression of its entry factors suggests that the ability of SARS-CoV-2 to infect the intestine may vary with cell type. Parallel cell-type expression patterns of ACE2 with B0 AT1 and SIT1 provides further evidence of ACE2's multifunctional properties and importance in AA absorption.

Rice SUT and SWEET Transporters.

Sugar transporters play important or even indispensable roles in sugar translocation among adjacent cells in the plant. They are mainly composed of sucrose-proton symporter SUT family members and SWEET family members. In rice, 5 and 21 members are identified in these transporter families, and some of their physiological functions have been characterized on the basis of gene knockout or knockdown strategies. Existing evidence shows that most SUT members play indispensable roles, while many SWEET members are seemingly not so critical in plant growth and development regarding whether their mutants display an aberrant phenotype or not. Generally, the expressions of SUT and SWEET genes focus on the leaf, stem, and grain that represent the source, transport, and sink organs where carbohydrate production, allocation, and storage take place. Rice SUT and SWEET also play roles in both biotic and abiotic stress responses in addition to plant growth and development. At present, these sugar transporter gene regulation mechanisms are largely unclear. In this review, we compare the expressional profiles of these sugar transporter genes on the basis of chip data and elaborate their research advances. Some suggestions concerning future investigation are also proposed.

Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that modulate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.