Gene Symbol Research Articles

Stitchr: stitching coding TCR nucleotide sequences from V/J/CDR3 information.

The study and manipulation of T cell receptors (TCRs) is central to multiple fields across basic and translational immunology research. Produced by V(D)J recombination, TCRs are often only recorded in the literature and data repositories as a combination of their V and J gene symbols, plus their hypervariable CDR3 amino acid sequence. However, numerous applications require full-length coding nucleotide sequences. Here we present Stitchr, a software tool developed to specifically address this limitation. Given minimal V/J/CDR3 information, Stitchr produces complete coding sequences representing a fully spliced TCR cDNA. Due to its modular design, Stitchr can be used for TCR engineering using either published germline or novel/modified variable and constant region sequences. Sequences produced by Stitchr were validated by synthesizing and transducing TCR sequences into Jurkat cells, recapitulating the expected antigen specificity of the parental TCR. Using a companion script, Thimble, we demonstrate that Stitchr can process a million TCRs in under ten minutes using a standard desktop personal computer. By systematizing the production and modification of TCR sequences, we propose that Stitchr will increase the speed, repeatability, and reproducibility of TCR research. Stitchr is available on GitHub.

Copy Number Variation Analysis of Euploid Pregnancy Loss.

Objectives: Copy number variant (CNV) is believed to be the potential genetic cause of pregnancy loss. However, CNVs less than 3 Mb in euploid products of conceptions (POCs) remain largely unexplored. The aim of this study was to investigate the features of CNVs less than 3 Mb in POCs and their potential clinical significance in pregnancy loss/fetal death. Methods: CNV data were extracted from a cohort in our institution and 19 peer-reviewed publications, and only those CNVs less than 3 Mb detected in euploid pregnancy loss/fetal death were included. We conducted a CNV map to analyze the distribution of CNVs in chromosomes using R packages karyoploteR_1.10.5. Gene names and annotated gene types covered by those CNVs were mined from the human Release 19 reference genome file and GENECODE database. We assessed the expression patterns and the consequences of murine knock-out of those genes using TiGER and Mouse Genome Informatics (MGI) databases. Functional enrichment and pathway analysis for genes in CNVs were performed using clusterProfiler V3.12.0. Result: Breakpoints of 564 CNVs less than 3 Mb were obtained from 442 euploid POCs, with 349 gains and 185 losses. The CNV map showed that CNVs were distributed in all chromosomes, with the highest frequency detected in chromosome 22 and the lowest frequency in chromosome Y, and CNVs showed a higher density in the pericentromeric and sub-telomeric regions. A total of 5,414 genes mined from the CNV regions (CNVRs), Gene Ontology (GO), and pathway analysis showed that the genes were significantly enriched in multiple terms, especially in sensory perception, membrane region, and tight junction. A total of 995 protein-coding genes have been reported to present mammalian phenotypes in MGI, and 276 of them lead to embryonic lethality or abnormal embryo/placenta in knock-out mouse models. CNV located at 19p13.3 was the most common CNV of all POCs. Conclusion: CNVs less than 3 Mb in euploid POCs distribute unevenly in all chromosomes, and a higher density was seen in the pericentromeric and sub-telomeric regions. The genes in those CNVRs are significantly enriched in biological processes and pathways that are important to embryonic/fetal development. CNV in 19p13.3 and the variations of ARID3A and FSTL3 might contribute to pregnancy loss.

DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021update).

DAVID is a popular bioinformatics resource system including a web server and web service for functional annotation and enrichment analyses of gene lists. It consists of a comprehensive knowledgebase and a set of functional analysis tools. Here, we report all updates made in 2021. The DAVID Gene system was rebuilt to gain coverage of more organisms, which increased the taxonomy coverage from 17 399 to 55 464. All existing annotation types have been updated, if available, based on the new DAVID Gene system. Compared with the last version, the number of gene-term records for most annotation types within the updated Knowledgebase have significantly increased. Moreover, we have incorporated new annotations in the Knowledgebase including small molecule-gene interactions from PubChem, drug-gene interactions from DrugBank, tissue expression information from the Human Protein Atlas, disease information from DisGeNET, and pathways from WikiPathways and PathBank. Eight of ten subgroups split from Uniprot Keyword annotation were assigned to specific types. Finally, we added a species parameter for uploading a list of gene symbols to minimize the ambiguity between species, which increases the efficiency of the list upload and eliminates confusion for users. These current updates have significantly expanded the Knowledgebase and enhanced the discovery power of DAVID.

L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact

The uptake transporter NaCT (gene symbol SLC13A5) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT, we tested whether arginine and the cardioactive L-arginine metabolites asymmetric dimethylarginine (ADMA) and L-homoarginine are also transported by human and mouse NaCT/Nact. Using HEK293 cells overexpressing human or mouse NaCT/Nact we characterized these substances as substrates. Furthermore, inhibition studies were performed using the arginine derivative symmetric dimethylarginine (SDMA), the NaCT transport inhibitor BI01383298, and the prototypic substrate citrate. Arginine and the derivatives ADMA and L-homoarginine were identified as substrates of human and mouse NaCT. Transport of arginine and derivatives mediated by human and mouse NaCT were dose-dependently inhibited by SDMA. Whereas BI01383298 inhibited only human NaCT-mediated citrate uptake, it inhibits the uptake of arginine and derivatives mediated by both human NaCT and mouse Nact. In contrast, the prototypic substrate citrate inhibited the transport of arginine and derivatives mediated only by human NaCT. These results demonstrate a so far unknown link between NaCT/Nact and L-arginine and its cardiovascular important derivatives.

The Use of "Retardation" in FRAXA, FMRP, FMR1 and Other Designations.

The European Fragile X Network met in Wroclaw, Poland, November 2021, and agreed to work towards the eradication of the word “retardation” in regard to the naming of the fragile X gene (FRAXA) and protein (FMRP). There are further genes which have “retardation” or abbreviations for “retardation” in their names or full designations, including FMR1, FMR2, FXR1, FXR2, NUFIP1, AFF1, CYFIP1, etc. “Retardation” was commonly used as a term in years past, but now any reference, even in an abbreviation, is offensive. This article discusses the stigmatisation associated with “retardation”, which leads to discrimination; the inaccuracy of using “retardation” in these designations; and the breadth of fragile X syndrome being beyond that of neurodiversity. A more inclusive terminology is called for, one which ceases to use any reference to “retardation”. Precedents for offensive gene names being altered is set out. The proposal is to approach the HGNC (HUGO [Human Genome Organisation] Gene Nomenclature Committee) for new terminology to be enacted. Ideas from other researchers in the field are welcomed.

Identification of novel alternative splicing associated with mastitis disease in Holstein dairy cows using large gap read mapping

BackgroundMastitis is a very common disease in the dairy industry that producers encounter daily. Transcriptomics, using RNA-Sequencing (RNA - Seq) technology, can be used to study the functional aspect of mastitis resistance to identify animals that have a better immune response to mastitis. When the cow has mastitis, not only genes but also specific mRNA isoforms generated via alternative splicing (AS) could be differentially expressed (DE), leading to the phenotypic variation observed. Therefore, the objective of this study was to use large gap read mapping to identify mRNA isoforms DE between healthy and mastitic milk somatic cell samples (N = 12). These mRNA isoforms were then categorized based on being 1) annotated mRNA isoforms for gene name and length, 2) annotated mRNA isoforms with different transcript length and 3) novel mRNA isoforms of non - annotated genes.ResultsAnalysis identified 333 DE transcripts (with at least 2 mRNA isoforms annotated, with at least one being DE) between healthy and mastitic samples corresponding to 303 unique genes. Of these 333 DE transcripts between healthy and mastitic samples, 68 mRNA isoforms are annotated in the bovine genome reference (ARS.UCD.1.2), 249 mRNA isoforms had novel transcript lengths of known genes and 16 were novel transcript lengths of non - annotated genes in the bovine genome reference (ARS.UCD.1.2). Functional analysis including gene ontology, gene network and metabolic pathway analysis was performed on the list of 288 annotated and unique DE mRNA isoforms. In total, 67 significant metabolic pathways were identified including positive regulation of cytokine secretion and immune response. Additionally, numerous DE novel mRNA isoforms showed potential involvement with the immune system or mastitis. Lastly, QTL annotation analysis was performed on coding regions of the DE mRNA isoforms, identifying overlapping QTLs associated with clinical mastitis and somatic cell score.ConclusionThis study identified novel mRNA isoforms generated via AS that could lead to differences in the immune response of Holstein dairy cows and be potentially implemented in future breeding programs.

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies.

In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

GeneCup: mining PubMed and GWAS catalog for gene-keyword relationships.

Interpreting and integrating results from omics studies typically requires a comprehensive and time consuming survey of extant literature. GeneCup is a literature mining web service that retrieves sentences containing user-provided gene symbols and keywords from PubMed abstracts. The keywords are organized into an ontology and can be extended to include results from human genome-wide association studies. We provide a drug addiction keyword ontology that contains over 300 keywords as an example. The literature search is conducted by querying the PubMed server using a programming interface, which is followed by retrieving abstracts from a local copy of the PubMed archive. The main results presented to the user are sentences where gene symbol and keywords co-occur. These sentences are presented through an interactive graphical interface or as tables. All results are linked to the original abstract in PubMed. In addition, a convolutional neural network is employed to distinguish sentences describing systemic stress from those describing cellular stress. The automated and comprehensive search strategy provided by GeneCup facilitates the integration of new discoveries from omic studies with existing literature. GeneCup is free and open source software. The source code of GeneCup and the link to a running instance is available at https://github.com/hakangunturkun/GeneCup.

OSgc: A Web Portal to Assess the Performance of Prognostic Biomarkers in Gastric Cancer.

Evaluating the prognostic value of genes of interest in different populations of gastric cancer (GC) is difficult and time-consuming for basic and translational researchers even though many datasets are available in public dataset depositories. In the current study, we developed a robust web-based portal called OSgc (Online consensus Survival analysis of gastric cancer) that enables easy and swift verification of known and novel biomarker candidates in GC. OSgc is composed of gene expression profiling data and clinical follow-up information of 1,824 clinical GC cases, which are collected from 7 public independent datasets derived from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). By OSgc, users input the official gene symbol and will promptly retrieve the Kaplan–Meier survival plot with hazard ratio (HR) and log rank p value on the output webpage, by which users could assess the prognostic value of interesting genes for GC patients. Five survival end points containing overall survival, progression-free survival, progression-free interval, relapse-free survival, and disease-free survival could be measured in OSgc. OSgc can greatly help cancer biologists and clinicians to explore the effect of gene expression on patient survival. OSgc is freely available without restrictions at http://bioinfo.henu.edu.cn/GC/GCList.jsp.

Bi-directional long short term memory using recurrent neural network for biological entity recognition

<p>Biomedical named entity recognition (NER) aims at identifying medical entities from unstructured data. A quintessential task in the supervision of biological databases is handling biomedical terms such as cancer type, DeoxyriboNucleic and RiboNucleic Acid, gene and protein name, and others. However, due to the massive size of online medical repositories, data processing becomes a challenge for a gazetteer without proper annotation. The traditional NER systems depend on feature engineering that is tedious and time-consuming. The research study presents a new model for Bio-NER using recurrent neural network. Unlike existing approaches, the proposed method uses bidirectional traversing with GloVe vector modelling performed at character and word levels. Bio-NER is performed in three stages; firstly, the relevant medical entities in electronic medical records from PubMed were extracted using the skip-gram model. Secondly, a vector representation for each word is created through the 1-hot method. Thirdly, the weights of the recurrent neural network (RNN) layers are adjusted using backward propagation. Finally, the long-short-term memory cells store the previously encountered medical entity to tackle context-dependency. The accuracy and F-score are calculated for each medical entity type. The MacroR, MacroP, and MacroF are equal to 0.86, 0.88, and 0.87. The overall accuracy achieved was 94%.</p>

EP369: Increased automation reduces turnaround time for submissions to ClinVar

eP369: Increased automation reduces turnaround time for submissions to ClinVar

Development of Biomarkers to Predict Recurrence by Determining the Metastatic Ability of Cancer Cells.

Adjuvant chemotherapy is administered to cancer patients after curative resection but is unnecessary when patients without micro-metastatic lesions undergo a perfectly curative surgical procedure. Patients who need adjuvant chemotherapy are those with micro-metastases outside the resection area that are not detectable by imaging, despite curative resection at primary sites. If biomarkers that reflect metastatic potential could be developed, personalized adjuvant chemotherapy could be provided in clinical settings. Actinin-4 (ACTN4, gene name ACTN4) is an actin-bundling protein identified in 1998 as a novel molecule involved in cancer invasion and metastasis. Overexpression of actinin-4 protein in cancer cells leads to an invasive phenotype, and patients with gene amplification of ACTN4 have a worse prognosis than patients with a normal copy number for cancers of the pancreas, lung, and salivary glands, among others. This review summarizes the biological roles of actinin-4 in cancer invasion and metastasis and examines the potential usefulness of actinin-4 as a biomarker for evaluation of metastatic ability.

Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p<0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p<0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]

BnVIR: bridging the genotype-phenotype gap to accelerate mining of candidate variations underlying agronomic traits in Brassica napus

BnVIR: bridging the genotype-phenotype gap to accelerate mining of candidate variations underlying agronomic traits in Brassica napus

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc spf‐ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8‐mediated delivery of a short hairpin RNA in Otc spf‐ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otc spf‐ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

Fascin enhances the vulnerability of breast cancer to erastin-induced ferroptosis

Ferroptosis, which is characterized by intracellular iron accumulation and lipid peroxidation, is a newly described form of regulated cell death that may play a key role in tumour suppression. In the present study, we investigated the expression profiles and biological effects of fascin actin-bundling protein 1 (Fascin, gene name FSCN1) in breast cancer. In addition, bioinformatics analysis of the TCGA cancer database and gain- and loss-of-function studies showed that Fascin enhances sensitivity to erastin-induced ferroptosis. Mechanistically, Fascin directly interacts with cysteine/glutamate transporter (xCT, gene name SLC7A11) and decreases its stability via the ubiquitin-mediated proteasome degradation pathway. Furthermore, we observed that Fascin is substantially upregulated in tamoxifen-resistant breast cancer cell lines, and drug-resistant cells were also more vulnerable to erastin-induced ferroptosis. Taken together, our findings reveal a previously unidentified role of Fascin in ferroptosis by regulating xCT. Thus, ferroptosis activation in breast cancer with high Fascin level may serve as a potential treatment.

Prediction the Molecular Mechanism of Shengmai Injection in Acute Treatment of COVID-19 Based on Network Pharmacology.

Objective: To predict the mechanism of Shengmai Injection (SMI) in the acute treatment of COVID-19 by network pharmacology and molecular docking. Methods: Search the compounds in the Traditional Chinese Medicine Systems Pharmacology (TCMSP), and screen them by Drug-like properties (DL) and Oral bioavailability (OB); Using PharmMapper database and GeneCards database to collect compounds targets and COVID-19 targets, and using UniProt database to standardize the names of target genes; Using DAVID database for KEGG pathway annotation and GO bioinformatics analysis; Using Cytoscape 3.8.2 software and STRING 10.5 database to construct “Component-Target-Pathway” network and Protein-Protein Interaction network (PPI); Using molecular docking to predict the binding ability of key compounds and key proteins. Results: A total of 34 active components, 38 core targets and 180 signaling pathways were screened out. The results of molecular docking showed that Schisantherin A and Moupinamide have strong binding with EGFR and MAPK1. Conclusion: The key active compounds of SMI in the treatment of COVID-19 may be Schisantherin A and Moupinamide, and the molecular mechanism may be related to key targets such as EGFR and MAPK1, and may be involved in the PI3K-Akt signaling pathway and MAPK signaling pathway.

Melatonin as a Smart Protector of Pregnancy in Dairy Cows.

The experimental objective was to examine the role of melatonin and its pathways in the maintenance of pregnancy in lactating dairy cows. Blood samples were collected at days 0, 16 and 32 after timed AI from cows (n = 200) in order to consider plasma melatonin concentrations and to conduct AOPP (advanced oxidation products of proteins) and TBARS (thiobarbituric acid reactive substances) tests. Luminal endometrial cells were collected at day 16 using a Cytobrush in all cows to determine mRNA expressions of melatonin receptor 1 (MT1), mouse double minute 2 (MDM2), MDM2 binding protein (MTBP), BCL2-associated X, apoptosis Regulator (BAX), p53 upregulated modulator of apoptosis (PUMA, gene symbol BBC3), mucin 1 (MUC1) and leukemia inhibitory factor (LIF). Plasma concentrations of melatonin were significantly greater in pregnant cows diagnosed pregnant at day 16 who sustained pregnancy to day 32 compared to nonpregnant cows at day 16, or pregnant at day 16 and who lost embryos by days 32. Concentrations of AOPP and TBARS were greater in nonpregnant cows at day 16 or pregnant at day 16 and who lost embryos by days 32 compared to those diagnosed pregnant at day 16 and who sustained pregnancy to day 32. In pregnant cows, endometrial mRNA expressions of MDM2, MTBP, MTR1 and LIF were higher compared to pregnant–embryo-loss cows (p < 0.05). In contrast, mRNA expressions of BBC3 and MUC1 were greater at day 16 in pregnant–embryo-loss cows compared to pregnant cows (p < 0.05). In conclusion, melatonin status is a modulator of embryo well-being and maintenance of pregnancy in lactating dairy cows.

Differential expression analyses reveal extensive transcriptional plasticity induced by temperature in New Zealand silver trevally (Pseudocaranx georgianus).

Ectotherm species, such as marine fishes, depend on environmental temperature to regulate their vital functions. In finfish aquaculture production, being able to predict physiological responses in growth and other economic traits to temperature is crucial to address challenges inherent in the selection of grow‐out locations. This will become an even more significant issue under the various predicted future climate change scenarios. In this study, we used the marine teleost silver trevally (Pseudocaranx georgianus), a species currently being explored as a candidate for aquaculture in New Zealand, as a model to study plasticity in gene expression patterns and growth in response to different temperatures. Using a captive study population, temperature conditions were experimentally manipulated for 1 month to mimic seasonal extremes. Phenotypic differences in growth were measured in 400 individuals, and gene expression patterns of pituitary gland and liver were determined in a subset of 100 individuals. Results showed that growth increased 50% in the warmer compared with the colder condition, suggesting that temperature has a large impact on metabolic activities associated with growth. A total of 265,116,678 single‐end RNA sequence reads were aligned to the trevally genome, and 28,416 transcript models were developed (27,887 of these had GenBank accessions, and 17,980 unique gene symbols). Further filtering reduced this set to 8597 gene models. 39 and 238 differentially expressed genes (DEGs) were found in the pituitary gland and the liver, respectively (|log2FC| > 0.26, p‐value < 0.05). Of these, 6 DEGs showed a common expression pattern between both tissues, all involved in housekeeping functions. Temperature‐modulated growth responses were linked to major pathways affecting metabolism, cell regulation and signalling, previously shown to be important for temperature tolerance in other fish species. An interesting finding of this study was that genes linked to the reproductive system were up‐regulated in both tissues in the high treatment, indicating the onset of sexual maturation. Few studies have investigated the thermal plasticity of the gene expression in the main organs of the somatotropic axis simultaneously. Our findings indicate that trevally exhibit substantial growth differences and predictable plastic regulatory responses to different temperature conditions. We identified a set of genes that provide a list of candidates for further investigations for selective breeding objectives and how populations may adapt to increasing temperatures.

Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery.

Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes.