Extreme Phenotypes Research Articles

High miR-133a levels in the circulation anticipates presentation of clinical events in familial hypercholesterolaemia patients.

Presentation of acute events in patients with atherosclerosis remains unpredictable even after controlling for classical risk factors. MicroRNAs (miRNAs) measured in liquid biopsies could be good candidate biomarkers to improve risk prediction. Here, we hypothesized that miRNAs could predict atherosclerotic plaque progression and clinical event presentation in familial hypercholesterolaemia (FH) patients. Circulating miRNAs (plasma, exosomes, and microvesicles) were investigated by TaqMan Array and RT-qPCR assays. Patients with genetic diagnosis of FH and healthy relatives from the SAFEHEART cohort were included. A differential signature of 10 miRNA was obtained by comparing two extreme phenotypes consisting of FH patients suffering a cardiovascular event (CVE) within a 8-year follow-up period (FH-CVE, N = 42) and non-FH hypercholesterolaemic relatives from the same cohort, matched for age and treatment, without CVE during the same period (nFH-nCVE, N = 30). The validation studies included two independent groups of patients with FH background (discovery group, N = 89, validation group N = 196), developing a future CVE (FH-CVE) or not (FH-nCVE) within the same time period of follow-up. Of the 10 miRNAs initially selected, miR-133a was significantly higher in FH-CVE than in FH-nCVE patients. Receiver operating characteristic analysis confirmed miR-133a as the best microRNA for predicting CVE in FH patients (0.76 ± 0.054; P < 0.001). Furthermore, Kaplan-Meier and COX analysis showed that high plasma miR-133a levels associated to the higher risk of presenting a CVE within the next 8 years (hazard ratio 3.89, 95% confidence interval 1.88-8.07; P < 0.001). In silico analysis of curate biological interactions related miR-133a with target genes involved in regulation of the cell-membrane lipid-receptor LRP6 and inflammatory cytokines (CXCL8, IL6, and TNF). These predictions were experimentally proven in human macrophages and endothelial cells transfected with agomiR-133a. Elevated levels of miR-133a in the circulation anticipate those FH patients that are going to present a clinical CVE within the next 2 years (average). Mechanistically, miR-133a is directly related with lipid- and inflammatory signalling in key cells for atherosclerosis progression.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

A proteomic study of resistance to Brown Ring disease in the Manila clam, Ruditapes philippinarum

Marine mollusk aquaculture has more than doubled over the past twenty years, accounting for over 15% of total aquaculture production in 2016. Infectious disease is one of the main limiting factors to the development of mollusk aquaculture, and the difficulties inherent to combating pathogens through antibiotic therapies or disinfection have led to extensive research on host defense mechanisms and host-pathogen relationships. It has become increasingly clear that characterizing the functional profiles of response to a disease is an essential step in understanding resistance mechanisms and moving towards more effective disease control. The Manila clam, Ruditapes philippinarum, is a main cultured bivalve species of economic importance which is affected by Brown Ring disease (BRD), an infection induced by the bacterium Vibrio tapetis.In this study, juvenile Manila clams were subjected to a 28-day controlled challenge with Vibrio tapetis, and visual and molecular diagnoses were carried out to distinguish two extreme phenotypes within the experimental clams: uninfected (“RES”, resistant) and infected (“DIS”, diseased) post-challenge. Total protein extractions were carried out for resistant and diseased clams, and proteins were identified using LC-MS/MS. Protein sequences were matched against a reference transcriptome of the Manila clam, and protein intensities based on label-free quantification were compared to reveal 49 significantly accumulated proteins in resistant and diseased clams. Proteins with known roles in pathogen recognition, lysosome trafficking, and various aspects of the energy metabolism were more abundant in diseased clams, whereas those with roles in redox homeostasis and protein recycling were more abundant in resistant clams.Overall, the comparison of the proteomic profiles of resistant and diseased clams after a month-long controlled challenge to induce the onset of Brown Ring disease suggests that redox homeostasis and maintenance of protein structure by chaperone proteins may play important and interrelated roles in resistance to infection by Vibrio tapetis in the Manila clam.

Kinome Analysis of Honeybee (Apis mellifera L.) Dark-Eyed Pupae Identifies Biomarkers and Mechanisms of Tolerance to Varroa Mite Infestation

The mite Varroa destructor is a serious threat to honeybee populations. Selective breeding for Varroa mite tolerance could be accelerated by biomarkers within individual bees that could be applied to evaluate a colony phenotype. Previously, we demonstrated differences in kinase-mediated signaling between bees from colonies of extreme phenotypes of mite susceptibility. We expand these findings by defining a panel of 19 phosphorylation events that differ significantly between individual pupae from multiple colonies with distinct Varroa mite tolerant phenotypes. The predictive capacity of these biomarkers was evaluated by analyzing uninfested pupae from eight colonies representing a spectrum of mite tolerance. The pool of biomarkers effectively discriminated individual pupae on the basis of colony susceptibility to mite infestation. Kinome analysis of uninfested pupae from mite tolerant colonies highlighted an increased innate immune response capacity. The implication that differences in innate immunity contribute to mite susceptibility is supported by the observation that induction of innate immune signaling responses to infestation is compromised in pupae of the susceptible colonies. Collectively, biomarkers within individual pupae that are predictive of the susceptibility of colonies to mite infestation could provide a molecular tool for selective breeding of tolerant colonies.

Modifier genes in SCN1A‐related epilepsy syndromes

Background SCN1A is one of the most important epilepsy‐related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A‐related phenotypes. We investigate the presence of rare and more common variants in epilepsy‐related genes as potential modifiers of SCN1A‐related disease severity.Methods87 patients with SCN1A‐related epilepsy were investigated. Whole‐exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database.ResultsStatistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of <0.05. Patients with extreme phenotypes showed much greater excesses of epilepsy gene variants than patients with intermediate phenotypes.ConclusionOur results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic, may play a large role in modulating SCN1A phenotypes. They may modify the phenotypes of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients.

Immune-Endocrine Links to Gregariousness in Wild House Mice.

Social interactions are critically important for survival and impact overall-health, but also impose costs on animals, such as exposure to contagious agents. The immune system can play a critical role in modulating social behavior when animals are sick, as has been demonstrated within the context of “sickness behaviors.” Can immune molecules affect or be affected by social interactions even when animals are not sick, therefore serving a role in mediating pathogen exposure? We tested whether markers of immune function in both the blood and the brain are associated with gregariousness, quantified as number of animals interacted with per day. To do this, we used remote tracking of social interactions of a wild population of house mice (Mus musculus domesticus) to categorize animals in terms of gregariousness. Blood, hair, brain and other tissue samples from animals with extreme gregariousness phenotypes were collected. We then tested whether the levels of three important cytokines (TNF-α, IFN-γ and IL-1β) in the serum, cortex and hypothalamus of these animals could be explained by the gregariousness phenotype and/or sex of the mice. Using the hair as a long-term quantification of steroid hormones, we also tested whether corticosterone, progesterone and testosterone differed by social phenotype. We found main effects of gregariousness and sex on the serum levels of TNF-α, but not on IFN-γ or IL-1β. Brain gene expression levels were not different between phenotypes. All hair steroids tended to be elevated in animals of high gregariousness phenotype, independent of sex. In sum, elements of the immune system may be associated with gregariousness, even outside of major disease events. These results extend our knowledge of the role that immune signals have in contributing to the regulation of social behaviors outside periods of illness.

IA04 Early-Stage Drug Development in the 21st Century

For centuries, physicians have been developing and using instruments to characterize, classify, and measure aspects of human health and disease. Such tools have been vital to the development of novel therapies. Concurrently, the study of “disease outliers” with “extreme phenotypes” as determined by such instruments has been a powerful approach to understand mechanisms of disease. Today, we are using a plethora of new tools such as smartphone apps, wearables, artificial intelligence, etc., that allow for “precision phenotyping.” The new ability to collect data on each patient across their journey at unprecedented depth, combined with the ability to generate data across large patient populations, i.e., “meaningful data at scale,” enables a more precise understanding of disease, disease activity, and response or resistance to therapy. Such efforts will lead to next-generation biologic insights, new drug targets, enhanced diagnostic and prognostic methods, new clinical endpoints, and ultimately the development of future breakthrough medicines that improve how patients feel, function, or survive.

More Than DNA Methylation: Does Pleiotropy Drive the Complex Pattern of Evolution of Dnmt1?

DNA methylation is an important chromatin modification that can stably alter gene expression in cells and maintain genome integrity in plants and vertebrates. The function of DNA methylation outside of these well-studied systems, however, is unclear. Insects, in particular, represent an understudied group. Variation in the level of DNA methylation and gains and losses in the maintenance methyltransferase, DNMT1, across the insect tree of life suggests that there is much we don’t understand about DMNT1 function and evolution. One constant across the studies examining patterns of Dnmt1 expression in insects is that expression is consistently high in reproductive tissues compared to somatic tissue. The explanation for this has been that DNMT1 is required in tissues that have high levels of cell division. Our previous study found that downregulation of Dnmt1 expression in the milkweed bug Oncopeltus fasciatus results in the expected reduction of DNA methylation, no global changes in gene expression reflecting changes in DNA methylation, and the loss of the ability to produce viable oocytes. Here, we show that females treated with ds-Dnmt1 RNA during larval development have a more extreme phenotype; they lack oocytes entirely but develop a normal somatic ovary. Our results indicate a specific role for DNMT1 in the formation of gametes and are consistent with data from other systems, including Tribolium castaneum, a species does not have DNA methylation. We propose that DNMT1 has multiple functional roles in addition to methylating DNA, which explains its complex patterns of evolution.

Metagenomic Characterization of Intestinal Regions in Pigs With Contrasting Feed Efficiency.

Greater feed efficiency (FE) is critical in increasing profitability while reducing the environmental impact of pig production. Previous studies that identified swine FE-associated bacterial taxa were limited in either sampling sites or sequencing methods. This study characterized the microbiomes within the intestine of FE contrasting Duroc × (Landrace × Yorkshire) (DLY) pigs with a comprehensive representation of diverse sampling sites (ileum, cecum, and colon) and a metagenomic sequencing approach. A total of 226 pigs were ranked according to their FE between weaning to 140 day old, and six with extreme phenotypes were selected, three for each of the high and low groups. The results revealed that the cecum and colon had similar microbial taxonomic composition and function, and had higher capacity in polysaccharide metabolism than the ileum. We found in cecum that the high FE pigs had slightly higher richness and evenness in their micriobiota than the low FE pigs. We identified 12 phyla, 17 genera, and 39 species (e.g., Treponema porcinum, Treponema bryantii, and Firmicutes bacterium CAG:110) that were potentially associated with swine FE variation in cecum microbiota through LEfSe analysis. Species enriched in the cecum of the high FE pigs had a greater ability to utilize dietary polysaccharides and dietary protein according to the KEGG annotation. Analysis of antibiotic resistance based on the CARD database annotation indicated that the macB resistant gene might play an important role in shaping the microbial community in the cecum of pigs with contrasting FE. The bacteria from the genus Prevotella was highly enriched in the cecum of low FE pigs, which may impair the establishment of a more effective nutrient harvesting microbiota because of the interaction between Prevotella and other benefical microbes. These findings improved our understanding of the microbial compositions in the different gut locations of DLY pigs and identified many biomarkers associated with FE variation wich may be used to develop strategies to improve FE in pigs.

Identification of Important Proteins and Pathways Affecting Feed Efficiency in DLY Pigs by iTRAQ-Based Proteomic Analysis.

Simple SummaryFeed efficiency is one of the most valuable economic traits in the pig industry. The small intestine is the site where most of the nutrients are absorbed from ingested food. Here, we studied the relationship between small intestinal proteomics and feed efficiency in Duroc × (Landrace × Yorkshire) pigs, which is the most popular commercial pig in the Chinese pork market. Exploring the molecular mechanisms of feed efficiency will create great value for the pig industry. Our research provided a reference for further understanding of the key proteins that affect small intestinal microvilli formation and the important pathways related to feed efficiency in pigs.Feed efficiency is an economically important trait controlled by multiple genes in pigs. The small intestine is the main organ of digestion and nutrient absorption. To explore the biological processes by which small intestine proteomics affects feed efficiency (FE), we investigated the small intestinal tissue proteomes of high-FE and low-FE pigs by the isobaric tag for relative and absolute quantification (iTRAQ) method. In this study, a total of 225 Duroc × (Landrace × Yorkshire) (DLY) commercial pigs were ranked according to feed efficiency, which ranged from 30 kg to 100 kg, and six pigs with extreme phenotypes were selected, three in each of the high and low groups. A total of 1219 differentially expressed proteins (DEPs) were identified between the high-FE and low-FE groups (fold change ≥1.2 or ≤0.84; p ≤ 0.05), of which 785 were upregulated, and 484 were downregulated. Enrichment analysis indicated that the DEPs were mainly enriched in actin filament formation, microvilli formation, and small intestinal movement pathways. Protein functional analysis and protein interaction networks indicated that RHOA, HCLS1, EZR, CDC42, and RAC1 were important proteins that regulate FE in pigs. This study provided new insights into the important pathways and proteins involved in feed efficiency in pigs.

Between-tumor and within-tumor heterogeneity in invasive potential.

For women with access to healthcare and early detection, breast cancer deaths are caused primarily by metastasis rather than growth of the primary tumor. Metastasis has been difficult to study because it happens deep in the body, occurs over years, and involves a small fraction of cells from the primary tumor. Furthermore, within-tumor heterogeneity relevant to metastasis can also lead to therapy failures and is obscured by studies of bulk tissue. Here we exploit heterogeneity to identify molecular mechanisms of metastasis. We use “organoids”, groups of hundreds of tumor cells taken from a patient and grown in the lab, to probe tumor heterogeneity, with potentially thousands of organoids generated from a single tumor. We show that organoids have the character of biological replicates: within-tumor and between-tumor variation are of similar magnitude. We develop new methods based on population genetics and variance components models to build between-tumor and within-tumor statistical tests, using organoids analogously to large sibships and vastly amplifying the test power. We show great efficiency for tests based on the organoids with the most extreme phenotypes and potential cost savings from pooled tests of the extreme tails, with organoids generated from hundreds of tumors having power predicted to be similar to bulk tests of hundreds of thousands of tumors. We apply these methods to an association test for molecular correlates of invasion, using a novel quantitative invasion phenotype calculated as the spectral power of the organoid boundary. These new approaches combine to show a strong association between invasion and protein expression of Keratin 14, a known biomarker for poor prognosis, with p = 2 × 10−45 for within-tumor tests of individual organoids and p < 10−6 for pooled tests of extreme tails. Future studies using these methods could lead to discoveries of new classes of cancer targets and development of corresponding therapeutics. All data and methods are available under an open source license at https://github.com/baderzone/invasion_2019.

Short- and long-term adverse events in patients on temporary circulatory support before durable ventricular assist device: An IMACS registry analysis

Patients with cardiogenic shock (CS) needing temporary circulatory support (TCS) have poor survival rates after implantation of durable ventricular assist device (dVAD). We aimed to characterize post-dVAD adverse event burden and survival rates in patients requiring pre-operative TCS. We analyzed 13,511 adults (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] Profiles 1-3) with continuous-flow dVADs in International Society for Heart and Lung Transplantation Registry for Mechanically Assisted Circulatory Support (2013-2017) according to the need for pre-operative TCS (n = 5,632) vs no TCS (n = 7,879). Of these, 726 (5.4%) had biventricular assist devices (BiVAD). Furthermore, we compared prevalent rates (events/100 patient-months) of bleeding, device-related infection, hemorrhagic and ischemic cerebrovascular accidents (hemorrhagic cerebral vascular accident [hCVA], and ischemic cerebral vascular accident [iCVA]) in early (<3 months) and late (≥3 months) post-operative periods. TCS included extracorporeal membrane oxygenation (ECMO) (n = 1,138), intra-aortic balloon pump (IABP) (n = 3,901), and other TCS (n = 593). Within 3 post-operative months, there were more major bleeding and cerebrovascular accidents (CVAs) in patients with pre-operative ECMO (events/100 patient-months rates: bleeding = 19, hCVA = 1.6, iCVA = 2.8) or IABP (bleeding = 17.3, hCVA = 1.5, iCVA = 1.5) vs no TCS (bleeding = 13.2, hCVA = 1.1, iCVA = 1.2, all p < 0.05). After 3 months, adverse events were lower and similar in all groups. Patients with ECMO had the worst short- and long-term survival rates. Patients with BiVAD had the worst survival rate regardless of need for pre-operative TCS. CVA and multiorgan failures were the common causes of death for patients with TCS and patients without TCS. Patients requiring TCS before dVAD had a sicker phenotype and higher rates of early post-operative adverse events than patients without TCS. ECMO was associated with very high early ischemic stroke, bleeding, and mortality. The extreme CS phenotype needing ECMO warrants a higher-level profile status, such as INTERMACS "0."

Candidate genes and gene markers for the resistance to porcine pleuropneumonia

Actinobacillus (A.) pleuropneumoniae is one of the most important respiratory pathogens in global pig production. Antimicrobial treatment and vaccination provide only limited protection, but genetic disease resistance is a very promising alternative for sustainable prophylaxis. Previous studies have discovered multiple QTL that may explain up to 30% of phenotypic variance. Based on these findings, the aim of the present study was to use genomic sequencing to identify genetic markers for resistance to pleuropneumonia in a segregating commercial German Landrace line. 163 pigs were infected with A. pleuropneumoniae Serotype 7 through a standardized aerosol infection method. Phenotypes were accurately defined on a clinical, pathological and microbiological basis. The 58 pigs with the most extreme phenotypes were genotyped by sequencing (next-generation sequencing). SNPs were used in a genome-wide association study. The study identified genome-wide associated SNPs on three chromosomes, two of which were chromosomes of QTL which had been mapped in a recent experiment. Each variant explained up to 20% of the total phenotypic variance. Combined, the three variants explained 52.8% of the variance. The SNPs are located in genes involved in the pathomechanism of pleuropneumonia. This study confirms the genetic background for the host’s resistance to pleuropneumonia and indicates a potential role of three candidates on SSC2, SSC12 and SSC15. Favorable gene variants are segregating in commercial populations. Further work is needed to verify the results in a controlled study and to identify the functional QTN.

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

Reactive Nitrogen Species (RNS) are a group of bactericidal molecules produced by macrophages in response to pathogens in a process called oxidative burst. Nitric oxide (NO−) is a member of RNS produced from arginine by inducible Nitric Oxide Synthase (iNOS) enzyme. The activity of iNOS and production of NO− by macrophages following stimulation is one of the indicators of macrophage polarization towards M1/proinflammatory. Production of NO− by bovine monocyte-derived macrophage (MDM) and mouse peritoneal macrophages has been shown to be strongly associated with host genetic with the heritability of 0.776 in bovine MDM and 0.8 in mouse peritoneal macrophages. However, the mechanism of genetic regulation of macrophage response has remained less explored. In the current study, the transcriptome of bovine MDMs was compared between two extreme phenotypes that had been classified as high and low responder based on NO− production. The results showed that 179 and 392 genes were differentially expressed (DE) between high and low responder groups at 3 and 18 hours after exposure to Escherichia coli, respectively. A set of 11 Transcription Factors (TFs) (STAT1, IRF7, SPI1, STAT4, IRF1, HIF1A, FOXO3, REL, NFAT5, HIC1, and IRF4) at 3 hours and a set of 13 TFs (STAT1, IRF1, HIF1A, STAT4, ATF4, TP63, EGR1, CDKN2A, RBL1, E2F1, PRDM1, GATA3, and IRF4) at 18 hours after exposure to E. coli were identified to be differentially regulated between the high and low responder phenotypes. These TFs were found to be divided into two clusters of inflammatory- and hypoxia-related TFs. Functional analysis revealed that some key canonical pathways such as phagocytosis, chemotaxis, antigen presentation, and cell-to-cell signalling are enriched among the over-expressed genes by high responder phenotype. Based on the results of this study, it was inferred that the functional characteristics of bovine MDMs are associated with NO-based classification. Since NO− production is strongly associated with host genetics, this study for the first time shows the distinct proinflammatory profiles of macrophages are controlled by the natural genetic polymorphism in an outbred population. In addition, the results suggest that genetics can be considered as a new dimension in the current model of macrophage polarization which is currently described by the combination of stimulants, only.

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

Trends in Stillbirths and Stillbirth Phenotypes in the United States: An Analysis of 131.5 Million Births.

We examined the trends in stillbirth across gestational age in the United States (US).We conducted a trend analysis using the U.S. Natality and Fetal Death datasets covering 1982 and 2017. We compared the incidence and rates of stillbirth for term, all preterm, moderate-to-late preterm, very preterm, and extreme preterm phenotypes. The incidence of stillbirth decreased for the entire birth cohort over the 36-year period. The rates of overall, term, all preterm, very preterm and moderate-to-late preterm stillbirth decreased from 1982 to 2017; however, the rates for extreme preterm stillbirth increased by about 7.6% over the same study period.

Transposable temperate phages promote the evolution of divergent social strategies in Pseudomonas aeruginosa populations

Transposable temperate phages randomly insert into bacterial genomes, providing increased supply and altered spectra of mutations available to selection, thus opening alternative evolutionary trajectories. Transposable phages accelerate bacterial adaptation to new environments, but their effect on adaptation to the social environment is unclear. Using experimental evolution of Pseudomonas aeruginosa in iron-limited and iron-rich environments, where the cost of producing cooperative iron-chelating siderophores is high and low, respectively, we show that transposable phages promote divergence into extreme siderophore production phenotypes. Iron-limited populations with transposable phages evolved siderophore over-producing clones alongside siderophore non-producing cheats. Low siderophore production was associated with parallel mutations in pvdgenes, encoding pyoverdine biosynthesis, and pqs genes, encoding quinolone signaling, while high siderophore production was associated with parallel mutations in phenazine-associated gene clusters. Notably, some of these parallel mutations were caused by phage insertional inactivation. These data suggest that transposable phages, which are widespread in microbial communities, can mediate the evolutionary divergence of social strategies.

Comprehensive engineering of the tarantula venom peptide huwentoxin-IV to inhibit the human voltage-gated sodium channel hNav1.7

Comprehensive engineering of the tarantula venom peptide huwentoxin-IV to inhibit the human voltage-gated sodium channel hNav1.7

Genetic Inheritance and Its Contribution to Tinnitus.

Tinnitus is the abnormal perception of sound that affects more than 15% of adult population around the globe. Severe tinnitus is considered a complex disorder that arises as result of the interaction of genetic and environmental factors, and it is associated with several comorbidities such as hearing loss, anxiety, and insomnia. We begin this review with an introduction to human molecular genetics and the role of genetic variation on the inheritance. There are some genetic reports on tinnitus heritability including concordance studies in twins and adoptees or aggregation in families providing some evidence for familial aggregation in patients with severe tinnitus and high concordance in monozygotic twins with bilateral tinnitus. So, sex differences in familial aggregation and heritability of bilateral tinnitus suggest a potential sexual dimorphism in tinnitus inheritance.Molecular genetic studies have been demonstrated to be a useful tool to understand the role of genetic variation in rare diseases and complex disorders. The reported associations in common variants in neurotrophic factors such as GDNF, BDNF, or potassium channels genes were underpowered, and the lack of replication questions these findings. Although candidate gene approaches have failed in replicating these genetic associations, the development of high throughput sequencing technology and the selection of extreme phenotypes are strategies that will allow the clinicians and researchers to combine genetic information with clinical data to implement a personalized diagnosis and therapy in patients with tinnitus.

Genetic variants in the fat mass and obesity-associated (FTO) gene confer risk for extreme obesity and modulate adiposity in a Brazilian population.

Obesity is a major public health problem worldwide. It has a complex etiology, influenced by environmental and genetic factors. FTO has been recognized as an important genetic factor for obesity development. This study evaluated the contribution of FTO polymorphisms (rs9939609 and rs17817449) for extreme obesity in terms of the period of obesity onset, anthropometric, and biochemical parameters. The haplotype and the combined effects of FTO risk alleles on obesity susceptibility were evaluated. We investigated 169 normal-weight subjects (body mass index, BMI: 22.8 [21.0; 24.0] kg/m2) and 123 extremely obese individuals (BMI: 47.6 [44.1; 53.1] kg/m2). Genotyping was performed by real time PCR. Our results showed a strong association between FTO variants and extreme obesity. Carriers of the AT haplotype had an increased risk for extreme obesity. Gene scores suggested that the risk of developing extreme obesity was increased 1.37-fold per risk allele added. Both polymorphisms also influenced BMI and body weight. Additionally, rs17817449 influenced triglyceride levels. No effect of FTO variants on the period of obesity onset was found. In conclusion, the FTO polymorphisms showed a strong association with development of extreme phenotype of obesity and adiposity modulation in a Brazilian population.