Insect genomes: progress and challenges.

In the wake of constant improvements in sequencing technologies, numerous insect genomes have been sequenced. Currently, 1219 insect genome-sequencing projects have been registered with the National Center for Biotechnology Information, including 401 that have genome assemblies and 155 with an official gene set of annotated protein-coding genes. Comparative genomics analysis showed that the expansion or contraction of gene families was associated with well-studied physiological traits such as immune system, metabolic detoxification, parasitism and polyphagy in insects. Here, we summarize the progress of insect genome sequencing, with an emphasis on how this impacts research on pest control. We begin with a brief introduction to the basic concepts of genome assembly, annotation and metrics for evaluating the quality of draft assemblies. We then provide an overview of genome information for numerous insect species, highlighting examples from prominent model organisms, agricultural pests and disease vectors. We also introduce the major insect genome databases. The increasing availability of insect genomic resources is beneficial for developing alternative pest control methods. However, many opportunities remain for developing data-mining tools that make maximal use of the available insect genome resources. Although rapid progress has been achieved, many challenges remain in the field of insect genomics.

The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.

Body-condition indices are repeatable across short, but not long, time periods in crimson finches Neochmia phaeton.

Abstract It is common in evolutionary ecology to interpret body-condition indices as indicators of individual quality, but this hypothesized relationship has been questioned and remains poorly validated. Here, we test one of the fundamental predictions of this condition-quality hypothesis, that relative-condition indices are repeatable within individuals, that is, that the index score of an individual relative to others is consistent over time. We sampled crimson finches (Neochmia phaeton) for seven commonly used condition indices and tested whether individual condition relative to conspecifics in the same context (e.g., breeding stage) was repeatable. We calculated the relative indices' repeatability across several temporal scales, from short (within breeding season) to long (more than 2 yr) time periods, as well as without consideration of timescale. Most relative-condition indices were repeatable when sampled without consideration of timescale, all were repeatable within a short time period, and none were repeatable over the longest time period. This provides only partial support for the condition-quality hypothesis, because although relative-condition indices were generally repeatable, this was primarily attributed to short-term, instead of long-term, repeatability. Condition indices may be meaningful indicators of short-term survival or fitness potential, but our findings are inconsistent with the idea that condition indices are indicators of inherent individual quality.

The role of near-patient coeliac serology testing in the follow-up of patients with coeliac disease.

OBJECTIVE: This pilot study was undertaken to assess the validity and effectiveness of near-patient coeliac immunological testing, compared to standard laboratory immunological techniques, used in the context of dietician-led coeliac disease follow-up clinics. DESIGN: The study was designed in two phases, each assessing the near-patient test and standard laboratory immunological techniques. Phase 1 analysed stored serum samples; Phase 2 analysed whole blood from patients attending the dietician-led coeliac disease clinics. SETTING: Patients were recruited from New Cross Hospital, Wolverhampton (n=50), and Imperial College London (n=30), between March 2010 and February 2011. PATIENTS: Those with a diagnosis of coeliac disease for greater than 12 months attending dietician-led coeliac disease clinics. INTERVENTIONS: In addition to whole blood taken for routine analysis, patients required a capillary finger-prick blood sample. MAIN OUTCOME MEASURE: To determine if the whole blood and serum near-patient test results were in correlation with outcomes of standard laboratory evaluation. RESULTS: Phase 1 demonstrated that the near-patient serum test had a sensitivity of 93.5% (95% CI 0.79% to 0.98%), specificity of 94.9% (0.83% to 0.99%), when compared to standard laboratory ELISA. Phase 2, involving patients whole blood, had a sensitivity of 77.8% (0.45% to 0.93%), and specificity of 100% (0.94% to 1%). CONCLUSIONS: This pilot study has demonstrated that there appears to be a role for near-patient testing in coeliac disease, but further studies are recommended.

Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.

BACKGROUND: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis. AIM: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea. METHODS: One hundred and fifty-two consecutive patients were grouped according to (75) Se-homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; ≤15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7α-hydroxy-4-cholesten-3-one (C4) and total bile acids. RESULTS: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 ≤ 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy. CONCLUSIONS: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy.

What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity.

One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.

Ecological, evolutionary, and conservation implications of incubation temperature-dependent phenotypes in birds.

Incubation is a vital component of reproduction and parental care in birds. Maintaining temperatures within a narrow range is necessary for embryonic development and hatching of young, and exposure to both high and low temperatures can be lethal to embryos. Although it is widely recognized that temperature is important for hatching success, little is known about how variation in incubation temperature influences the post-hatching phenotypes of avian offspring. However, among reptiles it is well known that incubation temperature affects many phenotypic traits of offspring with implications for their future survival and reproduction. Although most birds, unlike reptiles, physically incubate their eggs, and thus behaviourally control nest temperatures, variation in temperature that influences embryonic development still occurs among nests within a population. Recent research in birds has primarily been limited to populations of megapodes and waterfowl; in each group, incubation temperature has substantial effects on hatchling phenotypic traits important for future development, survival, and reproduction. Such observations suggest that incubation temperature (and incubation behaviours of parents) is an important but underappreciated parental effect in birds and may represent a selective force instrumental in shaping avian reproductive ecology and life-history traits. However, much more research is needed to understand how pervasive phenotypic effects of incubation temperature are among birds, the sources of variation in incubation temperature, and how effects on phenotype arise. Such insights will not only provide foundational information regarding avian evolution and ecology, but also contribute to avian conservation.

Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome.

BACKGROUND: Recurrent, watery diarrhoea affects one-third of patients diagnosed with irritable bowel syndrome ('IBS-D'). Idiopathic bile acid malabsorption ('I-BAM') may be the cause. AIM: To determine the prevalence of I-BAM in patients suffering from IBS-D. METHODS: A systematic search was performed of publications reporting patients presenting with IBS-D type symptoms, who were subsequently confirmed as having I-BAM by SeHCAT scanning. RESULTS: Eighteen relevant studies, 15 prospective, comprising 1223 patients were identified. Five studies (429 patients) indicated that 10% (CI: 7-13) patients had severe bile acid malabsorption (SeHCAT 7 day retention <5% of baseline value). 17 studies (1073 patients) indicated that 32% (CI: 29-35) patients had moderate bile acid malabsorption (SeHCAT <10%). 7 studies (618 patients) indicated that 26% (CI: 23-30) patients had mild (SeHCAT <15%) bile acid malabsorption. Pooled data from 15 studies showed a dose-response relationship according to severity of malabsorption to treatment with a bile acid binder: response to colestyramine occurred in 96% of patients with <5% retention, 80% at <10% retention and 70% at <15% retention. CONCLUSIONS: Idiopathic adult-onset bile acid malabsorption is not rare. International guidelines for the management of irritable bowel syndrome need to be revised so that clinicians become more aware of this possibility.

Review article: visceral hypersensitivity in irritable bowel syndrome: molecular mechanisms and therapeutic agents.

BACKGROUND: Although development of visceral pain is an important defensive mechanism, hypersensitivity results in a significant clinical problem and is likely to be one of the major factors involved in the pathogenesis of abdominal and chest pain in functional bowel disorders (FBDs). Understanding of the molecular mechanisms involved in peripheral sensitization of visceral nociceptors has advanced as a result of the experimental studies, especially in animal models, which have led to knowledge and identification of key mediators and receptors. AIM: To provide a comprehensive review focused on the peripheral mechanisms believed to be responsible for sensitization and potential molecular targets for a disorder which is common, distressing and has sub-optimal treatment options. METHODS: Literature review using Ovid and Pubmed from 1966. RESULTS: There is substantial interest in the development of new drugs for treatment of FBDs in the background of advances in understanding the molecular and physiological mechanisms of visceral hypersensitivity. The potential drug targets include TPRV1, ASICs, voltage-gated sodium channels, ATP, PAR-2, cannabinoid, prostaglandin, tachykinin and 5HT(3) receptors. CONCLUSION: It is anticipated that with advancing molecular understanding of the basis of visceral hypersensitivity, the next decade will see accelerated development of new molecules for treatment of functional bowel diseases.

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Functional connectivity of human striatum: a resting state FMRI study.

Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders.

Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain.

OBJECTIVE: The capsaicin receptor TRPV1 (transient receptor potential vanilloid type-1) may play an important role in visceral pain and hypersensitivity states. In irritable bowel syndrome (IBS), abdominal pain is a common and distressing symptom where the pathophysiology is still not clearly defined. TRPV1-immunoreactive nerve fibres were investigated in colonic biopsies from patients with IBS, and this was related to abdominal pain. METHODS: Rectosigmoid biopsies were collected from 23 IBS patients fulfilling Rome II criteria, and from 22 controls. Abdominal pain scores were recorded using a validated questionnaire. TRPV1-, substance P- and neuronal marker protein gene product (PGP) 9.5-expressing nerve fibres, mast cells (c-kit) and lymphocytes (CD3 and CD4) were quantified, following immunohistochemistry with specific antibodies. The biopsy findings were related to the abdominal pain scores. RESULTS: A significant 3.5-fold increase in median numbers of TRPV1-immunoreactive fibres was found in biopsies from IBS patients compared with controls (p<0.0001). Substance P-immunoreactive fibres (p = 0.01), total nerve fibres (PGP9.5) (p = 0.002), mast cells (c-kit) (p = 0.02) and lymphocytes (CD3) (p = 0.03) were also significantly increased in the IBS group. In multivariate regression analysis, only TRPV1-immuno-reactive fibres (p = 0.005) and mast cells (p = 0.008) were significantly related to the abdominal pain score. CONCLUSIONS: Increased TRPV1 nerve fibres are observed in IBS, together with a low-grade inflammatory response. The increased TRPV1 nerve fibres may contribute to visceral hypersensitivity and pain in IBS, and provide a novel therapeutic target.

Review article: glucagon-like peptide 2--current applications and future directions.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is an important peptide growth factor secreted from the human intestine. The trophic properties of GLP-2 are very specific to the gut where it is pivotal in the regulation of mucosal morphology, function and integrity. AIMS: This review details the current understanding of the molecular biology of GLP-2, its mechanisms of action and physiological properties. A major focus is the discussion of recent clinical data evaluating the use of GLP-2 as a therapeutic agent. METHODS: Relevant articles were identified using Medline searches and from the reference lists of key papers. RESULTS AND CONCLUSIONS: In the treatment of short bowel syndrome, GLP-2 has been shown to be highly effective in improving fluid absorption. In Crohn's disease, GLP-2 is superior to placebo in the induction of remission. Early data also suggest that the effects of GLP-2 on bone metabolism can provide a new treatment approach for patients with osteoporosis. In the future, the positive effects of GLP-2 on intestinal barrier function, splanchnic perfusion and mucosal healing could be utilized to expand its therapeutic application to other causes of intestinal injury. However, important safety aspects need to be considered when using this potent growth-promoting agent for a long term.

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine.

The goal of the present study was to determine the phase relationships of the slow oscillatory activity that emerges in basal ganglia nuclei in anesthetized rats after dopamine cell lesion in order to gain insight into the passage of this oscillatory activity through the basal ganglia network. Spike train recordings from striatum, subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNpr) were paired with simultaneous local field potential (LFP) recordings from SNpr or motor cortex ipsilateral to a unilateral lesion of substantia nigra dopamine neurons in urethane-anesthetized rats. Dopamine cell lesion induced a striking increase in incidence of slow oscillations (0.3-2.5 Hz) in firing rate in all nuclei. Phase relationships assessed through paired recordings using SNpr LFP as a temporal reference showed that slow oscillatory activity in GP spike trains is predominantly antiphase with oscillations in striatum, and slow oscillatory activity in STN spike trains is in-phase with oscillatory activity in cortex but predominantly antiphase with GP oscillatory activity. Taken together, these results imply that after dopamine cell lesion in urethane-anesthetized rats, increased oscillatory activity in GP spike trains is shaped more by increased phasic inhibitory input from the striatum than by phasic excitatory input from STN. In addition, results show that oscillatory activity in SNpr spike trains is typically antiphase with GP oscillatory activity and in-phase with STN oscillatory activity. While these observations do not rule out additional mechanisms contributing to the emergence of slow oscillations in the basal ganglia after dopamine cell lesion in the anesthetized preparation, they are compatible with 1) increased oscillatory activity in the GP facilitated by an effect of dopamine loss on striatal 'filtering' of slow components of oscillatory cortical input, 2) increased oscillatory activity in STN spike trains supported by convergent antiphase inhibitory and excitatory oscillatory input from GP and cortex, respectively, and 3) increased oscillatory activity in SNpr spike trains organized by convergent antiphase inhibitory and excitatory oscillatory input from GP and STN, respectively.

Lack of association of MYO9B genetic variants with coeliac disease in a British cohort.

BACKGROUND AND AIMS: Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS: Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS: UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS: Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.