The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension

BACKGROUND: Sitosterolemia is a recessively inherited disorder in humans that is associated with premature atherosclerotic disease. Mutations in ABCG5 or ABCG8, comprising the sitosterolemia locus, STSL, are now known to cause this disease. Three in-bred strains of rats, WKY, SHR and SHRSP, are known to be sitosterolemic, hypertensive and they carry a missense 'mutation' in a conserved residue of Abcg5, Gly583Cys. Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension. METHODS: To investigate whether the missense change in Abcg5 is responsible for the sitosterolemia we performed a segregation analysis in 103 F2 rats from a SHR × SD cross. Additionally, we measured tail-cuff blood pressure and measured intestinal lipid transport to identify possible mechanisms whereby this mutation causes sitosterolemia. RESULTS: Segregation analysis showed that the inheritance of the Gly583Cys mutation Abcg5 segregated with elevated plant sterols and this pattern was recessive, proving that this genetic change is responsible for the sitosterolemia in these rat strains. Tail-cuff monitoring of blood pressure in conscious animals showed no significant differences between wild-type, heterozygous and homozygous mutant F2 rats, suggesting that this alteration may not be a significant determinant of hypertension in these rats on a chow diet. CONCLUSION: This study shows that the previously identified Gly583Cys change in Abcg5 in three hypertension-susceptible rats is responsible for the sitosterolemia, but may not be a major determinant of blood pressure in these rats

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Can metamorphosis survival during larval development in spiny lobster Sagmariasus verreauxi be improved through quantitative genetic inheritance?

Abstract Background One of the major impediments to spiny lobster aquaculture is the high cost of hatchery production due to the long and complex larval cycle and poor survival during the many moult stages, especially at metamorphosis. We examined if the key trait of larval survival can be improved through selection by determining if genetic variance exists for this trait. Specifically, we report, for the first time, genetic parameters (heritability and correlations) for early survival rates recorded at five larval phases; early-phyllosoma stages (instars 1–6; S1), mid-phyllosoma stages (instars; 7–12; S2), late-phyllosoma stages (instars 13–17; S3), metamorphosis (S4) and puerulus stage (S5) in hatchery-reared spiny lobster Sagmariasus verreauxi. Results The data were collected from a total of 235,060 larvae produced from 18 sires and 30 dams over nine years (2006 to 2014). Parentage of the offspring and full-sib families was verified using ten microsatellite markers. Analysis of variance components showed that the estimates of heritability for all the five phases of larval survival obtained from linear mixed model were generally similar to those obtained from threshold logistic generalised models (0.03–0.47 vs. 0.01–0.50). The heritability estimates for survival traits recorded in the early larval phases (S1 and S2) were higher than those estimated in later phases (S3, S4 and S5). The existence of the additive genetic component in larval survival traits indicate that they could be improved through selection. Both phenotypic and genetic correlations among the five survival measures studied were moderate to high and positive. The genetic associations between successive rearing periods were stronger than those that are further apart. Conclusions Our estimates of heritability and genetic correlations reported here in a spiny lobster species indicate that improvement in the early survival especially during metamorphosis can be achieved through genetic selection in this highly economic value species

Potential importance of glomerular citrate synthase activity in remnant nephropathy

Potential importance of glomerular citrate synthase activity in remnant nephropathy.BackgroundAldosterone fosters progressive renal injury, but the mechanism is unknown. Both Wistar-Furth rats, which are resistant to aldosterone actions, and adrenalectomized Sprague-Dawley rats, which lack aldosterone, are characterized by resistance to remnant nephropathy and by reduced whole kidney citrate synthase activity. Increase in citrate synthase activity is a well-characterized, specific renal response to aldosterone. Therefore, we performed experiments to test the hypothesis that enhanced citrate synthase activity contributes to remnant nephropathy.MethodsRat models included Wistar (control for Wistar-Furth), Wistar-Furth (resistant to aldosterone), Sprague-Dawley (normal), adrenalectomy (lacking aldosterone), and 5/6 nephrectomy (renal injury). Glomeruli were obtained by differential sieving. Citrate synthase activity was determined spectrophotometrically. Binding characteristics of cytosolic mineralocorticoid receptors were determined by equilibrium competition binding between tritiated and unlabeled aldosterone. Gene sequencing was performed with reverse transcription-polymerase chain reaction (RT-PCR) and fluorescent dye terminators.ResultsIn glomeruli isolated from adrenalectomized Wistar rats with intact renal mass, aldosterone stimulated a threefold increase in citrate synthase activity; this stimulation was not observed in glomeruli from Wistar-Furth rats. Similarly, citrate synthase activity in glomeruli isolated from adrenally intact Sprague-Dawley rats was 65% greater than that from adrenalectomized Sprague-Dawley rats. Compared to sham surgery, subtotal nephrectomy resulted in 100% greater glomerular citrate synthase activity in Sprague-Dawley rats. In Wistar-Furth rats, mineralocorticoid receptor binding was not reduced, and mutations in the mineralocorticoid receptor DNA binding segment were not found.ConclusionCitrate synthase activity is elevated in remnant glomeruli, and experimental models characterized by reduced glomerular citrate synthase activity (Wistar-Furth rats, adrenalectomized Sprague-Dawley rats) are protected from remnant nephropathy

Mice Lacking the Systemic Vitamin A Receptor RBPR2 Show Decreased Ocular Retinoids and Loss of Visual Function

The systemic transport of dietary vitamin A/all-trans retinol bound to RBP4 into peripheral tissues for storage is an essential physiological process that continuously provides visual chromophore precursors to the retina under fasting conditions. This mechanism is critical for phototransduction, photoreceptor cell maintenance and survival, and in the support of visual function. While the membrane receptor STRA6 facilitates the blood transport of lipophilic vitamin A into the eye, it is not expressed in most peripheral organs, which are proposed to express a second membrane receptor for the uptake of vitamin A from circulating RBP4. The discovery of a novel vitamin A receptor, RBPR2, which is expressed in the liver and intestine, but not in the eye, alluded to this long-sort non-ocular membrane receptor for systemic RBP4-ROL uptake and transport. We have previously shown in zebrafish that the retinol-binding protein receptor 2 (Rbpr2) plays an important role in the transport of yolk vitamin A to the eye. Mutant rbpr2 zebrafish lines manifested in decreased ocular retinoid concentrations and retinal phenotypes. To investigate a physiological role for the second vitamin A receptor, RBPR2, in mammals and to analyze the metabolic basis of systemic vitamin A transport for retinoid homeostasis, we established a whole-body Rbpr2 knockout mouse (Rbpr2−/−) model. These mice were viable on both vitamin A-sufficient and -deficient diets. Rbpr2−/− mice that were fed a vitamin A-sufficient diet displayed lower ocular retinoid levels, decreased opsins, and manifested in decrease visual function, as measured by electroretinography. Interestingly, when Rbpr2−/− mice were fed a vitamin A-deficient diet, they additionally showed shorter photoreceptor outer segment phenotypes, altogether manifesting in a significant loss of visual function. Thus, under conditions replicating vitamin A sufficiency and deficiency, our analyses revealed that RBPR2-mediated systemic vitamin A transport is a regulated process that is important for vitamin A delivery to the eye when RBP4-bound ROL is the only transport pathway in the fasting condition or under vitamin A deficiency conditions

Low-frequency brain stimulation to the left dorsolateral prefrontal cortex increases the negative impact of social exclusion among those high in personal distress

The dorsolateral prefrontal cortex (DLPFC) is thought to play a key role in the cognitive control of emotion and has therefore, unsurprisingly, been implicated in the regulation of physical pain perception. This brain region may also influence the experience of social pain, which has been shown to activate similar neural networks as seen in response to physical pain. Here, we applied sham or active low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC, previously shown to exert bilateral effects in pain perception, in healthy participants. Following stimulation, participants played the “Cyberball Task”; an online ball-tossing game in which the subject participant is included or excluded. Compared to sham, rTMS did not modulate behavioural response to social exclusion. However, within the active rTMS group only, greater trait personal distress was related to enhanced negative outcomes to social exclusion. These results add further support to the notion that the effect of brain stimulation is not homogenous across individuals, and indicates the need to consider baseline individual differences when assessing response to brain stimulation. This seems particularly relevant in social neuroscience investigations, where trait factors may have a meaningful effect