Identification of the Otopetrin Domain, a conserved domain in vertebrate otopetrins and invertebrate otopetrin-like family members

<p>Abstract</p> <p>Background</p> <p><it>Otopetrin 1 (Otop1) </it>encodes a multi-transmembrane domain protein with no homology to known transporters, channels, exchangers, or receptors. Otop1 is necessary for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals and teleost fish that are required for the detection of linear acceleration and gravity. Vertebrate <it>Otop1 </it>and its paralogues <it>Otop2 </it>and <it>Otop3 </it>define a new gene family with homology to the invertebrate Domain of Unknown Function 270 genes (<it>DUF270</it>; pfam03189).</p> <p>Results</p> <p>Multi-species comparison of the predicted primary sequences and predicted secondary structures of 62 vertebrate otopetrin, and arthropod and nematode DUF270 proteins, has established that the genes encoding these proteins constitute a single family that we renamed the Otopetrin Domain Protein (<it>ODP</it>) gene family. Signature features of ODP proteins are three "Otopetrin Domains" that are highly conserved between vertebrates, arthropods and nematodes, and a highly constrained predicted loop structure.</p> <p>Conclusion</p> <p>Our studies suggest a refined topologic model for ODP insertion into the lipid bilayer of 12 transmembrane domains, and highlight conserved amino-acid residues that will aid in the biochemical examination of ODP family function. The high degree of sequence and structural similarity of the ODP proteins may suggest a conserved role in the intracellular trafficking of calcium and the formation of biominerals.</p

Left Ventricular Mechanical Dysfunction in Diet-Induced Obese Mice Is Exacerbated During Inotropic Stress: A Cine DENSE Cardiovascular Magnetic Resonance Study

BACKGROUND: Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline. METHODS: C57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 - 10 subjects per group per time point, 100 total; 4 - 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons. RESULTS: Reductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits. CONCLUSIONS: Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction

Simplified Post Processing of Cine DENSE Cardiovascular Magnetic Resonance for Quantification of Cardiac Mechanics

BACKGROUND: Cardiovascular magnetic resonance using displacement encoding with stimulated echoes (DENSE) is capable of assessing advanced measures of cardiac mechanics such as strain and torsion. A potential hurdle to widespread clinical adoption of DENSE is the time required to manually segment the myocardium during post-processing of the images. To overcome this hurdle, we proposed a radical approach in which only three contours per image slice are required for post-processing (instead of the typical 30-40 contours per image slice). We hypothesized that peak left ventricular circumferential, longitudinal and radial strains and torsion could be accurately quantified using this simplified analysis. METHODS AND RESULTS: We tested our hypothesis on a large multi-institutional dataset consisting of 541 DENSE image slices from 135 mice and 234 DENSE image slices from 62 humans. We compared measures of cardiac mechanics derived from the simplified post-processing to those derived from original post-processing utilizing the full set of 30-40 manually-defined contours per image slice. Accuracy was assessed with Bland-Altman limits of agreement and summarized with a modified coefficient of variation. The simplified technique showed high accuracy with all coefficients of variation less than 10% in humans and 6% in mice. The accuracy of the simplified technique was also superior to two previously published semi-automated analysis techniques for DENSE post-processing. CONCLUSIONS: Accurate measures of cardiac mechanics can be derived from DENSE cardiac magnetic resonance in both humans and mice using a simplified technique to reduce post-processing time by approximately 94%. These findings demonstrate that quantifying cardiac mechanics from DENSE data is simple enough to be integrated into the clinical workflow

Cardiac Remodeling and Dysfunction in Childhood Obesity: A Cardiovascular Magnetic Resonance Study

Background: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children. Methods and results: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index was 23 % greater (27 ± 4 g/m2.7 vs 22 ± 3 g/m2.7, p \u3c 0.001) and the LV myocardium was 10 % thicker (5.6 ± 0.8 mm vs 5.1 ± 0.8 mm, p \u3c 0.001) in the obese/overweight children. This evidence of cardiac remodeling was present in obese children as young as age 8. Twenty four percent of obese/overweight children had concentric hypertrophy, 59 % had normal geometry and 17 % had either eccentric hypertrophy or concentric remodeling. LV mass index, thickness, ejection fraction and peak longitudinal and circumferential strains all correlated with epicardial adipose tissue after adjusting for height and gender (all p \u3c 0.05). Peak longitudinal and circumferential strains showed a significant relationship with the type of LV remodeling, and were most impaired in children with concentric hypertrophy (p \u3c 0.001 and p = 0.003, respectively). Conclusions: Obese children show evidence of significant cardiac remodeling and dysfunction, which begins as young as age 8. Obese children with concentric hypertrophy and impaired strain may represent a particularly high risk subgroup that demands further investigation

The Aspergillus Genome Database, a curated comparative genomics resource for gene, protein and sequence information for the Aspergillus research community

The Aspergillus Genome Database (AspGD) is an online genomics resource for researchers studying the genetics and molecular biology of the Aspergilli. AspGD combines high-quality manual curation of the experimental scientific literature examining the genetics and molecular biology of Aspergilli, cutting-edge comparative genomics approaches to iteratively refine and improve structural gene annotations across multiple Aspergillus species, and web-based research tools for accessing and exploring the data. All of these data are freely available at http://www.aspgd.org. We welcome feedback from users and the research community at [email protected]

Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study

BACKGROUND: Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline. METHODS: C57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 – 10 subjects per group per time point, 100 total; 4 – 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons. RESULTS: Reductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits. CONCLUSIONS: Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-015-0180-7) contains supplementary material, which is available to authorized users

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Physical media independence: System support for dynamically available network interfaces

Advances in hardware technology has fueled the proliferation of dynamically con gurable network interface cards. This empowers mobile laptop users to select the most appropriate interface for their current environment. Unfortunately, the majority of system software remains &quot;customized&quot; for a particular network configuration, and assumes many network characteristics remain invariant over the runtime of the software. Physical Media Independence (PMI) is the concept of making assumptions about a particular device explicit, detecting events which invalidate these assumptions, and recovering once events are detected. This paper presents a model supporting PMI. Based on device availability, the model identifies implicit device-related assumptions made by contemporary network stacks, describes a methodology for making them explicit, and outlines what adaptation should occur when they are invalidated. The model is used to construct a new kernel entity, called the Interface Management Module (IMM), that supports PMI in the FreeBSD operating system. The bene ts and limitations of the system are illustrated using a variety of network applications. The results show that transparency is difficult to maintain for all applications because they cache information such as IP addresses and network bandwidth characteristics. We conclude that while low level support for PMI is important, the IMM needs to provide an interface for mapping application-level semantics down to low-level policy decisions