Variability in Exposure to Subspecialty Rotations During Orthopaedic Residency: A Website-based Review of Orthopaedic Residency Programs.

IntroductionThe variability in exposure to various subspecialty rotations during orthopaedic residency across the United States has not been well studied.MethodsData regarding program size, resident's sex, department leadership, university-based status of the program, outsourcing of subspecialty rotation, and geographic location were collected from websites of 151 US allopathic orthopaedic residency programs. The relationship of these factors with the time allotted for various clinical rotations was analyzed.ResultsThe number of residents in a program correlated positively with time allocated for elective rotations (r = 0.57, P = 0.0003). Residents in programs where the program director was a general orthopaedic surgeon spent more time on general orthopaedic rotations (22 versus 9.9 months, P = 0.001). Programs where the program director or chairman was an orthopaedic oncologist spent more time on oncology rotations ([3.8 versus 3 months, P = 0.01] and [3.5 versus 2.7 months, P = 0.01], respectively). Residents in community programs spent more time on adult reconstruction than university-based programs (6.6 versus 5.5 months, P = 0.014). Based on multiple linear regression analysis, time allotted for adult reconstruction (t = 2.29, P = 0.02) and elective rotations (t = 2.43, P = 0.017) was positively associated with the number of residents in the program.ConclusionsSubstantial variability exists in the time allocated to various clinical rotations during orthopaedic residency. The effect of this variability on clinical competence, trainees' career choices, and quality of patient care needs further study

Markers and Mechanisms of β-cell Dedifferentiation

Human and murine diabetes is characterized by pancreatic β-cell dedifferentiation, a process in which β-cells lose expression of markers of maturity and gain those of endocrine progenitors. Failing β-cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. Therefore, pathways involved in mitochondrial fuel selection and catabolism may represent potential targets for the prevention or reversal of dedifferentiation. In chapter I of this dissertation, we isolated and functionally characterized failing β-cells from various experimental models of diabetes. We found a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (Aldh1a3) as β-cells become dedifferentiated. Flow-sorted Aldh1a3-expressing (ALDH+) islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrated that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV, and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure. In chapter II of this dissertation, we report that cytochrome b5 reductase 3 (Cyb5r3) is a FoxO1-regulated mitochondrial oxidoreductase critical to β cell function. Expression of Cyb5r3 is greatly decreased in multiple murine models of diabetes, and in vitro Cyb5r3 knockdown leads to increased ROS generation and impairment of respiration, mitochondrial function, glucose-stimulated insulin secretion, and calcium mobilization. In vivo, mice with β-cell-specific ablation of Cyb5r3 (B-Cyb5r3) display impaired glucose tolerance with decreased insulin secretion, and their islets have significantly lower basal respiration and glucose-stimulated insulin secretion. B-Cyb5r3 β-cells lose expression of Glut2, MafA, and Pdx1 expression despite a compensatory increase in FoxO1 expression. Our data suggest that Cyb5r3 is a critical mediator of FoxO1’s protective response in β-cells, and that loss of Cyb5r3 expression is an early event in β-cell failure

Importance of branding property developers in Malaysia

This paper aims to study the brand consciousness of property purchasers in Malaysia. This study is based on a survey of purchasers in Klang Valley on the brand awareness and the brand personality traits of property developers. 5000 questionnaires were distributed and finally 214 were used for this study. The results show that property purchasers are brand conscious in relation to the property developers and they ranked developers based on the brand personality. Property purchasers look at trend, professionalism and investment as the top 3 priorities in the property brand. The conclusion is that all property firms, designers, real estate agents and stakeholders who?that are involved in property development are to ensure that their products are designed with brand consciousness in mind. The findings in this paper suggest that property designers should pay attention to trend in the property development, property marketers should be professional in dealing with purchasers and the developers should ensure good locations for property investments

Importance of branding for property developers in Malaysia.

This paper aims to study the brand consciousness of property purchasers in Malaysia. This study is based on a survey of purchasers in Klang Valley on the brand awareness and the brand personality traits of property developers. 5000 questionnaires were distributed and finally 214 were used for this study. The results show that property purchasers are brand conscious in relation to the property developers and they ranked developers based on the brand personality. Property purchasers look at trend, professionalism and investment as the top 3 priorities in the property brand. The conclusion is that all property firms, designers, real estate agents and stakeholders who/that are involved in property development are to ensure that their products are designed with brand consciousness in mind. The findings in this paper suggest that property designers should pay attention to trend in the property development, property marketers should be professional in dealing with purchasers and the developers should ensure good locations for property investments

Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H.

BackgroundOnly Clostridium botulinum strain IBCA10-7060 produces the recently described novel botulinum neurotoxin type H (BoNT/H). BoNT/H (N-terminal two-thirds most homologous to BoNT/F and C-terminal one-third most homologous to BoNT/A) requires antitoxin to toxin ratios ≥1190:1 for neutralization by existing antitoxins. Hence, more potent and safer antitoxins against BoNT/H are needed.MethodsWe therefore evaluated our existing monoclonal antibodies (mAbs) to BoNT/A and BoNT/F for BoNT/H binding, created yeast-displayed mutants to select for higher-affinity-binding mAbs by using flow cytometry, and evaluated the mAbs' ability to neutralize BoNT/H in the standard mouse bioassay.ResultsAnti-BoNT/A HCC-binding mAbs RAZ1 and CR2 bound BoNT/H with high affinity. However, only 1 of 6 BoNT/F mAbs (4E17.2A) bound BoNT/H but with an affinity >800-fold lower (equilibrium dissociation binding constant [KD] = 7.56 × 10(-8)M) than its BoNT/F affinity (KD= 9.1 × 10(-11)M), indicating that the N-terminal two-thirds of BoNT/H is immunologically unique. The affinity of 4E17.2A for BoNT/H was increased >500-fold to KD= 1.48 × 10(-10)M (mAb 4E17.2D). A combination of mAbs RAZ1, CR2, and 4E17.2D completely protected mice challenged with 280 mouse median lethal doses of BoNT/H at a mAb dose as low as 5 µg of total antibody.ConclusionsThis 3-mAb combination potently neutralized BoNT/H and represents a potential human antitoxin that could be developed for the prevention and treatment of type H botulism

Perplexity: Evaluating Transcript Abundance Estimation in the Absence of Ground Truth

There has been rapid development of probabilistic models and inference methods for transcript abundance estimation from RNA-seq data. These models aim to accurately estimate transcript-level abundances, to account for different biases in the measurement process, and even to assess uncertainty in resulting estimates that can be propagated to subsequent analyses. The assumed accuracy of the estimates inferred by such methods underpin gene expression based analysis routinely carried out in the lab. Although hyperparameter selection is known to affect the distributions of inferred abundances (e.g. producing smooth versus sparse estimates), strategies for performing model selection in experimental data have been addressed informally at best. Thus, we derive perplexity for evaluating abundance estimates on fragment sets directly. We adapt perplexity from the analogous metric used to evaluate language and topic models and extend the metric to carefully account for corner cases unique to RNA-seq. In experimental data, estimates with the best perplexity also best correlate with qPCR measurements. In simulated data, perplexity is well behaved and concordant with genome-wide measurements against ground truth and differential expression analysis. To our knowledge, our study is the first to make possible model selection for transcript abundance estimation on experimental data in the absence of ground truth

DHX33 transcriptionally controls genes involved in the cell cycle

The RNA helicase DHX33 has been shown to be a critical regulator of cell proliferation and growth. However, the underlying mechanisms behind DHX33 function remain incompletely understood. We present original evidence in multiple cell lines that DHX33 transcriptionally controls the expression of genes involved in the cell cycle, notably cyclin, E2F1, cell division cycle (CDC), and minichromosome maintenance (MCM) genes. DHX33 physically associates with the promoters of these genes and controls the loading of active RNA polymerase II onto these promoters. DHX33 deficiency abrogates cell cycle progression and DNA replication and leads to cell apoptosis. In zebrafish, CRISPR-mediated knockout of DHX33 results in downregulation of cyclin A2, cyclin B2, cyclin D1, cyclin E2, cdc6, cdc20, E2F1, and MCM complexes in DHX33 knockout embryos. Additionally, we found the overexpression of DHX33 in a subset of non-small-cell lung cancers and in Ras-mutated human lung cancer cell lines. Forced reduction of DHX33 in these cancer cells abolished tumor formation in vivo. Our study demonstrates for the first time that DHX33 acts as a direct transcriptional regulator to promote cell cycle progression and plays an important role in driving cell proliferation during both embryo development and tumorigenesis

A multi-species functional embedding integrating sequence and network structure

A key challenge to transferring knowledge between species is that different species have fundamentally different genetic architectures. Initial computational approaches to transfer knowledge across species have relied on measures of heredity such as genetic homology, but these approaches suffer from limitations. First, only a small subset of genes have homologs, limiting the amount of knowledge that can be transferred, and second, genes change or repurpose functions, complicating the transfer of knowledge. Many approaches address this problem by expanding the notion of homology by leveraging high-throughput genomic and proteomic measurements, such as through network alignment. In this work, we take a new approach to transferring knowledge across species by expanding the notion of homology through explicit measures of functional similarity between proteins in different species. Specifically, our kernel-based method, HANDL (Homology Assessment across Networks using Diffusion and Landmarks), integrates sequence and network structure to create a functional embedding in which proteins from different species are embedded in the same vector space. We show that inner products in this space and the vectors themselves capture functional similarity across species, and are useful for a variety of functional tasks. We perform the first whole-genome method for predicting phenologs, generating many that were previously identified, but also predicting new phenologs supported from the biological literature. We also demonstrate the HANDL embedding captures pairwise gene function, in that gene pairs with synthetic lethal interactions are significantly separated in HANDL space, and the direction of separation is conserved across species. Software for the HANDL algorithm is available at http://bit.ly/lrgr-handl.Published versio