Application of Bayesian regression with singular value decomposition method in association studies for sequence data

Genetic association studies usually involve a large number of single-nucleotide polymorphisms (SNPs) (k) and a relative small sample size (n), which produces the situation that k is much greater than n. Because conventional statistical approaches are unable to deal with multiple SNPs simultaneously when k is much greater than n, single-SNP association studies have been used to identify genes involved in a disease’s pathophysiology, which causes a multiple testing problem. To evaluate the contribution of multiple SNPs simultaneously to disease traits when k is much greater than n, we developed the Bayesian regression with singular value decomposition (BRSVD) method. The method reduces the dimension of the design matrix from k to n by applying singular value decomposition to the design matrix. We evaluated the model using a Markov chain Monte Carlo simulation with Gibbs sampler constructed from the posterior densities driven by conjugate prior densities. Permutation was incorporated to generate empirical p-values. We applied the BRSVD method to the sequence data provided by Genetic Analysis Workshop 17 and found that the BRSVD method is a practical method that can be used to analyze sequence data in comparison to the single-SNP association test and the penalized regression method

Development of Mathematical Models for the Analysis of Hepatitis Delta Virus Viral Dynamics

BACKGROUND: Mathematical models have shown to be extremely helpful in understanding the dynamics of different virus diseases, including hepatitis B. Hepatitis D virus (HDV) is a satellite virus of the hepatitis B virus (HBV). In the liver, production of new HDV virions depends on the presence of HBV. There are two ways in which HDV can occur in an individual: co-infection and super-infection. Co-infection occurs when an individual is simultaneously infected by HBV and HDV, while super-infection occurs in persons with an existing chronic HBV infection. METHODOLOGY/PRINCIPAL FINDINGS: In this work a mathematical model based on differential equations is proposed for the viral dynamics of the hepatitis D virus (HDV) across different scenarios. This model takes into consideration the knowledge of the biology of the virus and its interaction with the host. In this work we will present the results of a simulation study where two scenarios were considered, co-infection and super-infection, together with different antiviral therapies. Although, in general the predicted course of HDV infection is similar to that observed for HBV, we observe a faster increase in the number of HBV infected cells and viral load. In most tested scenarios, the number of HDV infected cells and viral load values remain below corresponding predicted values for HBV. CONCLUSIONS/SIGNIFICANCE: The simulation study shows that, under the most commonly used and generally accepted therapy approaches for HDV infection, such as lamivudine (LMV) or ribavirine, peggylated alpha-interferon (IFN) or a combination of both, LMV monotherapy and combination therapy of LMV and IFN were predicted to more effectively reduce the HBV and HDV viral loads in the case of super-infection scenarios when compared with the co-infection. In contrast, IFN monotherapy was found to reduce the HDV viral load more efficiently in the case of super-infection while the effect on the HBV viral load was more pronounced during co-infection. The results suggest that there is a need for development of high efficacy therapeutic approaches towards the specific inhibition of HDV replication. These approaches may additionally be directed to the reduction of the half-life of infected cells and life-span of newly produced circulating virions

Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and available of integrase inhibitors in Cape Town, South Africa

HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatmentnaive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2.85% (9/314) in database derived sequences. RAMs were present at IN-positions 66, 92, 143, 147 and 148, all of which may confer resistance to Raltegravir (RAL) and Elvitegravir (EVG), but are unlikely to affect second-generation Dolutegravir (DTG), except mutations in the Q148 pathway. Furthermore, protein modeling showed, naturally occurring polymorphisms impact the stability of the intasome-complex and therefore may contribute to an overall potency against InSTIs. Our data suggest the prevalence of InSTI RAMs, against InSTIs, is low in South Africa, but natural polymorphisms and subtype-specific differences may influence the effect of individual treatment regimens

Monte Carlo Simulations of HIV Capsid Protein Homodimer

Capsid protein (CA) is the building block of virus coats. To help understand how the HIV CA proteins self-organize into large assemblies of various shapes, we aim to computationally evaluate the binding affinity and interfaces in a CA homodimer. We model the N- and C-terminal domains (NTD and CTD) of the CA as rigid bodies and treat the five-residue loop between the two domains as a flexible linker. We adopt a transferrable residue-level coarse-grained energy function to describe the interactions between the protein domains. In seven extensive Monte Carlo simulations with different volumes, a large number of binding/unbinding transitions between the two CA proteins are observed, thus allowing a reliable estimation of the equilibrium probabilities for the dimeric vs monomeric forms. The obtained dissociation constant for the CA homodimer from our simulations, 20–25 μM, is in reasonable agreement with experimental measurement. A wide range of binding interfaces, primarily between the NTDs, are identified in the simulations. Although some observed bound structures here closely resemble the major binding interfaces in the capsid assembly, they are statistically insignificant in our simulation trajectories. Our results suggest that although the general purpose energy functions adopted here could reasonably reproduce the overall binding affinity for the CA homodimer, further adjustment would be needed to accurately represent the relative strength of individual binding interfaces

Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats

Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect. We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues. Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell. Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell. These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context

Red flags for the early detection of spinal infection in back pain patients

© 2019 The Author(s). Background: Red flags are signs and symptoms that are possible indicators of serious spinal pathology. There is limited evidence or guidance on how red flags should be used in practice. Due to the lack of robust evidence for many red flags their use has been questioned. The aim was to conduct a systematic review specifically reporting on studies that evaluated the diagnostic accuracy of red flags for Spinal Infection in patients with low back pain. Methods: Searches were carried out to identify the literature from inception to March 2019. The databases searched were Medline, CINHAL Plus, Web of Science, Embase, Cochrane, Pedro, OpenGrey and Grey Literature Report. Two reviewers screened article texts, one reviewer extracted data and details of each study, a second reviewer independently checked a random sample of the data extracted. Results: Forty papers met the eligibility criteria. A total of 2224 cases of spinal infection were identified, of which 1385 (62%) were men and 773 (38%) were women mean age of 55 (± 8) years. In total there were 46 items, 23 determinants and 23 clinical features. Spinal pain (72%) and fever (55%) were the most common clinical features, Diabetes (18%) and IV drug use (9%) were the most occurring determinants. MRI was the most used radiological test and Staphylococcus aureus (27%), Mycobacterium tuberculosis (12%) were the most common microorganisms detected in cases. Conclusion: The current evidence surrounding red flags for spinal infection remains small, it was not possible to assess the diagnostic accuracy of red flags for spinal infection, as such, a descriptive review reporting the characteristics of those presenting with spinal infection was carried out. In our review, spinal infection was common in those who had conditions associated with immunosuppression. Additionally, the most frequently reported clinical feature was the classic triad of spinal pain, fever and neurological dysfunction. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/