An integrative functional genomics approach towards quantitative trait gene nomination in existing and emerging mouse genetic reference populations

An approach that has been widely applied for the genetic dissection of complex traits is Quantitative Trait Locus (QTL) mapping. QTL mapping identifies genomic regions that harbor polymorphisms, responsible for the observed variation in a complex trait. If these polymorphisms are located within a gene, then these genes are called Quantitative Trait Genes (QTG). Prior to advancements in QTL mapping populations, QTL mapping resolution was often poor, resulting in large QTL intervals. Therefore, after mapping a QTL, fine mapping was initiated to further reduce the QTL interval and to identify the QTG. While successful, fine mapping using genetic approaches have been extremely time and resource intensive, making it the rate-limiting step in QTG discovery. Thus far, only a few QTGs have been successfully identified and validated. The disproportionate ratio of QTLs mapped to QTGs identified has been a cause of concern. Successful QTG discovery relies on the power and resolution with which QTLs are mapped and the genetic architecture of the underlying QTL mapping population. Here, QTL mapping performance in two recently developed QTL mapping populations, namely the expanded BXD Recombinant Inbred (RI) strain panel and the collaborative cross (CC) are assessed. Results indicate that while both the expanded BXD RI strain panel and the CC improve QTL mapping resolution, the CC is able to achieve greater precision and resolution in QTL v mapping. However, neither the BXD RI nor the CC facilitates gene level resolution in QTL mapping. Recent studies have used the integration and convergence of evidence among functional genomics studies as a successful strategy towards the efficient and rapid nomination of QTG. Here, the complementary in silico approach of integrative functional genomics, using GeneWeaver (www.geneweaver.org), is applied towards the reduction of two cocaine-induced locomotor activation QTLs, mapped in the expanded BXD RI strain panel. Integrative functional genomic analyses of these QTLs led to the nomination of Rab3b as a putative QTG. Functional assessment of Rab3b using Rab3bcd knockout mice reveals its role in acute habituation mediated cocaine response, serving as evidence of the efficiency and utility of integrative functional genomics for the identification of highly relevant QTG

Hybrid approximate message passing

Gaussian and quadratic approximations of message passing algorithms on graphs have attracted considerable recent attention due to their computational simplicity, analytic tractability, and wide applicability in optimization and statistical inference problems. This paper presents a systematic framework for incorporating such approximate message passing (AMP) methods in general graphical models. The key concept is a partition of dependencies of a general graphical model into strong and weak edges, with the weak edges representing interactions through aggregates of small, linearizable couplings of variables. AMP approximations based on the Central Limit Theorem can be readily applied to aggregates of many weak edges and integrated with standard message passing updates on the strong edges. The resulting algorithm, which we call hybrid generalized approximate message passing (HyGAMP), can yield significantly simpler implementations of sum-product and max-sum loopy belief propagation. By varying the partition of strong and weak edges, a performance--complexity trade-off can be achieved. Group sparsity and multinomial logistic regression problems are studied as examples of the proposed methodology.The work of S. Rangan was supported in part by the National Science Foundation under Grants 1116589, 1302336, and 1547332, and in part by the industrial affiliates of NYU WIRELESS. The work of A. K. Fletcher was supported in part by the National Science Foundation under Grants 1254204 and 1738286 and in part by the Office of Naval Research under Grant N00014-15-1-2677. The work of V. K. Goyal was supported in part by the National Science Foundation under Grant 1422034. The work of E. Byrne and P. Schniter was supported in part by the National Science Foundation under Grant CCF-1527162. (1116589 - National Science Foundation; 1302336 - National Science Foundation; 1547332 - National Science Foundation; 1254204 - National Science Foundation; 1738286 - National Science Foundation; 1422034 - National Science Foundation; CCF-1527162 - National Science Foundation; NYU WIRELESS; N00014-15-1-2677 - Office of Naval Research

Action detection using a neural network elucidates the genetics of mouse grooming behavior.

Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming is a prototypical stereotyped behavior that is often used as an endophenotype in psychiatric genetics. Here, we used mouse grooming behavior as an example and developed a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operating across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We surveyed grooming behavior in the open field in 2457 mice across 62 strains, determined its heritable components, conducted GWAS to outline its genetic architecture, and performed PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of behavioral mechanisms

Arthroscopic anterior cruciate ligament reconstruction with central quadriceps tendon bone (CQTB) graft: An outcome study in fifty Indian patients

Background: Arthroscopic ACL reconstruction using biologic autografts is the current gold standard in the management of symptomatic ACL tears. The commonly used BPTB (Bone-Patellar Tendon-Bone) and quadrupled hamstring tendon grafts have their own disadvantages. This study was conducted to evaluate the efficacy of CQTB (Central Quadriceps Tendon Bearing) graft as an autograft for ACL reconstruction in relieving instability in ACL deficient knees.Methods: 50 patients (45males; 5 females) with symptomatic ACL laxity, who underwent arthroscopic ACL reconstruction using the CQTB graft were followed up for 1 year. The functional improvement was analyzed by comparing the pre-operative Lysholm scores with those at 03 months, 06 months and 12 months post operatively. The objective improvement was analyzed comparing the Anterior Drawer and Lachman test grades pre-operatively and after 1 year follow up. The mean length of the graft and the post-operative morbidity were also noted.Results: The average Lysholm scores improved from a pre-operative value of 44.34 to 78.98,87.86 and 91.58 at 03months,06 months and 1 year respectively. (p<0.05; ANOVA). The number of patients with Grade I, II and III laxities on Anterior Drawer test improved from 01, 36 and 12 respectively to 43, 06 and 01 respectively 1 year after surgery (p<0.05; paired t test). The number of patients with Grade I, II and III laxities on Lachman test reduced from 1, 34 and 15 y to 39, 10 and 01 respectively. The average thickness of graft harvested was 9.21mm.Conclusions: CQTB autograft is a viable option along with other available autografts in its ability to reconstruct native ACL, without any hazards and additional complications

Concomitant bilateral medial malleolus stress fracture: a case report and review of literature of an extremely rare injury

Medial malleolus stress fractures are rare stress injuries and account for 4% of all the stress fractures. Bilateral medial malleolus stress fracture (MMSFs) is extremely rare with only five such cases reported in existing literature. We report an extremely rare injury pattern in the form of concomitant bilateral MMSF in a young military recruit who presented with severe pain in both his ankles for one month. A 20-year military recruit undergoing rigorous physical training presented to us with severe bilateral ankle pain of one month duration. Clinico-radiological examination revealed bilateral MMSFs. He was managed with open reduction and internal fixation using a one-third tubular plate in buttress mode. Patient was gradually rehabilitated and on one-year follow up, he is asymptomatic and performing all strenuous physical activities. Bilateral MMSFs are extremely rare injuries with only five such cases reported in existing medical literature and this is the fourth instance where bilateral MMSFs were diagnosed at the time of clinical presentation and managed simultaneously, in the same surgical setting.

Role of extracorporeal shockwave therapy and injectable corticosteroids in the treatment of lateral epicondylitis: a comparative study of 100 patients

Background: Even though considered to be self-limiting, lateral epicondylitis (tennis elbow) can cause significant impediment in professional and activities of daily living. A safe and minimally invasive procedure that will enable patients to return to their daily activities as soon as possible should be advocated in the management of this condition. The aim of the present study was to investigate the role of extracorporeal shock wave therapy (ESWT) and injectable corticosteroids in the treatment of lateral epicondylitis with the secondary objective of comparing the difference in pain relief and functional improvement in patients treated with both modalities.Methods: A cross sectional analytical study was conducted over an 18 month period.100 patients were randomized into two groups, A (51 patients) who received three sessions of ESWT on weekly intervals and B (49 patients) who received two intra-lesional injections of 1ml of methylprednisolone and 2% lignocaine on weekly intervals. The patients were followed up at 3 weeks, 6 weeks and 6 months after the interventions. Subjective and objective improvements were measured using visual analogue score (VAS) and Patient Rated Tennis Elbow Evaluation Score (PRTEE).Results: The mean VAS in both groups reduced from 8.47 and 8.53 to 2.51 and 1.67 respectively at the end of the follow up (p <0.001) .The mean PRTEE score in Group A reduced from 80.59 to 26.53 (p<0.001) and Group B from 82.76 to 13.59 (p<0.05). In Group A (ESWT), the average reduction In PRTEE Score at the end of follow up was 54.06 and Group B (steroids) was 69.16. The difference was found to be statistically significant (p<0.001) favouring steroid injections.Conclusions: Both ESWT and steroid injections were found to be effective in producing symptomatic pain relief and improving the functional disability in the management of lateral epicondylitis. The comparison of both modalities showed a statistically significant improvement in pain and functional disability in favour of steroids at a short duration of follow up i.e., 03 weeks, 06 weeks and 06 months.

Gradual distraction for treatment of severe knee flexion contractures using the Ilizarov’s apparatus

Background: Knee flexion contractures result in a significant amount of functional disability due to reduced mobility and limb length discrepancy. Treatment options include non-surgical methods like serial casting, dynamic splinting and traction or surgical methods like osteotomies and soft tissue procedures. External fixation has emerged as a highly successful means of achieving controlled gradual correction of joint contractures with low rates of complications including recurrence. The aim of this study is to evaluate the functional outcome in terms of residual deformity and change in ambulatory status following correction using the Ilizarov’s apparatus.Methods: 12 patients with knee flexion contractures ranging from 20°-70° underwent correction using the Ilizarov’s external fixator (IEF). The use of simple mathematic formulae enabled us to calculate and estimate the rate and duration of distraction. End results were assessed at one year by the residual contracture as: Excellent: 0-5°, Good: 6-15°, Fair: 16-30° and Poor: &gt;30°.Results: The functional assessment was graded as excellent in 7, good in 4 and fair in 1 out of 12 patients. All patients were independent ambulators and only 1 out of 12 patients required an additional orthosis for maintenance of the correction.Conclusions: The IEF is a safe and precise modality even for the most complex contractures of the knee. Accurate placement of the hinges along the center of rotation of the knee avoids undue subluxation of the tibia during correction. In order to ensure a low rate of complications, it is imperative to have a detailed pre-operative plan and all principles of fixation should be meticulously adhered to.

Chronic type B dissecting aortoiliac aneurysm repair complicated by congenital pelvic kidney

Although the association between abdominal aortic aneurysm and pelvic kidney is rare, previous reports have described various methods of repair with successful preservation of pelvic kidney function. We describe a unique case complicated by aortic dissection. Successful intra-operative perfusion of the kidney was maintained via a temporary axillorenal shunt

Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis

Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification o