Comparison between dedicated MRI and symphyseal fluoroscopic guided contrast agent injection in the diagnosis of cleft sign in athletic groin pain and association with pelvic ring instability.

OBJECTIVE: To compare dedicated MRI with targeted fluoroscopic guided symphyseal contrast agent injection regarding the assessment of symphyseal cleft signs in men with athletic groin pain and assessment of radiographic pelvic ring instability. METHODS: Sixty-six athletic men were prospectively included after an initial clinical examination by an experienced surgeon using a standardized procedure. Diagnostic fluoroscopic symphyseal injection of a contrast agent was performed. Additionally, standing single-leg stance radiography and dedicated 3-Tesla MRI protocol were employed. The presence of cleft injuries (superior, secondary, combined, atypical) and osteitis pubis was recorded. RESULTS: Symphyseal bone marrow edema (BME) was present in 50 patients, bilaterally in 41 patients and in 28 with an asymmetrical distribution. Comparison of MRI and symphysography was as followed: no clefts: 14 cases (MRI) vs. 24 cases (symphysography), isolated superior cleft sign: 13 vs. 10, isolated secondary cleft sign: 15 vs. 21 cases and combined injuries: 18 vs. 11 cases. In 7 cases a combined cleft sign was observed in MRI but only an isolated secondary cleft sign was visible in symphysography. Anterior pelvic ring instability was observed in 25 patients and was linked to a cleft sign in 23 cases (7 superior cleft sign, 8 secondary cleft signs, 6 combined clefts, 2 atypical cleft injuries). Additional BME could be diagnosed in 18 of those 23. CONCLUSION: Dedicated 3-Tesla MRI outmatches symphysography for purely diagnostic purposes of cleft injuries. Microtearing at the prepubic aponeurotic complex and the presence of BME is a prerequisite for the development of anterior pelvic ring instability. CLINICAL RELEVANCE STATEMENT: For diagnostic of symphyseal cleft injuries dedicated 3-T MRI protocols outmatch fluoroscopic symphysography. Prior specific clinical examination is highly beneficial and additional flamingo view x-rays are recommended for assessment of pelvic ring instability in these patients. KEY POINTS: • Assessment of symphyseal cleft injuries is more accurate by use of dedicated MRI as compared to fluoroscopic symphysography. • Additional fluoroscopy may be important for therapeutic injections. • The presence of cleft injury might be a prerequisite for the development of pelvic ring instability.

Performance and scaling behavior of bioinformatic applications in virtualization environments to create awareness for the efficient use of compute resources.

The large amount of biological data available in the current times, makes it necessary to use tools and applications based on sophisticated and efficient algorithms, developed in the area of bioinformatics. Further, access to high performance computing resources is necessary, to achieve results in reasonable time. To speed up applications and utilize available compute resources as efficient as possible, software developers make use of parallelization mechanisms, like multithreading. Many of the available tools in bioinformatics offer multithreading capabilities, but more compute power is not always helpful. In this study we investigated the behavior of well-known applications in bioinformatics, regarding their performance in the terms of scaling, different virtual environments and different datasets with our benchmarking tool suite BOOTABLE. The tool suite includes the tools BBMap, Bowtie2, BWA, Velvet, IDBA, SPAdes, Clustal Omega, MAFFT, SINA and GROMACS. In addition we added an application using the machine learning framework TensorFlow. Machine learning is not directly part of bioinformatics but applied to many biological problems, especially in the context of medical images (X-ray photographs). The mentioned tools have been analyzed in two different virtual environments, a virtual machine environment based on the OpenStack cloud software and in a Docker environment. The gained performance values were compared to a bare-metal setup and among each other. The study reveals, that the used virtual environments produce an overhead in the range of seven to twenty-five percent compared to the bare-metal environment. The scaling measurements showed, that some of the analyzed tools do not benefit from using larger amounts of computing resources, whereas others showed an almost linear scaling behavior. The findings of this study have been generalized as far as possible and should help users to find the best amount of resources for their analysis. Further, the results provide valuable information for resource providers to handle their resources as efficiently as possible and raise the user community's awareness of the efficient usage of computing resources.

The Phosphodiesterase Inhibitor IBMX Blocks the Potassium Channel THIK-1 from the Extracellular Side.

The two-pore domain potassium channel (K2P-channel) THIK-1 has several predicted protein kinase A (PKA) phosphorylation sites. In trying to elucidate whether THIK-1 is regulated via PKA, we expressed THIK-1 channels in a mammalian cell line (CHO cells) and used the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX) as a pharmacological tool to induce activation of PKA. Using the whole-cell patch-clamp recording, we found that THIK-1 currents were inhibited by application of IBMX with an IC50 of 120 µM. Surprisingly, intracellular application of IBMX or of the second messenger cAMP via the patch pipette had no effect on THIK-1 currents. In contrast, extracellular application of IBMX produced a rapid and reversible inhibition of THIK-1. In patch-clamp experiments with outside-out patches, THIK-1 currents were also inhibited by extracellular application of IBMX. Expression of THIK-1 channels in Xenopus oocytes was used to compare wild-type channels with mutated channels. Mutation of the putative PKA phosphorylation sites did not change the inhibitory effect of IBMX on THIK-1 currents. Mutational analysis of all residues of the (extracellular) helical cap of THIK-1 showed that mutation of the arginine residue at position 92, which is in the linker between cap helix 2 and pore helix 1, markedly reduced the inhibitory effect of IBMX. This flexible linker region, which is unique for each K2P-channel subtype, may be a possible target of channel-specific blockers. SIGNIFICANCE STATEMENT: The potassium channel THIK-1 is strongly expressed in the central nervous system. We studied the effect of 3-isobutyl-1-methyl-xanthine (IBMX) on THIK-1 currents. IBMX inhibits breakdown of cAMP and thus activates protein kinase A (PKA). Surprisingly, THIK-1 current was inhibited when IBMX was applied from the extracellular side of the membrane, but not from the intracellular side. Our results suggest that IBMX binds directly to the channel and that the inhibition of THIK-1 current was not related to activation of PKA.

TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms.

Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm, cancer cell migration, and intracellular trafficking of pathogens such as Ebola virus or bacterial toxins (e.g., cholera toxin). In a genome-wide association study for variants associated with human pigmentation characteristics two coding variants of TPC2, rs35264875 (encoding M484L) and rs3829241 (encoding G734E), have been found to be associated with a shift from brown to blond hair color. In two recent follow-up studies a role for TPC2 in pigmentation has been further confirmed. However, these human polymorphic variants have not been functionally characterized until now. The development of endolysosomal patch-clamp techniques has made it possible to investigate directly ion channel activities and characteristics in isolated endolysosomal organelles. We applied this technique here to scrutinize channel characteristics of the polymorphic TPC2 variants in direct comparison with WT. We found that both polymorphisms lead to a gain of channel function by independent mechanisms. We next conducted a clinical study with more than 100 blond- and brown/black-haired individuals. We performed a genotype/phenotype analysis and subsequently isolated fibroblasts from WT and polymorphic variant carriers for endolysosomal patch-clamp experimentation to confirm key in vitro findings.

[Diagnostic algorithm "FAI and sports hernia" : Results of the consensus meeting for groin pain in athletes]. / Diagnostik-Algorithmus Grenzbereich "FAI und Sportlerleiste" : Ergebnisse des Konsensustreffens Leistenschmerz beim Sportler.

As a result of the complexity and diversity of diseases in the region of the groin, differentiation of the various soft-tissue and bone pathologies remains a challenge for differential diagnosis in routine clinical practice. In the case of athletes with pain localized in the area of the groin, femoroacetabular impingement (FAI) and athlete's groin must be considered as important causes of the groin pain, whereby the common occurrence of double pathologies further complicates diagnosis. Despite the importance of groin pain and its differential diagnoses in everyday clinical practice, there has been a lack of recognized recommendations for diagnostic procedure to date. To this end, a consensus meeting was held in February 2017, in which a group composed equally of groin and hip surgeons took part. With the formulation of recommendations and the establishment of a practicable diagnostic path, colleagues that are involved in treating such patients should be sensitized to this issue and the quality of the diagnosis of groin pain improved in routine clinical practice.

DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats.

Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats.

ballaxy: web services for structural bioinformatics.

MOTIVATION: Web-based workflow systems have gained considerable momentum in sequence-oriented bioinformatics. In structural bioinformatics, however, such systems are still relatively rare; while commercial stand-alone workflow applications are common in the pharmaceutical industry, academic researchers often still rely on command-line scripting to glue individual tools together. RESULTS: In this work, we address the problem of building a web-based system for workflows in structural bioinformatics. For the underlying molecular modelling engine, we opted for the BALL framework because of its extensive and well-tested functionality in the field of structural bioinformatics. The large number of molecular data structures and algorithms implemented in BALL allows for elegant and sophisticated development of new approaches in the field. We hence connected the versatile BALL library and its visualization and editing front end BALLView with the Galaxy workflow framework. The result, which we call ballaxy, enables the user to simply and intuitively create sophisticated pipelines for applications in structure-based computational biology, integrated into a standard tool for molecular modelling. AVAILABILITY AND IMPLEMENTATION: ballaxy consists of three parts: some minor modifications to the Galaxy system, a collection of tools and an integration into the BALL framework and the BALLView application for molecular modelling. Modifications to Galaxy will be submitted to the Galaxy project, and the BALL and BALLView integrations will be integrated in the next major BALL release. After acceptance of the modifications into the Galaxy project, we will publish all ballaxy tools via the Galaxy toolshed. In the meantime, all three components are available from http://www.ball-project.org/ballaxy. Also, docker images for ballaxy are available at https://registry.hub.docker.com/u/anhi/ballaxy/dockerfile/. ballaxy is licensed under the terms of the GPL.

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization.

Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor κB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.

Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP.

Activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated in vivo by direct binding of the second messenger cAMP. This process plays a fundamental role in the fine-tuning of HCN channel activity and is critical for the modulation of cardiac and neuronal rhythmicity. Here, we identify the pyrimidine cyclic nucleotide cCMP as another regulator of HCN channels. We demonstrate that cCMP shifts the activation curves of two members of the HCN channel family, HCN2 and HCN4, to more depolarized voltages. Moreover, cCMP speeds up activation and slows down deactivation kinetics of these channels. The two other members of the HCN channel family, HCN1 and HCN3, are not sensitive to cCMP. The modulatory effect of cCMP is reversible and requires the presence of a functional cyclic nucleotide-binding domain. We determined an EC(50) value of ∼30 µm for cCMP compared with 1 µm for cAMP. Notably, cCMP is a partial agonist of HCN channels, displaying an efficacy of ∼0.6. cCMP increases the frequency of pacemaker potentials from isolated sinoatrial pacemaker cells in the presence of endogenous cAMP concentrations. Electrophysiological recordings indicated that this increase is caused by a depolarizing shift in the activation curve of the native HCN current, which in turn leads to an enhancement of the slope of the diastolic depolarization of sinoatrial node cells. In conclusion, our findings establish cCMP as a gating regulator of HCN channels and indicate that this cyclic nucleotide has to be considered in HCN channel-regulated processes.

APL@Voro: a Voronoi-based membrane analysis tool for GROMACS trajectories.

APL@Voro is a new program developed to aid in the analysis of GROMACS trajectories of lipid bilayer simulations. It can read a GROMACS trajectory file, a PDB coordinate file, and a GROMACS index file to create a two-dimensional geometric representation of a bilayer. Voronoi diagrams and Delaunay triangulations--generated for different selection models of lipids--support the analysis of the bilayer. The values calculated on the geometric structures can be visualized in a user-friendly interactive environment and, then, plotted and exported to different file types. APL@Voro supports complex bilayers with a mix of various lipids and proteins. For the calculation of the projected area per lipid, a modification of the well-known Voronoi approach is presented as well as the presentation of a new approach for including atoms into an existing triangulation. The application of the developed software is discussed for three example systems simulated with GROMACS. The program is written in C++, is open source, and is available free of charge.

Molecular dynamics simulations and conductance studies of the interaction of VP1 N-terminus from Polio virus and gp41 fusion peptide from HIV-1 with lipid membranes.

The icosahedral Polio virus capsid consists of 60 copies of each of the coat proteins VP1, VP2, VP3 and myristolyated VP4 (myrVP4). Catalyzed by the host cell receptor the Polio virus enters the host cell via externalization of myrVP4 and the N terminal part of VP1. There are several assumptions about the individual role of both of the proteins in the mechanism of membrane attachment and genome injection. We use the first 32 N terminal amino acids of VP1 and applied molecular dynamics simulations to assess its mechanism of function when attached and inserted into hydrated lipid membranes (POPC). Helical models are placed in various positions in regard to the lipid membrane to start with. As a comparison, the first 33 amino acids of the fusion peptide of gp41 of HIV-1 are simulated under identical conditions. Computational data support the idea that VP1 is not penetrating into the membrane to form a pore; it rather lays on the membrane surface and only perturbs the membrane. Furthermore, this idea is strengthened by channel recordings of both peptides showing irregular openings.

ORF8a of SARS-CoV forms an ion channel: experiments and molecular dynamics simulations.

ORF8a protein is 39 residues long and contains a single transmembrane domain. The protein is synthesized using solid phase peptide synthesis and reconstituted into artificial lipid bilayers that forms cation-selective ion channels with a main conductance level of 8.9±0.8pS at elevated temperature (38.5°C). Computational modeling studies including multi nanosecond molecular dynamics simulations in a hydrated POPC lipid bilayer are done with a 22 amino acid transmembrane helix to predict a putative homooligomeric helical bundle model. A structural model of a pentameric bundle is proposed with cysteines, serines and threonines facing the pore.

Workflow-enhanced conformational analysis of guanidine zinc complexes via a science gateway.

The new science gateway MoSGrid (Molecular Simulation Grid) enables users to submit and process molecular simulation studies on a large scale. A conformational analysis of guanidine zinc complexes, which are active catalysts in the ring-opening polymerization of lactide, is presented as an example. Such a large-scale quantum chemical study is enabled by workflow technologies. Two times 40 conformers have been generated, for two guanidine zinc complexes. Their structures were optimized using Gaussian03 and the energies processed within the quantum chemistry portlet of the MoSGrid portal. All meta- and post-processing steps have been performed in this portlet. All workflow features are implemented via WS-PGRADE and submitted to UNICORE.

Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.

BACKGROUND AND OBJECTIVES: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. METHODS: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). RESULTS: The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: ß(SE)COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: ß(SE)COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: ß(SE)COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10-8). DISCUSSION: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

CELLmicrocosmos 2.2 MembraneEditor: a modular interactive shape-based software approach to solve heterogeneous membrane packing problems.

New perspectives have been developed to understand the processes of modeling heterogeneous membranes. These are crucial steps prior to applying advanced techniques like molecular dynamic simulations of whole membrane systems. Lipid, protein, and membrane packing problems are addressed based on biochemical properties in combination with computational optimization techniques. The CELLmicrocosmos 2.2 MembraneEditor (CmME) is introduced as an appropriate framework to handle such problems by offering diverse algorithmic approaches. Its algorithm plug-in-interface enables modelers to generate problem-specific algorithms. Good solutions concerning runtime and lipid density are realized by focusing on the outer shapes of the PDB-based molecules. Application cases are presented like the publication-based modeling of inner and outer mitochondrial membrane-fragments, semiautomatic incorporation of proteins, and the assembly of rafts. Concerning geometrical aspects of the lipids, the achieved results are consistent with experimental observations related to lipid densities and distributions. Finally, two membranes simulated with GROMACS are analyzed and compared: the first is generated with conventional scripting techniques, the second with the CmME Distributor algorithm. The examples prove that CmME is a valuable and versatile tool for a broad set of applications in analysis and visualization of biomembranes.

A Multi-Modular System for the Visualization and Classification of MER Data During Neurostimulation Procedures.

This paper proposes an interactive analysis and visualization tool for the accuracy improvement of electrode placement during neurostimulation therapy surgery. During the procedure, the presented system assists the surgeon in the crucial tissue type detection by providing a fused visualization of the current electrode location and the microelectrode recordings (MER). The system processes the MER in real-time and utilizes a convolutional neural network (CNN) to classify the targeted tissue type. In addition to presenting the MER in its raw waveform, the system also offers the visualization of the frequency domain and the result of the neural network. To further assist the decision-making process, additional visualization methods are integrated into the system. Using the pre-operative taken CT and MRI scans, the system offers 3D visualization in the form of direct volume rendering (DVR) and axis-aligned slice views in 2D. Both domains are enriched by the MER readings and the result of the machine learning classifier.

A Discrete Probabilistic Approach to Dense Flow Visualization.

Dense flow visualization is a popular visualization paradigm. Traditionally, the various models and methods in this area use a continuous formulation, resting upon the solid foundation of functional analysis. In this work, we examine a discrete formulation of dense flow visualization. From probability theory, we derive a similarity matrix that measures the similarity between different points in the flow domain, leading to the discovery of a whole new class of visualization models. Using this matrix, we propose a novel visualization approach consisting of the computation of spectral embeddings, i.e., characteristic domain maps, defined by particle mixture probabilities. These embeddings are scalar fields that give insight into the mixing processes of the flow on different scales. The approach of spectral embeddings is already well studied in image segmentation, and we see that spectral embeddings are connected to Fourier expansions and frequencies. We showcase the utility of our method using different 2D and 3D flows.

Sample-based surface coloring.

In this paper, we present a sample-based approach for surface coloring, which is independent of the original surface resolution and representation. To achieve this, we introduce the Orthogonal Fragment Buffer (OFB)-an extension of the Layered Depth Cube-as a high-resolution view-independent surface representation. The OFB is a data structure that stores surface samples at a nearly uniform distribution over the surface, and it is specifically designed to support efficient random read/write access to these samples. The data access operations have a complexity that is logarithmic in the depth complexity of the surface. Thus, compared to data access operations in tree data structures like octrees, data-dependent memory access patterns are greatly reduced. Due to the particular sampling strategy that is employed to generate an OFB, it also maintains sample coherence, and thus, exhibits very good spatial access locality. Therefore, OFB-based surface coloring performs significantly faster than sample-based approaches using tree structures. In addition, since in an OFB, the surface samples are internally stored in uniform 2D grids, OFB-based surface coloring can efficiently be realized on the GPU to enable interactive coloring of high-resolution surfaces. On the OFB, we introduce novel algorithms for color painting using volumetric and surface-aligned brushes, and we present new approaches for particle-based color advection along surfaces in real time. Due to the intermediate surface representation we choose, our method can be used to color polygonal surfaces as well as any other type of surface that can be sampled.

Deadeye Visualization Revisited: Investigation of Preattentiveness and Applicability in Virtual Environments.

Visualizations rely on highlighting to attract and guide our attention. To make an object of interest stand out independently from a number of distractors, the underlying visual cue, e.g., color, has to be preattentive. In our prior work, we introduced Deadeye as an instantly recognizable highlighting technique that works by rendering the target object for one eye only. In contrast to prior approaches, Deadeye excels by not modifying any visual properties of the target. However, in the case of 2D visualizations, the method requires an additional setup to allow dichoptic presentation, which is a considerable drawback. As a follow-up to requests from the community, this paper explores Deadeye as a highlighting technique for 3D visualizations, because such stereoscopic scenarios support dichoptic presentation out of the box. Deadeye suppresses binocular disparities for the target object, so we cannot assume the applicability of our technique as a given fact. With this motivation, the paper presents quantitative evaluations of Deadeye in VR, including configurations with multiple heterogeneous distractors as an important robustness challenge. After confirming the preserved preattentiveness (all average accuracies above 90%) under such real-world conditions, we explore VR volume rendering as an example application scenario for Deadeye. We depict a possible workflow for integrating our technique, conduct an exploratory survey to demonstrate benefits and limitations, and finally provide related design implications.

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.