Biology subjects

Rawi, R.

Publications and source records attributed to Rawi, R..

18 recordsLinked to original sources

bioRxiv2025

Vaccine Elicitation of HIV-1 Neutralizing Antibodies Against Both V2 Apex and Fusion Peptide in Rhesus Macaques

Broadly neutralizing antibodies targeting multiple sites of HIV-1 Env vulnerability can be induced by infection, but simultaneous elicitation of neutralizing antibodies (NAbs) against multiple epitopes has not yet been achieved by vaccination. In this study, we designed a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex and evaluated its capacity to induce NAbs against both epitopes in rhesus macaques. This vaccine combined an FP conjugate with a cocktail of engineered Env trimers with enhanced V2 apex recognition and increased antigen retention in lymph nodes. Immunization of macaques with the dual-epitope vaccine elicited >1000-fold higher autologous tier 2-neutralization titers than the wildtype Env trimer and enhanced heterologous NAb breadth. Both FP and V2-apex monoclonal antibodies (mAb) were isolated from immunized macaques and showed heterologous neutralization with genetic and structural signatures that were similar to well-characterized FP and V2 apex bNAbs, although the V2 apex mAbs showed incomplete maturation. These results demonstrate proof-of-concept for simultaneous vaccine elicitation of NAbs against multiple sites of Env vulnerability, which will likely be critical for an effective HIV-1 vaccine. HIGHLIGHTSO_LIDesigned a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex C_LIO_LIV2-SET Env trimer conferred higher binding of V2 apex bNAbs, longer retention in draining lymph nodes, and >1000-fold higher induction of autologous neutralization titers compared with wildtype Env trimer C_LIO_LIDual-epitope vaccine enhanced serum tier 2 neutralization breadth C_LIO_LIDual-epitope vaccine elicited FP- and V2 apex-specific neutralizing mAbs with genetic signatures similar to well-characterized FP and V2 apex bNAbs C_LI

immunology↗

bioRxiv2025

BRAVE: a highly accurate method for predicting HIV-1 antibody resistance using large language models for proteins

MotivationBroadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) of human immunodeficiency virus-1 (HIV-1) have been utilized in clinical trials aimed at preventing and treating HIV-1 infections. However, the emergence of neutralization resistance to bNAbs occurs rapidly due to the high mutation rate of HIV-1. Previous studies have suggested the use of in silico methods to effectively predict the resistance of HIV-1 isolates to bNAbs. In this study, we present a novel machine learning approach called BRAVE (Bnab Resistance Analysis Via Evolutionary scale modeling 2) designed to predict HIV-1 resistance against 33 known bNAbs. This innovative tool employs a Random Forests classifier that uses a protein language model to reliably capture protein features. ResultsBRAVE outperformed leading resistance prediction tools on various performance metrics, attaining the highest performance in established classification measures including accuracy, area under the curve, logarithmic loss, and F1-score. Importantly, rigorous statistical comparisons (p<0.001) show that BRAVE is significantly more accurate than state-of-the-art neutralization prediction tools. BRAVE will facilitate informed decisions of antibody usage and sequence-based monitoring of viral escape in clinical settings. Availability and implementationBRAVE software is available for download under GitHub (https://github.com/kiryst/BRAVE/tree/master). Contactreda.rawi@nih.gov Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2025

VIProDesign: Viral Protein Panel Design for Highly Variable Viruses to Evaluate Immune Responses and Identify Broadly Neutralizing Antibodies

MotivationHighly mutable viruses continuously evolve, with some posing major pandemic risks. However, standardized neutralization assays and up-to-date viral panels are often lacking, limiting evaluation of immunogens and identification of broadly neutralizing antibodies. Closing these gaps is essential for guiding effective countermeasure development. ResultsIn this study, we present Viral Protein Panel Design (VIProDesign), a computational tool for designing viral protein panels that address the high sequence diversity of rapidly evolving viruses. VIProDesign uses the Partitioning Around Medoids (PAM) algorithm to select representative strains and applies the elbow-point method based on cumulative Shannon entropy to balance diversity and panel size. We used VIProDesign to generate optimized panels for Betacoronavirus, human immunodeficiency virus-1 (HIV-1), Influenza virus, Norovirus, and Lassa virus. The tool also supports customizable panel sizes, making it suitable for both resource-limited contexts and early-stage research. This flexible approach streamlines viral panel design across diverse pathogens. Although VIProDesign was originally developed for viral proteins, its underlying framework is broadly applicable to the selection of representative protein panels across diverse taxa, including bacterial species, toxins, and other biologically relevant protein families.

bioinformatics↗

bioRxiv2025

GLYCO-2: a Tool to Quantify Glycan Shielding of Glycosylated Proteins with Improved Data Processing and Computation Speed

MotivationGlycans bound to glycoproteins mediate immune response, including antibody recognition and immune evasion. Previously, we developed an in silico tool GLYCO (GLYcan COverage) to quantify the glycan shielding of a protein surface, applying it to various studies. However, GLYCO lacks sufficient computational efficiency when analyzing larger datasets. ResultsHere we introduce GLYCO-2 which improves the computational speed by [~]4- fold compared to GLYCO by adopting a new analytical cylinder method with k-d trees. GLYCO-2 can calculate glycan shielding from a single coordinate file or from multiple frames derived from molecular dynamics simulations accounting for the inherent flexibility of oligosaccharides. We applied GLYCO-2 to quantify glycan shielding of influenza hemagglutinin (HA) proteins across diverse subtypes that infect humans, revealing an increasing trend in glycan shielding over time within each subtype, likely contributing to immune evasion. Overall, the enhanced computational efficiency of GLYCO-2 allows for faster and easier quantification of glycans, which contributes to the understand of glycan shielding effects in fields such as immunology and vaccine design. Availability and implementationGLYCO-2 is freely available at https://github.com/meteosR/GLYCO-2/ Contactmyungjin.lee@nih.gov or reda.rawi@nih.gov Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2024

HIV-1-envelope trimer transitions from prefusion-closed to CD4-bound-open conformations through an occluded-intermediate state

HIV-1 infection is initiated by the interaction between the gp120 subunit in the envelope (Env) trimer and the cellular receptor CD4 on host cells. This interaction induces substantial structural rearrangement of the Env trimer. Currently, static structural information for prefusion-closed trimers, CD4-bound prefusion-open trimers, and various antibody-bound trimers is available. However, dynamic features between these static states (e.g., transition structures) are not well understood. Here, we investigate the full transition pathway of a site specifically glycosylated Env trimer between prefusion-closed and CD4-bound-open conformations by collective molecular dynamics and single-molecule Forster resonance energy transfer (smFRET). Our investigations reveal and confirm important features of the transition pathway, including movement of variable loops to generate a glycan hole at the trimer apex and formation or rearrangements of -helices and {beta}-strands. Notably, by comparing the transition pathway to known Env-structures, we uncover evidence for a transition intermediate, with four antibodies, Ab1303, Ab1573, b12, and DH851.3, recognizing this intermediate. Each of these four antibodies induce population shifts of Env to occupy a newly observed smFRET state: the "occluded-intermediate" state. We propose this occluded-intermediate state to be both a prevalent state of Env and an on-path conformation between prefusion-closed and CD4-bound-open states, previously overlooked in smFRET analyses.

bioinformatics↗

bioRxiv2024

Vaccine-elicited and naturally elicited antibodies differ in their recognition of the HIV-1 fusion peptide

Broadly neutralizing antibodies have been proposed as templates for HIV-vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1-fusion peptide, which comprises envelope (Env) residues 512-526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with negative-charge substitutions around residues 517-520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512-516 showing increased binding. Molecular dynamics analysis and cryo-EM structure of the naturally elicited ACS202 antibody in complex with HIV-Env trimer with A517E suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence. HIGHLIGHTSPeptide substitution scan reveals naturally elicited antibodies against fusion peptide (FP) can bind select non-canonical FP sequences with high affinity. Peptide substitution scan data for FP antibodies correlates significantly with their differential selection indicating variation in binding relates to neutralization tolerance. Structure and energetic analysis of naturally elicited ACS202 with HIV-Env trimer reveals basis for improved recognition of A517E mutant. Atomic level interactions from MD simulation analysis corroborate trends observed with peptide substitutions. verall, peptide substitution scans reveal vaccine-elicited antibodies against FP to be less permissive to FP-sequence variability than naturally elicited antibodies.

immunology↗

bioRxiv2024

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to [~]103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/L. In PWOH and PWH with CD4 counts [≥]200 cells/L, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

microbiology↗

bioRxiv2022

In Silico Improvement of Highly Protective Anti-Malarial Antibodies

Antibody CIS43 binds Plasmodium falciparum circumsporozoite protein (PfCSP) and protects against malaria, as recently demonstrated clinically. To improve the efficacy of CIS43, we developed an in silico pipeline to optimize the interaction energy of CIS43 to its junctional epitope (peptide 21: PfCSP residues 101-115). Starting from two improved CIS43 variants, recently elicited from a CIS43-germline knock-in mice, single and double amino acid substitutions in the peptide 21-proximal heavy (VH) and light (VL) variable regions were introduced. CIS43-variants, selected on the basis of improved in silico interface and stability energies, showed increased affinity to peptide 21 and superior malaria-protective efficacy. The best designed variant, antibody P3-43, was significantly more protective than its template antibody m43.151, with greater liver-burden protection than the current best-in-class (antibody iGL-CIS43.D3). Crystal structures of improved antibodies revealed atomic-level interactions explaining gains in binding affinity. The reported pipeline provides a powerful in silico approach to improve antibody functionality.

immunology↗

bioRxiv2022

Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

Current influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.

immunology↗

bioRxiv2022

Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability

Immunization with SARS-CoV-2 spike elicits diverse antibodies, but can any of these neutralize broadly? Here, we report the isolation and characterization of antibody WS6, from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, MERS-CoV, and hCoV-OC43. The crystal structure at 2-[A] resolution of WS6 with its S2 epitope revealed recognition to center on a conserved helix, which was occluded in both prefusion and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion, post-viral attachment. Comparison of WS6 to other antibodies recently identified from convalescent donors or mice immunized with diverse spikes indicated a stem-helical supersite - centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156 - to be a promising target for vaccine design. HighlightsO_LISARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronaviruses C_LIO_LIWS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related viruses C_LIO_LICrystal structure at 2-[A] resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitope C_LIO_LIWS6 neutralizes by inhibition of fusion, post-viral attachment C_LIO_LIWS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodies C_LIO_LIHelical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turn C_LIO_LIGenetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogenies C_LI

immunology↗

bioRxiv2021

Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs. Highlights* Long-term infected NHPs develop antibodies neutralizing up to 54% of HIV-1 strains * Antibody J038 binds one V2 loop on HIV-1 Env trimer in a unique "up" position * UCA of the J038 lineage effectively neutralizes the autologous virus * J038 lineage antibodies mature through gradually increased contact to glycans

immunology↗

bioRxiv2021

Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite

Numerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycans N17, N74, N122, and N149. This site - formed primarily by a mobile {beta}-hairpin and several flexible loops - was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.

biochemistry↗

bioRxiv2018

Accurate Prediction of Antibody Resistance in Clinical HIV-1 Isolates

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have promising utility in prevention and treatment of HIV-1 infection with several undergoing clinical trials. Due to high sequence diversity and mutation rate of HIV-1, viral isolates are often resistant to particular bNAbs. Resistant strains are commonly identified by time-consuming and expensive in vitro neutralization experiments. Here, we developed machine learning-based classifiers that accurately predict resistance of HIV-1 strains to 33 neutralizing antibodies. Notably, our classifiers achieved an overall prediction accuracy of 96% for 212 clinical isolates from patients enrolled in four different clinical trials. Moreover, use of the tree-based machine learning method gradient boosting machine enabled us to identify critical epitope features that distinguish between antibody resistance and sensitivity. The availability of an in silico antibody resistance predictor will facilitate informed decisions of antibody usage in clinical settings.

bioinformatics↗

bioRxiv2018

Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

HIV-1 broadly neutralizing antibodies are desired for their therapeutic potential and as templates for vaccine design. Such antibodies target the HIV-1-envelope (Env) trimer, which is shielded from immune recognition by extraordinary glycosylation and sequence variability. Recognition by broadly neutralizing antibodies thus provides insight into how antibody can bypass these immune-evasion mechanisms. Remarkably, antibodies neutralizing >25% of HIV-1 strains have now been identified that recognize all major exposed surfaces of the prefusion-closed Env trimer. Here we analyzed all 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB with resolution suitable to define their interaction chemistries. These segregated into 20 antibody classes based on ontogeny and recognition, and into 6 epitope categories (V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide, and subunit interface) based on recognized Env residues. We measured antibody neutralization on a 208-isolate panel and analyzed features of paratope and B cell ontogeny. The number of protruding loops, CDR H3 length, and level of somatic hypermutation for broadly HIV-1 neutralizing antibodies were significantly higher than for a comparison set of non-HIV-1 antibodies. For epitope, the number of independent sequence segments was higher (P < 0.0001), as well as the glycan component surface area (P = 0.0005). Based on B cell ontogeny, paratope, and breadth, the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design. In terms of epitope-based vaccine design, antibody VRC34.01 had few epitope segments, low epitope-glycan content, and high epitope-conformational variability, which may explain why VRC34.01-based design is yielding promising vaccine results.

bioinformatics↗

bioRxiv2018

Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV

Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape provide a template to improve the breadth or potency of future vaccine-induced antibodies against Envs fusion peptide.\n\nAuthor summaryA major goal of HIV-1 vaccine design is to elicit antibodies that neutralize diverse strains of HIV-1. Recently, some of us elicited such antibodies in animal models using immunogens based on the epitope of a broad antibody (VRC34.01) isolated from an infected individual. Further improving these vaccine-elicited antibody responses will require a detailed understanding of how the resulting antibodies target HIVs envelope protein (Env). Here, we used mutational antigenic profiling to precisely map the epitope of two vaccine-elicited antibodies and the template VRC34.01 antibody. We did this by quantifying the effect of all possible amino acid mutations to Env on antibody neutralization. Although all antibodies target a similar region of Env, we found clear differences in the functional interaction of Env with the vaccine- and infection-elicited antibodies. We combined these functional data with structural analyses to identify antibody-Env interactions that could improve the breadth of vaccine-elicited antibodies, and thereby help to refine vaccination schemes to achieve broader responses.

immunology↗

bioRxiv2018

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

immunology↗

bioRxiv2017

Integrative Statistical Inferences for Drug Sensitivity Biomarkers in Cancer

Personal medicine has been associated with different patient responses to different anti-cancer therapies. Recently, scientists are looking not only for new biomarkers associated with a disease such as cancer but also identifying biomarkers that predict patients who are most likely to respond to a particular cancer treatment. Orderly endeavors to relate cancer mutational information with biological conditions may encourage the interpretation of somatic mutation indexes into significant biomarkers for patient stratification.\n\nWe have screened and incorporated a board of cancer cell lines from Genomics of Drug Sensitivity in Cancer (GDSC) database to recognize genomic highlights related with drug sensitivity. We used mutation, DNA copy number variation, and gene expression information from Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome ATLAS (TCGA) for cell lines with their reactions to associate focused and cytotoxic treatments with approved drugs and drugs under clinical and preclinical examination.\n\nWe discovered mutated cancer genes were related with cell reaction to, mostly accessible, cancer medications and some mutated genes were related with sensitivity to an expansive scope of therapeutic agents. By connecting drug activity to the useful many-sided quality of cancer genomes, efficient pharmacogenomic profiling in tumor cell lines gives an intense biomarker revelation stage to guide balanced malignancy remedial systems.\n\nOur study highlights that gene ANK2 amplification, and gene CELSER1 amplification and deletion are highly associated with anti-leukemic drug candidate LFM-A13. It also highlights that gene NUP214 and ROS1 copy number and gene NSD1 amplification are as a group highly associated with the parkinson drug Nilotinib. Finally, our study confirms that gene BRAF mutation is interacting with the BRAF-selective inhibitors drugs PLX4720 and SB590885. On the other hand, our study provides two open source analysis packages: bastah for the multitask-association analysis, and UNGeneAnno for automatic annotation of the variants.

genomics↗

bioRxiv2017

Application of High-Dimensional Statistics and Network based Visualization techniques on Arab Diabetes and Obesity data

BackgroundObesity and its co-morbidities are characterized by a chronic low-grade inflammatory state, uncontrolled expression of metabolic measurements and dis-regulation of various forms of stress response. However, the contribution and correlation of inflammation, metabolism and stress responses to the disease are not fully elucidated. In this paper a cross-sectional case study was conducted on clinical data comprising 117 human male and female subjects with and without type 2 diabetes (T2D). Characteristics such as anthropometric, clinical and bio-chemical measurements were collected.\n\nMethodsAssociation of these variables with T2D and BMI were assessed using penalized hierarchical linear and logistic regression. In particular, elastic net, hdi and glinternet were used as regularization models to distinguish between cases and controls. Differential network analysis using closed-form approach was performed to identify pairwise-interaction of variables that influence prediction of the phenotype.\n\nResultsFor the 117 participants, physical variables such as PBF, HDL and TBW had absolute coefficients 0.75, 0.65 and 0.34 using the glinternet approach, biochemical variables such as MIP, ROS and RANTES were identified as determinants of obesity with some interaction between inflammatory markers such as IL4, IL-6, MIP, CSF, Eotaxin and ROS. Diabetes was associated with a significant increase in thiobarbituric acid reactive substances (TBARS) which are considered as an index of endogenous lipid peroxidation and an increase in two inflammatory markers, MIP-1 and RANTES. Furthermore, we obtained 13 pairwise effects. The pairwise effects include pairs from and within physical, clinical and biochemical features, in particular metabolic, inflammatory, and oxidative stress markers.\n\nConclusionsWe showcase that markers of oxidative stress (derived from lipid peroxidation) such as MIP-1 and RANTES participate in the pathogenesis of diseases such as diabetes and obesity in the Arab population.

bioinformatics↗