Biology subjects

George, K.

Publications and source records attributed to George, K..

9 recordsLinked to original sources

bioRxiv2026

Antibodies with Engineered Fc Domains Having Absolute Binding Selectivity to either FcγRIIa or FcγRI Delineate the Respective Effector Phenotypes by Human Monocytes and Macrophages

IgG1 immune complexes bind to all the Fc{gamma} receptors (Fc{gamma}R) expressed on myeloid cells, making it challenging to determine the precise role of each Fc{gamma}R on Fc effector phenotypes. Here we report the engineering of Fc2KG, an aglycosylated human IgG1 Fc domain that binds with near physiological affinity to Fc{gamma}RIIa/b with no detectable binding to any other Fc{gamma}Rs. Crystallographic analysis elucidated the structural basis of how mutations in the Fc domain compensate for the absence of the N297 glycan and enable selective binding. Using single-cell phagocytosis assays, we show that particles opsonized with Fc-engineered antibodies formatted with Fc2KG or with an Fc domain that binds only Fc{gamma}RI (Fc5), are ingested by THP-1 cells with near identical kinetics. We find that with CD16+ primary human monocytes, selective Fc{gamma}RII engagement is a major contributor to the ADCP mediated by wild-type IgG1. Additionally, we showed that Fc2KG formatted antibodies induce high levels of GM-CSF. With M1-like monocyte-derived human macrophages, trastuzumab formatted with wild-type IgG1 Fc, with Fc2KG or Fc5 were all equally proficient in the trogocytotic killing of opsonized SK-BR-3 HER2+ cells but only Fc{gamma}RI engagement led to secretion of proinflammatory cytokines. Collectively, our results highlight how precisely tuned, Fc-engineered antibodies can be deployed to answer long-standing questions regarding the precise effector functions mediated by human Fc{gamma}Rs, information which is key for the optimization of therapeutic antibodies.

immunology↗

bioRxiv2025

Amphetamine and Nicotine Reduce Sucrose Self-Administration Independent of Sex

Amphetamine and nicotine are two widely used and abused drugs that are taken for legitimate pharmaceutical purposes but are also highly abused through illicit recreational use. Both of these drugs have been widely shown to decrease food intake in both humans and pre-clinical models, and although amphetamine and nicotine clearly affect food intake under normal baseline ( homeostatic) conditions, there has been limited examination of the ability of these drugs to affect reward-related ( hedonic) aspects of feeding. Furthermore, there are sex differences in the behavioral responses to both drugs, but it is unclear if these sex differences also translate to their effects on feeding. This study examined whether nicotine and amphetamine regulate sucrose intake in a food self-administration paradigm in a sex-dependent manner across both fixed and progressive schedules of reinforcement. Amphetamine reduced operant responding for sucrose pellets and decreased acute intake of sucrose during ad libitum free-feeding access in a dose-dependent manner, whereas nicotine reduced sucrose self-administration and free intake only at higher doses that also impaired locomotor activity in open field tests. The effects of both amphetamine and nicotine did not differ by sex for either drug. Overall, these results suggest that the mechanisms mediating the addictive qualities of these drugs and their appetite suppressing effects may be distinct and therefore could be a potential target for future obesity therapeutics.

neuroscience↗

bioRxiv2024

GRIP: physics-informed neural network for gradient retention time prediction in liquid chromatography

Gradient liquid chromatography has numerous applications in life sciences. Retention time prediction remains challenging due to complex underlying physical processes and highly variable chromatographic conditions. Here, we present GRIP, a physics-informed neural network for gradient retention time prediction that explicitly uses experimental setup parameters. GRIP demonstrates zero-shot generalization to unseen chromatographic systems while being on par or out-performing the transfer learning-based baseline. This approach can computationally guide the experimental setup configuration tailored to specific compounds of interest.

bioinformatics↗

bioRxiv2020

Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma

Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq1) to the spike ectodomain (S-ECD2) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro, we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 [A]2). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning3,4 our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection.

immunology↗

bioRxiv2020

Initial insights into the genetic epidemiology of SARS-CoV-2 isolates from Kerala suggest local spread from limited introductions

Coronavirus disease 2019 (COVID-19) rapidly spread from a city in China to almost every country in the world, affecting millions of individuals. Genomic approaches have been extensively used to understand the evolution and epidemiology of SARS-CoV-2 across the world. Kerala is a unique state in India well connected with the rest of the world through a large number of expatriates, trade, and tourism. The first case of COVID-19 in India was reported in Kerala in January 2020, during the initial days of the pandemic. The rapid increase in the COVID-19 cases in the state of Kerala has necessitated the understanding of the genetic epidemiology of circulating virus, evolution, and mutations in SARS-CoV-2. We sequenced a total of 200 samples from patients at a tertiary hospital in Kerala using COVIDSeq protocol at a mean coverage of 7,755X. The analysis identified 166 unique high-quality variants encompassing 4 novel variants and 89 new variants identified for the first time in SARS-CoV-2 samples isolated from India. Phylogenetic and haplotype analysis revealed that the circulating population of the virus was dominated (94.6% of genomes) by three distinct introductions followed by local spread, apart from identifying polytomies suggesting recent outbreaks. The genomes formed a monophyletic distribution exclusively mapping to the A2a clade. Further analysis of the functional variants revealed two variants in the S gene of the virus reportedly associated with increased infectivity and 5 variants that mapped to five primer/probe binding sites that could potentially compromise the efficacy of RT-PCR detection. To the best of our knowledge, this is the first and most comprehensive report of genetic epidemiology and evolution of SARS-CoV-2 isolates from Kerala.

genomics↗

bioRxiv2020

Dynamics of the COVID -19 Related Publications

BackgroundThis study aims to analyze the dynamics of the published articles and preprints of Covid-19 related literature from different scientific databases and sharing platforms. MethodsThe PubMed, Elsevier, and Research Gate (RG) databases were under consideration in this study over a specific time. Analyses were carried out on the number of publications as (a) function of time (day), (b) journals and (c) authors. Doubling time of the number of publications was analyzed for PubMed "all articles" and Elsevier published articles. Analyzed databases were (1A) PubMed "all articles" (01/12/2019-12/06/2020) (1B) PubMed Review articles (01/12/2019-2/5/2020) and (1C) PubMed Clinical Trials (01/01/2020-30/06/2020) (2) Elsevier all publications (01/12/2019-25/05/2020) (3) RG (Article, Pre Print, Technical Report) (15/04/2020-30/4/2020). FindingsTotal publications in the observation period for PubMed, Elsevier, and RG were 23000, 5898 and 5393 respectively. The average number of publications/day for PubMed, Elsevier and RG were 70.0 {+/-}128.6, 77.6{+/-}125.3 and 255.6{+/-}205.8 respectively. PubMed shows an avalanche in the number of publication around May 10, number of publications jumped from 6.0{+/-}8.4/day to 282.5{+/-}110.3/day. The average doubling time for PubMed, Elsevier, and RG was 10.3{+/-}4 days, 20.6 days, and 2.3{+/-}2.0 days respectively. In PubMed average articles/journal was 5.2{+/-}10.3 and top 20 authors representing 935 articles are of Chinese descent. The average number of publications per author for PubMed, Elsevier, and RG was 1.2{+/-}1.4, 1.3{+/-}0.9, and 1.1{+/-}0.4 respectively. Subgroup analysis, PubMed review articles mean and median review time for each article were <0|17{+/-}17|77> and 13.9 days respectively; and reducing at a rate of-0.21 days (count)/day. InterpretationAlthough the disease has been known for around 6 months, the number of publications related to the Covid-19 until now is huge and growing very fast with time. It is essential to rationalize the publications scientifically by the researchers, authors, reviewers, and publishing houses. FundingNone

scientific communication and education↗

bioRxiv2019

Geographical distribution of Anopheles stephensi in eastern Ethiopia

BackgroundThe recent detection of the South Asian malaria vector An. stephensi in Ethiopia and other regions in the Horn of Africa has raised concerns about its potential impact on malaria transmission. We report here findings of survey for this species in eastern Ethiopia using both morphological and molecular methods for species identification.\n\nMethodsAdult and larval/pupal collections were conducted at ten sites in eastern Ethiopia and Anopheles specimens species were determined using standard morphological keys and genetic analysis.\n\nResultsIn total, 2,231 morphologically identified An. stephensi were collected. A molecular approach incorporating both PCR endpoint assay and sequencing of portions of the internal transcribed spacer 2 (ITS2) and cytochrome oxidase I (COI) loci confirmed the identity of the An. stephensi in most cases (119/124 of the morphologically identified An. stephensi confirmed molecularly). Additionally, we observed Aedes aegypti larvae and pupae at many of the An. stephensi larval habitats.\n\nConclusionsOur findings show that An. stephensi is widely distributed in eastern Ethiopia and highlight the need for further surveillance in the southern, western and northern parts of the country and throughout the Horn of Africa.

ecology↗

bioRxiv2019

Differential expansion microscopy

Expansion microscopy (ExM) involves the use of hydration-competent polymers to physically expand biological specimens approximately 4-fold linear increase to achieve 70 nanometer resolution using an ordinary diffraction limited optical microscope. Optimal conditions however for antigen retention during the expansion process and the relative expansion between organelles within cells has remained unclear. It is reported that different tissues expand to different extents, suggesting that although isotropic expansion is believed to occur, different subcellular compartments with different composition would undergo anisotropic or differential expansion (DiEx). Consequently, there would be distortion of the native shape and size of subcellular compartments upon expansion, parameters which are critical in assessing cellular states in health and disease. Here we report optimal fixation and expansion conditions that retain structural integrity of cells while exhibiting up to 8-fold linear and therefore 512-fold volumetric expansion. Anisotropic expansion is observed not just between tissues, but between different subcellular compartments and even within subcellular compartments. Combining image analysis and machine learning, we provide an approach for the rapid and precise measurement of cellular and subcellular structures in expanded tissue. Using both manual and computation assessment of morphometric parameters, we demonstrate expansion to be anisotropic and name this method differential expansion microscopy (DiExM).

cell biology↗

bioRxiv2019

LSF small molecule inhibitors phenocopy LSF-targeted siRNAs causing mitotic defects and senescence in cancer cells

BackgroundThe oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple mouse models, with no observable toxicity. MethodsCell proliferation and cell cycle progression were analyzed after loss of LSF activity, using HeLa cells as a model cancer cell line responsive to FQI1. In addition, results were compared after treatment with either FQI1 or siRNA targeting LSF to test for biological specificity of targeting LSF by FQI1. ResultsCellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA targeting LSF produced highly similar phenotypes. Inhibition of LSF activity by either mechanism induced a strong delay prior to metaphase during progression through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. ConclusionsSpecific inhibition of LSF by small molecules or siRNA results in mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings not only confirm that LSF is a promising target for cancer treatment, but also that FQIs are promising compounds for obtaining therapeutic effects for multiple LSF-driven cancers with unmet medical need.

cancer biology↗