Biology subjects

Khurana, S.

Publications and source records attributed to Khurana, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Radiological Patterns in Maxillofacial Ewing Sarcoma: A systematic review with pooled patient-level descriptive analysis

BackgroundEwing sarcoma (ES) is a rare malignant bone tumor with predilection for the mandible and maxilla in the head and neck region. However, existing literature comprises fragmented case reports and small case series that fail to establish consolidated, evidence-based understanding of characteristic radiological patterns in the maxillofacial region, hindering timely diagnosis and potentially leading to misdiagnosis or delayed intervention. MethodologyA systematic review and pooled patient-level descriptive analysis were conducted according to the PRISMA guidelines and pre-registered on PROSPERO. Comprehensive searches of PubMed, OVID, and Cochrane databases (inception to July 2025) identified studies reporting radiological findings of biopsy-confirmed maxillofacial Ewing sarcoma. Quality assessment using Joanna-Briggs Institute criteria ensured inclusion of only high-quality cases (quality score [≥]4/5). Synthesis Without Meta-analysis (SWiM) methodology with pooled prevalence estimation and binomial vote-counting analysis were employed for 68 published cases. ResultsFour radiological features demonstrated consistent predominance across pooled cases: soft tissue mass presence (100%, 95% CI: 94.7-100.0%), enhancing soft tissue (77.6%, 95% CI: 65.8-86.9%), cortical destruction (69.0%, 95% CI: 55.5-80.5%), and notably, absence of periosteal reaction (84.7%, 95% CI: 73.0-92.8%). Location-specific radiological phenotypes were evident: maxillary tumors demonstrated near-universal sinus involvement (100%) with high soft tissue enhancement (92.3%), whereas mandibular tumors showed predominant cortical destruction (80.0%) and teeth involvement (81.2%). ConclusionMRI and CT are essential for characterizing the distinctive radiological profile of maxillofacial Ewing sarcoma, enabling early identification and improving patient outcomes in this rare malignancy. HighlightsO_LIFirst pooled review to summarize imaging features of maxillofacial Ewing sarcoma C_LIO_LIAnalysis of 68 published cases reveals consistent imaging patterns. C_LIO_LIMost tumors show soft tissue mass and bone damage without surface reaction. C_LIO_LIJaw tumors differ from long bone tumors in their imaging appearance. C_LIO_LIUpper and lower jaw tumors show distinct location-specific features. C_LI

cancer biology↗

bioRxiv2026

G quadruplex DNA facilitates a pervasive path to homologous recombination

Homologous recombination (HR) requires efficient homology search and strand invasion, yet how homologous templates are identified within nuclear space remains unclear. Here, we identify G-quadruplex (G4) DNA structures as pervasive effectors of template strand invasion and uncover the G4 helicase DHX36 as a potent suppressor of this process. DHX36 loss stabilizes G4s, enhances HR, and accelerates repair of replication-associated DNA breaks. G4-mediated HR depends on the non-canonical strand invasion factors RAD51AP1, WDR48, and USP1, and requires G4 motifs within the homologous repair template. DHX36 loss partially restores HR and PARP inhibitor resistance in BRCA1-deficient cells, while promoting aberrant recombination and Alternative Lengthening of Telomeres (ALT). Together, our findings establish dynamic G4 regulation as a key determinant of homology search, genome maintenance, and recombination fidelity.

molecular biology↗

bioRxiv2026

Ablation of glypican-3 enhances radiosensitivity in liver cancer by prolonging G2/M arrest and activating the ATM/CHK2 pathway

Glypican-3 (GPC3) is an oncofetal protein widely being explored as a diagnostic and therapeutic target in hepatocellular carcinoma (HCC). Given that radiotherapy in the form of external beam and radioembolization are standard-of-care treatments for HCC, we aimed to determine whether there was any relationship between GPC3 and response to radiotherapy. Here, we demonstrate that GPC3 expression confers radioresistance in liver cancer through integrated in vitro, in vivo, and patient-level clinical analyses. Stable GPC3-knockout in liver cancer cell lines (HepG2, Hep3B, Huh7) and ectopic GPC3 expression in GPC3-negative liver cancer cells (SNU449), as well as in non-hepatic A431 cells, demonstrated that GPC3-mediated radioresistance is not restricted to hepatic lineage. Following irradiation, GPC3-deficient cells exhibited reduced proliferation, impaired clonogenic survival, persistent DNA damage, prolonged G2/M arrest, and increased apoptosis. Transcriptomic profiling demonstrated enrichment of cell-cycle and DNA damage response pathways in irradiated GPC3-deficient cells compared with GPC3-positive cells, and protein analyses confirmed sustained activation of the ATM/CHK2 axis. In vivo, GPC3 deletion markedly enhanced radiation-induced tumor growth delay in both HepG2 and A431 xenograft models. Consistent with these findings, high GPC3 expression was associated with inferior clinical outcomes in patients with HCC undergoing external-beam radiotherapy or radioembolization. Together, these findings identify GPC3 as a determinant of radioresistance in liver cancer and suggest its potential utility as a biomarker to guide radiotherapeutic strategies. Significance statementRadiotherapy is an important treatment option for HCC, but biomarkers that predict tumor response remain limited. GPC3 is highly expressed in most HCCs and is being investigated as an important biomarker for diagnosis and treatment of this disease, yet its relationship, if any, on radiosensitivity has not been previously reported. Here, we identify GPC3 as a modulator of radioresistance. GPC3 loss enhances radiosensitivity and is associated with persistent unresolved DNA damage, prolonged G2/M arrest, and sustained activation of the ATM/CHK2 pathway, resulting in delayed tumor growth after irradiation. In a clinical cohort of patients treated with radiotherapy, high GPC3 expression was associated with poorer overall survival. These findings suggest that GPC3 expressing tumors may necessitate either more dose-intense radiotherapy, radiobioligically ablative and/or combined with other modalities, or alternative therapeutic modalities to adequately treat HCC.

cancer biology↗

bioRxiv2025

Pharmacologic activation of HNF4α/γ restores epithelial barrier function in Crohn's disease.

Background & Aims: Ileal barrier dysfunction in Crohn,s disease (CD) can occur in macroscopically non-inflamed mucosa, persist despite clinical and endoscopic remission, and predict adverse outcomes. The epithelial mechanisms underlying this defect remain unclear. We investigated whether coordinated reduction of hepatocyte nuclear factor 4, (HNF4) and HNF4{gamma} defines an epithelial-intrinsic, barrier-defective state in ileal CD. Methods: Barrier-associated transcriptional programs were compared in small-intestinal and colonic epithelium from wild-type mice and mice with intestinal epithelial deletion of Hnf4, Hnf4{gamma}, or both paralogs. Paracellular permeability was assessed in wild-type and Hnf4/{gamma} double-knockout (Hnf4{gamma}DKO) small-intestinal organoids. HNF4, HNF4{gamma}, and the direct HNF4 transcriptional target claudin-15 (CLDN15) were evaluated in human ileal CD tissue, patient-derived organoids (PDOs) generated from macroscopically non-inflamed ileal mucosa, and ileal tissue and organoids from Tnf{delta}ARE/+ mice. The effects of HNF4 agonists N-trans-caffeoyltyramine (NCT) and N-trans-feruloyltyramine (NFT) were assessed in CD PDOs and Tnf{delta}ARE/+ organoids. Results: Combined, but not individual, loss of HNF4-paralog broadly disrupted small-intestinal transcriptional programs governing tight junction (TJ) organization, epithelial polarity, junctional-cytoskeletal coupling, and TJ repair, with limited effects in the colon. Hnf4{gamma}DKO organoids exhibited size-selective paracellular permeability in the absence of inflammatory and stromal cells, demonstrating that combined Hnf4{gamma} loss is sufficient to produce an epithelial-intrinsic barrier defect. HNF4, HNF4{gamma}, and CLDN15 were coordinately reduced in human ileal CD epithelium and this HNF4-low phenotype was retained in PDOs from macroscopically non-inflamed ileal mucosa. Chronic TNF-driven ileitis reproduced this HNF4-low state, which was retained ex vivo in organoids. HNF4 agonists restored HNF4, HNF4{gamma}, and CLDN15 expression and improved transepithelial electrical resistance (TEER) in CD PDOs. They also increased HNF4 and CLDN15 expression in Tnf{delta}ARE/+ organoids. Conclusions: Coordinated HNF4/{gamma} suppression defines an epithelial-intrinsic, barrier-defective state in ileal CD that is present in PDOs derived from macroscopically non-inflamed ileal mucosa and retained ex vivo without continued exposure to the inflammatory tissue environment. Its pharmacologic reversibility identifies incomplete restoration of the HNF4-dependent epithelial program as a potential mechanism of persistent ileal barrier dysfunction and supports further evaluation of HNF4-directed barrier-restorative strategies.

pathology↗

bioRxiv2025

Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer drugs for Permeability Barrier Healing.

Background and AimsEpithelial permeability barrier dysfunction is a central pathogenic driver of Crohns disease (CD), fueling microbial translocation, chronic inflammation, and progressive tissue injury. While current therapies suppress inflammation, none directly restore epithelial barrier function. Importantly, in CD patients, permeability barrier healing (BH) rather than mucosal healing is associated with long-term remission and a reduced risk of disease complications. Yet BH remains an unaddressed therapeutic target in CD. Here, we investigated whether pharmacologic inhibition of the integrated stress response (ISR) and RIPK3-mediated necroptosis, two convergent pathways of epithelial injury, can promote epithelial viability, regeneration, and barrier integrity in CD. MethodsWe employed villin-1/gelsolin double knockout (DKO) mice with epithelial-intrinsic ISR activation, TNF{Delta}ARE/+ mice with chronic inflammation, and CD patient-derived enteroids (PDEs). Animals and PDE were treated with ISR inhibitor ISRIB, RIPK3 inhibitor Necrostatin-1 (Nec-1), or FDA-approved cancer drugs pazopanib and ponatinib, repurposed as potent RIPK3 inhibitors. Epithelial survival, regenerative growth (enteroid formation, budding), and barrier function (transepithelial electrical resistance, TEER) were assessed. ResultsChronic ISR activation and necroptosis were prominent in both murine models and CD PDEs, causing epithelial death, Paneth cell expansion, impaired enteroid survival, and regenerative failure. Pharmacologic inhibition with ISRIB, Nec-1, pazopanib, or ponatinib restored villus architecture, reduced inflammation, enhanced epithelial survival and regeneration, and significantly improved TEER. ConclusionsISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib restored epithelial regeneration and BH, offering an immediately translatable therapeutic strategy for sustained remission in CD. SynopsisISR activation and RIPK3-mediated necroptosis drive epithelial injury in Crohns disease. Repurposed RIPK3 inhibitors, pazopanib and ponatinib, restore epithelial homeostasis and permeability barrier function, providing a translational strategy to achieve sustained remission in CD.

pathology↗

bioRxiv2025

Differentiation of Toxoplasma into latent forms is linked to central carbon metabolism and requires a GID/CTLH-type E3 ubiquitin ligase

Toxoplasma and other Apicomplexan parasites, switch between different developmental stages to persist in and transmit between hosts. Toxoplasma can alternate between systemic tachyzoites and encysted bradyzoite forms found in the CNS and muscle tissues. How parasites sense these tissue types and trigger differentiation remains largely unknown. We show that Toxoplasma differentiation is induced under glucose-limiting conditions and using a CRISPR screen identify parasite genes required for growth under these conditions. From [~]25 identified genes important for differentiation we show that lactate and glutamine metabolism is linked to differentiation and demonstrate the importance of an E3 ubiquitin ligase complex, orthologous to glucose induced degradation deficient (GID) complex in yeast and CTLH complex in humans. We show that TgGID likely regulates translational repression of a key transcription factor required for differentiation, BFD1, through its 3 utr. Overall, this work provides important new insight into how these divergent parasites sense different host cell niches and trigger stage conversion through a ubiquitination-dependent program.

microbiology↗

bioRxiv2025

Rate Limiting Enzymes in Nucleotide Metabolism Synchronize Nucleotide Biosynthesis and Chromatin Formation

Chromatin formation requires both an adequate nucleotide supply and sufficient availability of histones. Chromatin must be assembled following DNA-based fundamental cellular processes such as replication and transcription to preserve genome integrity. Chromatin assembly is regulated by the orderly engagement of histones with a series of histone chaperones that guide newly synthesized histones from ribosomes to DNA. Although the synthesis of nucleotides and the histone proteins are the two major biosynthetic processes that complete the formation of chromatin, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs) catalyze the first and rate-limiting step in the nucleotide biosynthesis pathway. PRPS enzymes form a complex with PRPS-associated proteins (PRPSAPs). In the present study, we discover that PRPS-PRPSAP enzyme complex are part of histone chaperone network. We show that PRPS enzymes are essential not only for nucleotide biogenesis, but together with PRPSAP also play a key role in the early steps in the process of histone maturation by regulating the interaction of histone chaperones with histone H3 and H4. Importantly, this regulation is separate from PRPS nucleotide biosynthetic activity. Depletion of PRPS proteins leads to limited histone availability and impaired chromatin assembly. Our discovery bridges cellular metabolism and chromatin regulation and provides the evidence of how nucleotide biogenesis and histone deposition are coordinated.

cell biology↗

bioRxiv2024

Identification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen

A significant portion of human cancers utilize a recombination-based pathway, Alternative Lengthening of Telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (Telomeric ALT In situ Localization Screen), to identify genes that either promote or inhibit ALT activity. Screening over 1000 genes implicated in DNA transactions, TAILS revealed both well-established and novel ALT modulators. We have identified new factors that promote ALT, such as the nucleosome-remodeling factor CHD4 and the chromatin reader SGF29, as well as factors that suppress ALT, including the RNA helicases DDX39A/B, the replication factor TIMELESS, and components of the chromatin assembly factor CAF1. Our data indicate that defects in histone deposition significantly contribute to ALT-associated phenotypes. Based on these findings, we demonstrate that pharmacological treatments can be employed to either exacerbate or suppress ALT-associated phenotypes.

molecular biology↗

bioRxiv2024

Proliferative events ameliorate DNA damage accumulation without affecting function in hematopoietic stem cells

Upon aging, HSCs show functional decline with increased proliferation, myeloid skewing, and poor engraftment efficiency. Accumulation of DNA damage has been causally linked with this phenomenon, with the debatable role of proliferative events. In this study, we sought to enquire the effect of increased hematopoietic stem cell (HSC) proliferation during the lifetime on the hematopoietic aging in mice. Multiple rounds of blood withdrawals were performed between two to twelve months of adult life to maintain higher proliferation rate in HSC population. Our experiments showed little effect of increased proliferation rate on age-associated functional decline in hematopoietic system. However, we noted a decrease in the double strand breaks (DSBs) accumulated with age in mice that underwent serial bleeding regimen. Analysis of single-cell sequencing data from mouse and human HSPCs showed enrichment of DNA damage response pathways confirmed by increased expression of the genes involved. Importantly, we demonstrate that the induction of HSC proliferation in aged mice is sufficient to decrease the load of DSBs. Hence, our results show that proliferative events during lifetime might aid in clearing age-associated DSBs. While these DNA damages might not be directly linked with the functional decline, proliferation induced clearance can have clinical implications.

cell biology↗

bioRxiv2023

Contribution of CENP-F to FOXM1-mediated discordant centromere and kinetochore transcriptional regulation

Proper chromosome segregation is required to ensure genomic and chromosomal stability. The centromere is a unique chromatin domain present throughout the cell cycle on each chromosome defined by the CENP-A nucleosome. Centromeres (CEN) are responsible for recruiting the kinetochore (KT) during mitosis, ultimately regulating spindle attachment and mitotic checkpoint function. Upregulation of many genes that encode the CEN/KT proteins is commonly observed in cancer. Here, we show although that FOXM1 occupies the promoters of many CEN/KT genes with MYBL2, occupancy is insufficient alone to drive the FOXM1 correlated transcriptional program. We show that CENP-F, a component of the outer kinetochore, functions with FOXM1 to coregulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in alteration of chromatin accessibility at G2/M genes, including CENP-A, and leads to reduced FOXM1-MBB complex formation. The FOXM1-CENP-F transcriptional coordination is a cancer-specific function. We observed that a few CEN/KT genes escape FOXM1 regulation such as CENP-C which when upregulated with CENP-A, leads to increased chromosome misegregation and cell death. Together, we show that the FOXM1 and CENP-F coordinately regulate G2/M gene expression, and this coordination is specific to a subset of genes to allow for proliferation and maintenance of chromosome stability for cancer cell survival.

cell biology↗

bioRxiv2023

Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs. One Sentence SummaryNon-stabilized SARS-CoV-2 Spike mRNA vaccination activated B cells that target either conserved epitopes on SARS-CoV-2 Omicron variants of concern, or cross-neutralizing epitopes on pre-emergent Sarbecoviruses.

immunology↗

bioRxiv2023

Extremely potent pan-sarbecovirus neutralizing antibodies generated by immunization of macaques with an AS03-adjuvanted monovalent subunit vaccine against SARS-CoV-2

The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination. 514 monoclonal antibodies (mAbs) were generated from antigen-specific memory B cells. Antibodies isolated at 5 to 12 months following vaccination displayed greater potency and breadth, relative to those identified at 1.4 months. Notably, 15 out of 338 ([~]4.4%) antibodies isolated at 1.4[~]6 months after the primary vaccination showed extraordinary neutralization potency against SARS-CoV-2 omicron BA.1, despite the absence of BA.1 neutralization in serum. Two of them, 25F9 and 20A7, neutralized authentic clade Ia sarbecoviruses (SARS-CoV, WIV-1, SHC014) and clade Ib sarbecoviruses (SARS-CoV-2 D614G, SARS-CoV-2 BA.1, Pangolin-GD) with half-maximal inhibition concentrations of (0.85 ng/ml, 3 ng/ml, 6 ng/ml, 6 ng/ml, 42 ng/ml, 6 ng/ml) and (13 ng/ml, 2 ng/ml, 18 ng/ml, 9 ng/ml, 6 ng/ml, 345 ng/ml), respectively. Furthermore, 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants of concern and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1 and XBB variants. X-ray crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved RBD sites. In vivo prophylactic protection of 25F9, 20A7 and 27A12 was confirmed in aged Balb/c mice. Notably, administration of 25F9 provided complete protection against SARS-CoV-2, SARS-CoV-2 BA.1, SARS-CoV, and SHC014 challenge, underscoring that these mAbs are promising pan-sarbecovirus therapeutic antibodies. One Sentence SummaryExtremely potent pan-sarbecovirus neutralizing antibodies

immunology↗

bioRxiv2022

The sulfonylpiperazine MMV020291 prevents red blood cell invasion by the malaria parasite Plasmodium falciparum through interference with actin-1/profilin dynamics

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell invasion, and have generated analogues with improved potency. Here, we identify actin and profilin as putative targets of the MMV020291 series through resistance selection and whole genome sequencing of three MMV020291 resistant populations. This revealed three non-synonymous single nucleotide polymorphisms in two genes; two in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wildtype parasites which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade red blood cells. Additionally, the series inhibits the actin-1 dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro co-sedimentation experiments using recombinant P. falciparum actin-1 and profilin proteins indicate that potent MMV020291 analogues amplify the actin-monomer sequestering effect of profilin, thereby reducing the formation of filamentous actin. Altogether, this study identifies the first compound series targeting the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.

molecular biology↗

bioRxiv2022

Humanized antibody potently neutralizes all SARS-CoV-2 variants by a novel mechanism

SARS-CoV-2 Omicron variants have generated a world-wide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of antibodies induced by vaccination. Here, we describe the SARS-CoV-2 neutralizing SP1-77 antibody that was generated from a humanized mouse model with a single human VH1-2 and V{kappa}1-33-associated with immensely diverse complementarity-determining-region-3 (CDR3) sequences. SP1-77 potently and broadly neutralizes SARS-CoV-2 variants of concern and binds the SARS-CoV-2 spike protein receptor-binding-domain (RBD) via a novel-CDR3-based mode. SP1-77 does not block RBD-binding to the ACE2-receptor or endocytosis step of viral entry, but rather blocks membrane fusion. Our findings provide the first mechanistic insight into how a non-ACE2 blocking antibody potently neutralizes SARS-CoV-2, which may inform strategies for designing vaccines that robustly neutralize current and future SARS-CoV-2 variants.

immunology↗

bioRxiv2022

In BRAFV600E-mutated colorectal cancer cells, fascin1 restructures adherens junctions to drive Wnt activation

Fascin1 expression in colorectal carcinomas (CRCs) is linked to a clinically aggressive disease with poor prognosis. Despite that fascin1s role in the etiology of CRCs has not been directly investigated. We show fascin1 expression in one-third of all CRCs underscoring the critical need to identify fascin1s function in colorectal carcinogenesis. Here, we identify for the first time, fascin1s role as a mechanosensor that modulates CRC cell adherens junction (AJ) plasticity to induce tumor growth and metastasis. We show that fascin1 expression drives protein sorting to transform AJ mechanotransduction and we reveal how these force-sensitive pathways activate oncogenic signaling in CRC cells. We made the novel finding that AJ remodeling by fascin1 also controls "collective plasticity" and bidirectional cell migration. Few studies have examined AJ plasticity in cancer cells, which remains poorly understood and has not been therapeutically targeted. Our findings could have widespread implications for understanding and treating metastatic carcinomas.

cancer biology↗

bioRxiv2022

Unsupervised outlier detection applied to SARS-CoV-2 nucleotide sequences can identify sequences of common variants and other variants of interest

As of June 2022, the GISAID database contains more than one million SARS-CoV-2 genomes, including several thousand nucleotide sequences for the most common variants such as delta or omicron. These SARS-CoV-2 strains have been collected from patients around the world since the beginning of the pandemic. We start by assessing the similarity of all pairs of nucleotide sequences using the Jaccard index and principal component analysis. As shown previously in the literature, an unsupervised cluster analysis applied to the SARS-CoV-2 genomes results in clusters of sequences according to certain characteristics such as their strain or their clade. Importantly, we observe that nucleotide sequences of common variants are often outliers in clusters of sequences stemming from variants identified earlier on during the pandemic. Motivated by this finding, we are interested in applying outlier detection to nucleotide sequences. We demonstrate that nucleotide sequences of common variants (such as alpha, delta, or omicron) can be identified solely based on a statistical outlier criterion. We argue that outlier detection might be a useful surveillance tool to identify emerging variants in real time as the pandemic progresses.

bioinformatics↗

bioRxiv2022

Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine

Coronavirus vaccines that are highly effective against SARS-CoV-2 variants are needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected monkeys from SARS-CoV-2 WA-1 infection. Here, we demonstrate SARS-CoV-2 RBD-scNP immunization induces potent neutralizing antibodies in non-human primates (NHPs) against all eight SARS-CoV-2 variants tested including the Beta, Delta, and Omicron variants. The Omicron variant was neutralized by RBD-scNP-induced serum antibodies with a mean of 10.6-fold reduction of ID50 titers compared to SARS-CoV-2 D614G. Immunization with RBD-scNPs protected NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protected mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect NHPs and mice from multiple different SARS-related viruses. Such a vaccine could provide the needed immunity to slow the spread of and reduce disease caused by SARS-CoV-2 variants such as Delta and Omicron.

immunology↗

bioRxiv2021

Unsupervised genome-wide cluster analysis: nucleotide sequences of the omicron variant of SARS-CoV-2 are similar to sequences from early 2020

The GISAID database contains more than 1,000,000 SARS-CoV-2 genomes, including sequences of the recently discovered SARS-CoV-2 omicron variant and of prior SARS-CoV-2 strains that have been collected from patients around the world since the beginning of the pandemic. We applied unsupervised cluster analysis to the SARS-CoV-2 genomes, assessing their similarity at a genome-wide level based on the Jaccard index and principal component analysis. Our analysis results show that the omicron variant sequences are most similar to sequences that have been submitted early in the pandemic around January 2020. Furthermore, the omicron variants in GISAID are spread across the entire range of the first principal component, suggesting that the strain has been in circulation for some time. This observation supports a long-term infection hypothesis as the omicron strain origin.

bioinformatics↗