Biology subjects

Platt, S.

Publications and source records attributed to Platt, S..

7 recordsLinked to original sources

bioRxiv2026

High resolution Streptococcus pyogenes core genome MLST and LIN coding scheme for outbreak detection

Streptococcus pyogenes is a globally important pathogen responsible for at least 500,000 deaths a year, causing significant burden on healthcare systems. It is the causative agent for ailments such as impetigo and strep throat to septicaemia and necrotizing fasciitis. Assessment of genetic relatedness for the detection of outbreaks within communities or healthcare facilities is vital in decreasing the propagation of S. pyogenes within these settings, alongside epidemiological data. As the volume of isolates being sequenced increases year on year, more scalable and sharable methodologies of assessing genetic relatedness are required by reference laboratories and for international collaboration. LIN codes, applied to core genome MLST (cgMLST) represent a method which is extensible to large scale whole genome sequencing (WGS) while still being sufficiently sensitive to detect outbreak clusters. Here we present a novel cgMLST and LIN code scheme, hosted by PubMLST, enabling international collaboration and global tracking of variants, that is highly scalable and usable for all. The schemes are available at https://pubmlst.org/organisms/streptococcus-pyogenes. Data SummaryGenome sequences and metadata are available at https://pubmlst.org/organisms/streptococcus-pyogenes. PubMLST and ENA accessions and metadata can additionally be found in the supplementary data. Raw reads for UKHSA sequences are available in ENA study PRJEB115996. Impact StatementStreptococcus pyogenes is a globally relevant pathogen capable of causing invasive and non-invasive disease across a multitude of settings. Assessment of genetic relatedness is an increasingly important aspect of managing outbreaks, requiring solutions that are scalable, high resolution and comparable across laboratories. Here we present a high resolution core genome multi locus sequence typing (MLST) and associated life identification number (LIN) code scheme, The schemes were developed using a combination of 4,916 UKHSA and 2,391 publicly available S. pyogenes isolates in order to cover a wide range of EMM types both within the UK and globally. These new schemes enable high resolution typing of S. pyogenes isolates, suitable for analysis of lineages to genomic epidemiology in outbreak detection and management. Both cgMLST and LIN code schemes are available on PubMLST as an open access resource for the public health and academic communities and can enable both intra laboratory and global coordination.

bioinformatics↗

bioRxiv2026

Sharp cell type boundaries emerge from coordinated morphogen signaling

Classic models of the French flag problem depict sharp cell-type boundaries emerging from threshold responses to morphogen gradients. How discrete cell-type boundaries arise from morphogen signals that vary continuously across developing tissues is not completely understood. We use hair follicle dermal condensate formation to study a sharp developmental transition in which proliferative progenitors undergo cell-cycle exit concurrent with molecular differentiation. Using genetic and genomic approaches, we show that Wnt and Hedgehog signaling interact to coordinate the timing of these two processes. We identify a division of labor between the pathways: Wnt signaling promotes cell-cycle exit by regulating chromatin binding of the Hedgehog mediator GLI3, while Hedgehog signaling induces differentiation genes in a Wnt-dependent manner and simultaneously elevates Wnt activity. When Wnt and Hedgehog activities are temporally aligned, differentiation and cell-cycle exit occur within the same developmental window, restricting both the duration and abundance of intermediate states and producing a sharp cell-type boundary. When these signals are misaligned, intermediate states persist and expand, producing fuzzy boundaries. These findings reveal a mechanism in which interacting morphogen signals regulate the duration and abundance of intermediate states during a developmental transition, thereby controlling how continuous cell-state progression is translated into discrete tissue patterning.

developmental biology↗

bioRxiv2026

Homozygosity for rare or common hypomorphic IL23R variants confers a predisposition to tuberculosis in humans

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-{gamma} production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12R{beta}1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-{gamma} production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria. One sentence summaryHomozygous hypomorphic IL23R variants impair IL-23-dependent IFN-{gamma} production and underlie tuberculosis.

genetics↗

bioRxiv2025

Co-targeting MERTK and EGFR with a Bispecific Antibody Overcomes Drug Resistance Across Mutations in Exons 19, 20, and 21

Resistance of lung cancer to EGFR-specific tyrosine kinase inhibitors (TKIs), such as osimertinib, often arises from secondary mutations or the activation of bypass signaling pathways. We noted elevated levels of GAS6 and its receptor, MERTK, in patients acquiring resistance to osimertinib, hence hypothesized that the GAS6-MERTK axis can serve as a therapeutic target. GAS6 promoted cell survival and an anti-GAS6 antibody we generated delayed tumor relapses in a xenograft model. Likewise, MERTK ablation sensitized lung cancer cells to osimertinib due to a newly described EGFR-to-MERTK crosstalk. Hence, we developed Bis3, a bispecific antibody targeting both MERTK and EGFR and promoting their degradation. Bis3 plus TKIs cooperatively inhibited the growth of TKI-resistant lung cancer spheroids and markedly delayed relapses of patient-derived xenografts harboring the clinically challenging exon-20 mutations. These findings establish the GAS6-MERTK axis as a driver of drug resistance and provide a rationale for clinical development of Bis3.

cancer biology↗

bioRxiv2025

Interaction of Wnt and SHH gradients synchronizes cell cycle 1 exit and differentiation

Classic models of the French flag problem depict sharp cell-type boundaries emerging from threshold responses to morphogen gradients. Yet, how such boundaries arise during dynamic cell-state transitions remains unclear. We use hair follicle dermal condensates to study a sharp cell-type transition in which proliferative progenitors synchronously undergo cell-cycle exit and molecular differentiation. Using genetic and genomic approaches, we show that Wnt and Hedgehog signaling interact to coordinate the timing of these processes. When their activities are temporally aligned, intermediate transitional states are compressed through cell-cycle exit, producing a sharp cell-type boundary; when misaligned, transitional states expand, yielding fuzzy borders. Mechanistically, elevated Wnt activity promotes cell-cycle exit by regulating chromatin binding of the Hedgehog mediator GLI3. Hedgehog signaling induces differentiation genes in a Wnt-dependent manner and simultaneously elevates Wnt activity, aligning arrest and differentiation in time. These findings reveal a mechanism wherein morphogen interactions coordinate transitions to generate precise cell-type boundaries.

developmental biology↗

bioRxiv2022

Tumor Segmentation using temporal Independent Component Analysis for DCE-MRI

In this study, we developed the temporal independent component analysis (tICA) to solve the partial volume effect (PVE) in canine brain tumor segmentation. The performance of the tICA is compared to that of spatial ICA (sICA) and an expert manual delineation of tumors based on three criteria: percent volume overlap or Dice coefficient, and percent volume difference. Seven in vivo DCE-MRI datasets of spontaneously occurring canine brain tumors were acquired on a 3 Tesla MRI system. The mean value of percent volume overlap (76.00%) between sICA and manual segmentation is lower than that between tICA and manual segmentation, which is 81.11%. In conclusion, the performance of the two ICA methods for segmenting tumors is very close to that of the expert delineation method. However, the tICA has the advantage over the sICA method in its ability to separate independent tissue signals in a voxel containing different types of tissues.

bioinformatics↗

bioRxiv2020

Canine cognitive dysfunction (CCD) patients have reduced total hippocampal volumes compared with aging control dogs: a comparative MRI study

Hippocampal atrophy is a key pathologic and MRI feature of human Alzheimers disease (AD). Hippocampal atrophy has not been documented via MRI in canine cognitive dysfunction (CCD), which is considered the dog model of human AD. The purpose of this retrospective comparative volumetric MRI study was to compare total hippocampal volumes between successfully aging (control) dogs and dogs diagnosed with CCD. Mimics(R) software was used to derive total hippocampal volumes and total brain volumes from the MRI studies of 42 aging dogs ([≥] 9 years): 16 dogs diagnosed with CCD and 26 successfully aging controls. Total hippocampal volume normalized to total brain volume was significantly less for CCD patients compared with control dogs (p=0.04). The results of this study suggest that-similar to human AD-hippocampal atrophy is a pathological feature of CCD. This finding has potential importance for both investigating disease mechanisms related to dementia as well as future hippocampal-targeted therapies.

neuroscience↗