Biology subjects

Abrams, S.

Publications and source records attributed to Abrams, S..

12 recordsLinked to original sources

bioRxiv2026

Bacterial histone-like proteins released during antibiotic treatment mediate vascular injury in meningococcal sepsis.

Vascular injury and coagulopathy are key drivers of mortality in bacterial sepsis. In Neisseria meningitidis infection, endothelial adhesion and thrombosis cause the characteristic petechial rash and, in the most severe cases, purpura fulminans. Although antibiotics rapidly kill bacteria, inflammation and vascular injury often persist or worsen after bacterial clearance, suggesting ongoing toxicity from released bacterial components. Here we identify bacterial histone-like proteins (HLPs), small positively charged DNA-binding proteins conserved across bacterial species, as previously unrecognized mediators of vascular damage. In vitro HLPs are released following antibiotic exposure, disrupting endothelial integrity. In patients with severe sepsis, they are detectable in plasma and tissue, colocalising with areas of vascular leak and coagulopathy. Non-anticoagulant heparins and anti-HLP antibodies neutralize HLP-induced endothelial disruption and toxicity in vitro and in vivo. These findings reveal HLPs as antibiotic-released bacterial toxins and suggest new therapeutic strategies to prevent vascular injury in sepsis. One sentence summaryAntibiotic treatment of meningococcal and other sepsis causative bacteria triggers the release of histone-like proteins (HLPs) that damage the endothelium and drive coagulopathy, but these effects can be neutralized by non-anticoagulant heparins or anti-HLP antibodies.

microbiology↗

bioRxiv2026

Multimodal non-ionizing quantitative characterization of enamel hypomineralization

Enamel hypomineralization is clinically graded but difficult to quantify with visual and radiographic assessment. We evaluated whether optical coherence tomography (OCT) and lock-in thermography imaging (LITI) provide non-ionizing, quantitative lesion localization and phenotyping, using clinical mDDE classification as a practical benchmark and micro-CT ({micro}CT) mineral density as an in vitro reference in a subset. Twenty-five extracted first permanent molars were classified as control, hypomineralized (Type 1 white-cream; Type 2 yellow-brown), or other enamel defects. Co-localized OCT A-scan decay slopes and LITI lock-in phase-contrast were measured in predefined ROIs; six teeth underwent {micro}CT with hydroxyapatite calibration. Clinical scoring showed substantial agreement (inter-rater {kappa}=0.61; intra-rater {kappa}=0.70). OCT decay slopes differed across clinical groups (Kruskal-Wallis p=0.00028), separating controls from defect groups, while separation between hypomineralization and other defects was limited. LITI detected thermophotonic "hot spots" at many clinically identified sites (sensitivity 80%) but showed low specificity (20%) at a single modulation frequency, consistent with high anomaly sensitivity but limited etiologic discrimination. In the {micro}CT subset, hypomineralized ROIs showed reduced mineral density relative to adjacent enamel and spatial concordance with OCT and LITI contrast. Together, OCT+LITI support objective lesion mapping and motivate multi-frequency thermophotonics and expanded reference sampling to improve specificity for chairside translation.

biophysics↗

bioRxiv2025

p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer

Metastatic breast cancer (MBC) is a life-threatening disease with limited therapeutic options. The immune suppressive tumor microenvironment (TME) limits the potency of the antitumor immune response and facilitates disease progression and metastasis. Our current study demonstrates that p38 is a druggable target in the TME that regulates the outcome of the immune-tumor interaction. The study revealed that systemic blockade of p38 reduces metastasis, and this anti-metastatic response is negated by depletion of CD8+ T cells. Single-cell transcriptomic analysis of the immune-TME showed that pharmacological p38 inhibition (p38i) or tumor-specific inactivation of p38 by CRISPR/Cas9 (p38KO) resulted in a less exhausted and more activated CD8+ T cell phenotype. Immunophenotyping analyses demonstrated that p38 blockade reduced the expression of multiple inhibitory receptors on CD8+ T cells (i.e., PD-1, LAG-3, CTLA-4), indicating a reversal of immune exhaustion and enhanced immune activation systemically and in the TME. In contrast, p38 blockade did not exhibit inhibitory effects on T cells in proliferation assays in vitro and did not affect the proportion of regulatory T cells in vivo. The major negative impact of p38 blockade in vivo was on the myeloid populations, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Further, tumor p38 activity was required for the expression of cytokines/chemokines and tumor-derived exosomes with high chemotactic capacity for myeloid cells. Altogether, this study highlights a previously unrecognized p38-driven pathway that promotes an immune suppressive TME and metastasis, and that therapeutic blockade of p38 has important implications for improving antitumor immunity and patient outcomes. STATEMENT OF SIGNIFICANCEThis study highlights a previously unrecognized p38-driven tumor pathway that promotes an immune suppressive microenvironment and metastasis, and that therapeutic blockade of p38 has important implications for improving antitumor immunity and patient outcomes.

cancer biology↗

bioRxiv2022

A Bayesian approach to estimate the probability of resistance to bedaquiline in the presence of a genomic variant

BackgroundBedaquiline is a core drug for treatment of rifampicin-resistant tuberculosis. Few genomic variants have been statistically associated with bedaquiline resistance. Alternative approaches for determining the genotypic-phenotypic association are needed to guide clinical care. MethodsUsing published phenotype data for variants in Rv0678, atpE, pepQ and Rv1979c genes in 756 Mycobacterium tuberculosis isolates and survey data of the opinion of 33 experts, we applied Bayesian methods to estimate the posterior probability of bedaquiline resistance and corresponding 95% credible intervals. ResultsExperts agreed on the role of Rv0678, and atpE, were uncertain about the role of pepQ and Rv1979c variants and overestimated the probability of bedaquiline resistance for most variant types, resulting in lower posterior probabilities compared to prior estimates. The posterior median probability of bedaquiline resistance was low for synonymous mutations in atpE (0.1%) and Rv0678 (3.3%), high for missense mutations in atpE (60.8%) and nonsense mutations in Rv0678 (55.1%), relatively low for missense (31.5%) mutations and frameshift (30.0%) in Rv0678 and low for missense mutations in pepQ (2.6%) and Rv1979c (2.9%), but 95% credible intervals were wide. ConclusionsBayesian probability estimates of bedaquiline resistance given the presence of a specific mutation could be useful for clinical decision-making as it presents interpretable probabilities compared to standard odds ratios. For a newly emerging variant, the probability of resistance for the variant type and gene can still be used to guide clinical decision-making. Future studies should investigate the feasibility of using Bayesian probabilities for bedaquiline resistance in clinical practice.

microbiology↗

bioRxiv2021

Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment

Stimulatory dendritic cells (SDC), enriched within Batf3-DC (cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of "poised" cross-presenting Batf3-DC within stromal sheets, distal to tumoral nests, is unlikely to simply reflect passive exclusion away from immunosuppressive tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling may generate developmentally conserved cell-fate cues that regulate Batf3-DC behavior. We find that CD8+ T-cells massively infiltrate tumor matrices undergoing proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. VCAN proteolysis releases a bioactive fragment (matrikine), versikine, that is necessary and sufficient for Batf3-DC accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive activation program conferring exquisite sensitivity to DNA-sensing, coupled with survival support from atypical innate lymphoid cells. Thus, homeostatic signals from stroma invasion regulate SDC survival and activity to promote T- cell inflammation. HIGHLIGHTSO_LITumor stroma remodeling generates cross-presenting DC survival and activation cues. C_LIO_LIStromal-activated Batf3-DC are hypersensitive to dsDNA-sensing. C_LIO_LIStromal signals promote atypical innate lymphoid cells (GM-CSFhi/ IFN{gamma}lo). C_LIO_LIT-cell repriming by stroma-licensed Batf3-DC may overcome exclusion at tumor margins. C_LI

immunology↗

bioRxiv2020

Extracellular histones stimulate collagen expression and potentially promote liver fibrogenesis via TLR4-MyD88 signalling pathway

BACKGROUNDLiver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually. Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood. Recently, the Toll-like receptor (TLR) 4-MyD88 signalling pathway has been reported to contribute to fibrosis. Extracellular histones are the ligands of TLR4 but their roles in liver fibrosis have not been investigated. AIMThis study aims to investigate the roles and potential mechanisms of extracellular histones in liver fibrosis. METHODSIn vitro, the LX2 cells, a human hepatic stellate cell (HSC) line, were treated with histones in the presence or absence of non-anticoagulant heparin (NAHP) for neutralising histones or TLR4-blocking antibody. The cells resultant expression of collagen I was detected using Western blotting and immunofluorescent staining. In vivo, the CCl4-induced liver fibrosis model was generated in male 6 week old ICR mice and in TLR4 or MyD88 knockout and parental mice. Circulating histones were detected and the effect of NAHP was evaluated. RESULTSExtracellular histones strongly stimulated LX2 cells to produce collagen I. The histone-enhanced collagen expression was significantly reduced by NAHP and TLR4 blocking antibody. In CCl4-treated wild type mice, circulating histones were dramatically increased and maintained high levels during the whole course of fibrosis-induction. Injection of NAHP not only reduced alanine aminotransferase (ALT) and liver injury scores, but also significantly reduced fibrogenesis. Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC, the CCl4 model with TLR-4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signalling pathway in CCl4-induced liver fibrosis. The levels of liver fibrosis were indeed significantly lower than in these knockout mice than the wild type parental mice. CONCLUSIONThis study demonstrated that extracellular histones are able to stimulate HSC to produce collagen I and TLR4 is involved in this process. The in vivo findings support the novel concept that high levels of circulating histones potentially stimulate TLR4 receptor to enhance fibrogenesis via the TLR4-MyD88 signalling pathway. NAHP detoxify extracellular histones and thus has a potential therapeutic role by reducing liver injury and fibrogenesis. Core tipThis work fills the gap between recurrent liver injury and liver fibrosis. When liver cells die, histones will be released. High levels of extracellular histones not only cause a secondary liver injury, but also activate the TLR4-MyD88 signalling pathway to enhance collagen I production and liver fibrosis. Binding of non-anticoagulant heparin (NAHP) to extracellular histones reduces histone toxicity, alleviates liver injury and prevent histones from activating the TLR4-MyD88 signalling pathway. These results may explain why NAHP reduces liver fibrosis in this animal model although further investigations are required. ARTICLE HIGHLIGHTSO_ST_ABSResearch backgroundC_ST_ABSCurrently, the molecular mechanisms of liver fibrosis are not fully understood. Recurrent liver injury or inflammation initiate wound healing process along with fibrogenesis. However, what initiates this process is not clear. When cells die, damage-associated molecular patterns (DAMPs) will be released. Histones are the most abundant DAMP and are also the ligands for TLR4, which in turn has been demonstrated to be involved in bile duct ligation-induced liver fibrosis. Lipopolysaccharides (LPS) has been proposed to be a ligand for TLR4. Since recurrent liver injury does not naturally produce LPS but abundant extracellular histones, this study sought to investigate the potential roles of extracellular histones as TLR4 ligands in liver fibrosis. Research motivationSince our laboratory has been involved in studying the roles of DAMPs in critical illnesses, extracellular histones in liver fibrosis is of great interest in terms of biological and clinical significance. Research objectivesOur study aimed to clarify the roles of extracellular histones in fibrogenesis in vitro and in vivo. Research methodsIn our study, a HSC cell line and animal models of liver fibrosis were employed. Intervention studies with NAHP to detoxify histones and TLR4 blocking antibodies to inhibit TLR4 was performed. In addition, TLR4 and MyD88 knockout mice were used to support that the theory that the TLR4-MyD88 signalling pathway is involved in liver fibrosis in the CCl4 mouse model. Research resultsO_LIDemonstrated that high levels of circulating histones exist when fibrosis is induced by CCl4 in the mouse model. C_LIO_LIDemonstrated in vitro that extracellular histones are able to stimulate HSC cells to produce collagen I. C_LIO_LIDemonstrated that NAHP is able to inhibit histone-enhanced collagen production in the HSC cell line, and reduce liver injury and fibrosis in the animal model. C_LIO_LIDemonstrated that TLR4 is involved in histone-enhanced collagen I production in HSC cells. In vivo, the TLR4-MyD88 signalling pathway was demonstrated to be involved in liver fibrosis, but whether circulating histones are the major activators of the pathway is not fully clear. C_LI Research conclusionRecurrent liver injury releases extracellular histones which potentially activate TLR4-MyD88 signalling pathway to promote liver fibrosis. The ability of NAHP to detoxify circulating histones holds the potential for the treatment of liver injury and prevention of liver fibrosis. Research perspectivesFuture studies demonstrating the contributions of circulating histones in activating the TLR4-MyD88 signalling pathway in vivo will validate their role in liver fibrosis. Development of better anti-histone reagents to reduce liver injury and prevent liver fibrosis will hold great potential in the management of diseases with recurrent liver injury.

pathology↗

bioRxiv2020

A transient role of primary cilia in controlling direct versus indirect neurogenesis in the developing cerebral cortex

During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in this process. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with increased Akt and mTOR signalling and reduced Gli3 repressor levels. Genetically re-storing Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct vs indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.

developmental biology↗

bioRxiv2019

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Pancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.

cancer biology↗

bioRxiv2019

Parasite histones mediate leak and coagulopathy in cerebral malaria

Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.

microbiology↗

bioRxiv2018

The impact of behavioral interventions on co-infectiondynamics: an exploration of the effects of home isolation

Behavioral changes due to the development of symptoms have been studied in mono-infections. However, in reality, multiple infections are circulating within the same time period and behavioral changes resulting from contraction of one of the diseases affect the dynamics of the other.\n\nThe present study aims at assessing the effect of home isolation on the joint dynamics of two infectious diseases, including co-infection, assuming that the two diseases do not confer cross-immunity. We use an age- and time- structured co-infection model based on partial differential equations. Social contact matrices, describing different mixing patterns of symptomatic and asymptomatic individuals are incorporated into the calculation of the age- and time-specific marginal forces of infection.\n\nTwo scenarios are simulated, assuming that one of the diseases has more severe symptoms than the other. In the first scenario, people stay only at home when having symptoms of the most severe disease. In the second scenario, twice as many people stay at home when having symptoms of the most severe disease than when having symptoms of the other disease.\n\nThe results show that the impact of home isolation on the joint dynamics of two infectious diseases depends on the epidemiological parameters and properties of the diseases (e.g., basic reproduction number, symptom severity). In case both diseases have a low to moderate basic reproduction number, and there is no home isolation for the less severe disease, the final size of the less severe disease increases with the proportion of symptomatic cases of the most severe disease staying at home, after an initial decrease. When twice as many people stay at home when having symptoms of the most severe disease than when having symptoms of the other disease, increasing the proportion staying at home always reduces the final size of both diseases, and the number of co-infections.\n\nIn conclusion, when providing advise if people should stay at home in the context of two or more co-circulating diseases, one has to take into account epidemiological parameters and symptom severity.

epidemiology↗

bioRxiv2018

Sample size calculation for estimating key epidemiological parameters using serological data and mathematical modelling

BackgroundOur work was motivated by the need to, given serum availability and/or financial resources, decide on which samples to test for different pathogens in a serum bank. Simulation-based sample size calculations were performed to determine the age-based sampling structures and optimal allocation of a given number of samples for testing across various age groups best suited to estimate key epidemiological parameters (e.g., seroprevalence or force of infection) with acceptable precision levels in a cross-sectional seroprevalence survey.\n\nMethodsStatistical and mathematical models and three age-based sampling structures (survey-based structure, population-based structure, uniform structure) were used. Our calculations are based on Belgian serological survey data collected in 2002 where testing was done, amongst others, for the presence of IgG antibodies against measles, mumps, and rubella, for which a national mass immunisation programme was introduced in 1985 in Belgium, and against varicella-zoster virus and parvovirus B19 for which the endemic equilibrium assumption is tenable in Belgium.\n\nResultsThe optimal age-based sampling structure to use in the sampling of a serological survey as well as the optimal allocation distribution varied depending on the epidemiological parameter of interest for a given infection and between infections.\n\nConclusionsWhen estimating key epidemiological parameters with acceptable levels of precision within the context of a single cross-sectional serological survey, attention should be given to the age-based sampling structure. Simulation-based sample size calculations in combination with mathematical modelling can be utilised for choosing the optimal allocation of a given number of samples over various age groups.

epidemiology↗

bioRxiv2018

Modelling longitudinal binary outcomes with outcome-dependent observation times: an application to a malaria cohort study

Inspite of the global reduction of 21% in malaria incidence between 2010 and 2015, the disease still threatens many lives of children and pregnant mothers in African countries. A correct assessment and evaluation of the impact of malaria control strategies still remains quintessential in order to eliminate the disease and its burden. Malaria follow-up studies typically involve routine visits at pre-scheduled time points and/or clinical visits whenever individuals experience malaria-like symptoms. In the latter case, infection triggers outcome assessment, thereby leading to outcome-dependent sampling (ODS). Ordinary methods used to analyse such longitudinal data ignore ODS and potentially lead to biased estimates of malaria-specific transmission parameters, hence, inducing an incorrect assessment and evaluation of malaria control strategies. In this paper, we propose novel methodology to handle ODS using a joint model for the longitudinal binary outcome measured at routine visits and the clinical event times. The methodology is applied to malaria parasitaemia data from a cohort of n = 988 Ugandan children aged 0.5-10 years from 3 regions (Walukuba - 300 children, Kihihi - 355 children and Nagongera - 333 children) with varying transmission intensities (entomological inoculation rate equal to 2.8, 32 and 310 infectious bites per unit year, respectively) collected between 2011-2014. The results indicate that malaria parasite prevalence and force of infection (FOI) increase with age in the region of high malaria intensities with FOI highest in age group 5-10 years. For the region of medium intensity, the prevalence slightly increases with age and the FOI for the routine process is highest in age group 5-10 years yet for the clinically observed infections, the FOI gradually decreases with increasing age. For the region with low intensity, both the prevalence and FOI peak at the age of one year after which the former remains constant with age yet the latter suddenly decreases with age for the clinically observed infections. In all study sites, both the prevalence and FOI are highest among previously asymptomatic children and lowest among their symptomatic counterparts. Using a simulation study inspired by the malaria data at hand, the proposed methodology shows to have the smallest bias, especially when consecutive positive malaria parasitaemia presence results within a time period of 35 days were considered to be due to the same infection.

epidemiology↗