Biology subjects

Nowak, P.

Publications and source records attributed to Nowak, P..

10 recordsLinked to original sources

bioRxiv2026

FairTCR: Equity-Aware TCR--pMHC Binding Prediction\\Across HLA Alleles and Cohort Strata

Public TCR-pMHC binding databases are heavily skewed toward a handful of well-studied HLA alleles-- most prominently HLA-A*02:01, which covers [~]45% of curated records--and toward patients from European-ancestry cohorts. Standard empirical risk minimization (ERM) trained on such data achieves strong pooled accuracy but routinely underperforms on rare alleles and underrepresented cohorts, creating systematic disparities that are invisible in single-metric benchmarks. We introduce FairTCR, a group distributionally robust optimization (GDRO) framework that minimizes worstgroup loss across HLA supertypes and cohort strata via online exponentiated gradient updates. FairTCR reduces the average- worst-group AUPRC disparity from 0.190 (ERM) to 0.098 on a curated VDJdb-IEDB benchmark, achieving a 48.4% disparity reduction while maintaining competitive average AUPRC (0.432 vs. 0.431 for ERM). Per-HLA analysis shows that rare allele groups (B*08:01, B*44:02) gain up to 0.062 AUPRC points, directly improving the equity of computational pre-screening for underrepresented patient populations.

bioinformatics↗

bioRxiv2025

Disrupted α-ketoglutarate homeostasis trains monocyte-derived macrophages towards M2-like phenotype in long-term treated HIV-infection

Cells of the myeloid lineage, particularly monocytes and macrophages, are central to HIV pathogenesis, contributing to viral persistence and immune regulation during suppressive therapy. We hypothesized that metabolic reprogramming and altered chemokine signaling in people with HIV (PWH) on long-term ART impair monocyte trafficking and macrophage polarization. Using single-cell RNA sequencing, immunophenotyping, and metabolic modeling, we identified altered receptor expression and disrupted metabolic flux linked to reduced monocyte migration. Plasma secretome profiling revealed a nonclassical inflammatory microenvironment, while integrative multi-omics and single-cell proteomics of monocyte-derived macrophages (MDMs) demonstrated metabolic rewiring of the Glycolysis-TCA Anaplerosis Axis, orchestrated in part by elevated -ketoglutarate (AKG). Differentiation with PWH serum or AKG, skewed MDMs toward an M2-like phenotype, and enhanced HIV susceptibility. Together, these systems-level and mechanistic analyses reveal that metabolic training drives macrophage dysfunction in well-treated PWH, sustaining low-grade inflammation and highlighting potential therapeutic targets.

systems biology↗

bioRxiv2024

TORC2-regulated sterol redistribution mediates recovery from membrane perturbation by small amphipathic molecules.

To maintain plasma membrane (PM) integrity, cells need to acutely regulate PM lipid composition. The Target Of Rapamycin (TOR) complex 2 is a protein kinase that acts as a central regulator of PM homeostasis, but the mechanisms by which it monitors and reacts to membrane stresses are poorly understood. To address this knowledge gap, we characterized a family of amphiphilic molecules that physically perturb PM organization and in doing so inhibit TORC2 in yeast and mammalian cells. Using fluorescent lipid associated reporters in budding yeast, we show that these small molecules first cause a transient increase in the amount of biochemically accessible ergosterol at the PM. Contemporaneous TORC2 inhibition stimulates a rapid removal of accessible ergosterol from the PM by the PM-ER sterol transporters Lam2 and Lam4, necessary for TORC2 reactivation. Thus, we show that TORC2 acts in a feedback loop to control active sterol levels at the PM and introduce sterols as possible TORC2 signalling modulators.

cell biology↗

bioRxiv2024

De novo PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription

HIV-1 infection establishes a reservoir of long-lived cells with integrated proviral DNA that can persist despite antiretroviral therapy (ART). Some of these reservoir cells can at anytime be reactivated and reinitiate infection. The mechanisms governing proviral latency the transcriptional regulation of the provirus are complex and have not yet been sufficiently described. Here, we identified a role for histone H3 citrullination, a post-translational modification catalyzed by protein-arginine deiminase type-4 (PADI4), in HIV-1 transcription and latency. We found that PADI4 inhibition by GSK484 reduced HIV-1 transcription after T cell activation in ex vivo cultures of CD4 T cells from people living with HIV-1 (PLWH). The effect was more pronounced in individuals with active viremia compared to individuals with effective ART. Using cell models of HIV-1 latency, we showed that PADI4-mediated citrullination of histone H3 occurred at the HIV-1 promoter upon T cell stimulation which facilitated proviral transcription. HIV-1 preferentially integrated into genomic regions marked by H3 citrullination and these integrated proviruses were less prone to latency compared to those in non-citrullinated chromatin. Inhibiting PADI4 led to compaction of the HIV-1 promoter chromatin and an increase of HP1-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism to explain HIV-1 latency and transcriptional regulation. HighlightsO_LIThe PADI4 enzyme stimulates HIV-1 transcription during T cell activation. C_LIO_LIPADI4 citrullinates histone H3 at the HIV-1 promoter upon T cell activation and inhibiting PADI4 reduces HIV-1 reactivation in ex vivo CD4 T cells from people living with HIV-1. C_LIO_LIH3cit is mostly found at gene promoters, and productive HIV-1 proviruses are more likely than latent or reactivatable proviruses, to integrate in chromatin susceptible for citrullination. C_LIO_LIH3cit inhibits latency establishment by interfering with the binding of HP1 to H3K9me3, preventing heterochromatin formation. C_LI

microbiology↗

bioRxiv2022

Plastid DNA sequences and oospore characters of some European species of Tolypella section Tolypella (Obtusifolia, Characeae) indicate a new cryptic Tolypella species from the Mediterranean island Sardinia

In Europe, the genus Tolypella (Characeae) comprises four to eight Tolypella species in sections Rothia and Tolypella that have been distinguished by vegetative morphology and gametangial characters such as antheridial size and oospore cell wall ornamentation. However, morphological species differentiation is difficult in some cases due to overlapping and variable vegetative features, which in many cases are difficult to observe clearly. To clarify the taxonomic status of the five European species of Tolypella in section Tolypella, sequence data of the plastid genes atpB, rbcL and psbC for Tolypella glomerata (Desv.) Leonh., Tolypella hispanica Allen, Tolypella nidifica (O.F. Mull.) A. Braun, Tolypella normaniana (Nordst.) Nordst. and Tolypella salina Cor. were combined with data on oospore morphology, including oospore wall ornamentation. Gene sequence data identified five distinct clusters, but they differed from the morphologically identified five species. T. glomerata consisted of some of the samples morphologically identified as T. glomerata and seven samples of T. normaniana, while the remaining T. glomerata samples clustered with specimens of unclear affiliation ("Tolypella. sp."). T. hispanica I consisted of samples from various locations, whereas "T. hispanica II" consisted of samples of T. hispanica from the Mediterranean island, Sardinia. The remaining cluster consisted of all the specimens that had been determined as T. salina or T. nidifica in addition to two specimens of T. normaniana. Oospore morphology was most clearly distinguishable for T. glomerata. Oospore characteristics for all other taxa were not as informative but showed some geographical and/or environmentally influenced differences, especially for T. nidifica and T. salina. Our results suggest a significantly different taxonomy of Tolypella sect. Tolypella in which specimens normally identified as T. glomerata might be two different species, T. glomerata and an unidentified species; T. nidifica and T. salina are not separate species; T. normaniana is a diminutive variant of T. nidifica or T. salina; and T. hispanica comprises two different species, one from the Mediterranean island Sardnia.

plant biology↗

bioRxiv2021

Combined effects of salinity and temperature on grazing activity of invasive Gammarus tigrinus on charophytes

Charophytes are a refuge for zooplankton and stabilize sediments, but they are also a food source for various animal species (water birds, fishes, invertebrates). Especially the introduction of new species, like Gammarus tigrinus, into the Baltic Sea led to yet not understood changes in the food web. Furthermore, future projections point to increased water temperatures at lowered salinity levels affecting species capacity to acclimatize to changing abiotic factors. In this study we investigated the influence of temperature and salinity on the grazing pressure of Gammarus tigrinus on two charophyte species: Chara aspera and Chara tomentosa. The grazing experiments were conducted in a full factorial design with the factors salinity (3 - 13 g kg-1), temperature (5 - 30 {degrees}C), and charophyte species. Grazing rates were determined as mass deviation within 48 hours considering biomass changes in the presence and absence of gammarids. Grazing rate were further used to calculate charophyte losses in two coastal lagoons with different salinity concentrations for recent and future time periods. The potential grazing peak of about 24 {degrees}C is not yet reached in these coastal waters but may be reached in the near future as shown by our future projection results. However, the temperature increase, and desalination will cause a shift in seasonal individual grazing patterns from summer to spring and autumn. Desalination and temperature increase can lead to a shift in optimal habitats for G. tigrinus in the future.

ecology↗

bioRxiv2021

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

microbiology↗

bioRxiv2020

Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who are able to suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naive viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into mechanisms governing EC status. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP while inflammation markers were increased in VP compared to EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared to HC and CCL20/CCR6 axis can play important role. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to control of viral replication. One Sentence SummaryHIV-1 elite controllers had a distinct lipid profile, reduced inflammation, and increased antioxidant defense that might contribute to elite control status.

microbiology↗

bioRxiv2019

A neuroprosthetic system to restore neuronal communication in modular networks

Recent advances in neurotechnology allow neurological impairments to be treated or reduced by brain machine interfaces and neuroprostheses. To develop energy-efficient and real-time capable devices, neuromorphic computing systems are envisaged as the core of next-generation neurobiohybrid systems for brain repair. We demonstrate here the first exploitation of a neuromorphic prosthesis to restore bidirectional interactions between two neuronal populations, even when one is damaged or completely missing. We used in vitro modular cell cultures to mimic the mutual interaction between neuronal assemblies and created a focal lesion to functionally disconnect the two populations. Then, we employed our neuromorphic prosthesis for two specific applications with future clinical implications: bidirectional bridging to artificially reconnect two disconnected neuronal modules and hybrid bidirectional bridging to replace the activity of one module with a neuromorphic spiking neural network. Our neuroprosthetic system opens up new avenues for the development of novel bioelectrical therapeutics for human applications.

bioengineering↗

bioRxiv2018

Systemic inflammation following long-term successful antiretroviral therapy in people living with HIV (PLHIV)

The ART program in low- and middle-income countries (LMIC) like India, has a public health approach with the standardized regimen for all people living with HIV (PLHIV). Based on the evidence from high-income countries (HIC), the successful implication and scale-up of ART in India, the risk of an enhanced and accentuated onset of premature-aging or age-related diseases could be observed in PLHIV. However, very limited data is available on residual inflammation and immune activation in the populations who are on first-generation anti-HIV drugs like zidovudine and lamivudine that had more toxic side effects. Therefore, the aim of the present study was to evaluate the levels of systemic inflammation and understand the risk of age-associated diseases in PLHIV on long-term suppressive ART using a large number of biomarkers of the inflammation and immune activation. Blood samples were obtained from therapy naive PLHIV (Pre-ART, n=43), PLHIV on ART for >5 years (ART, n=53), and HIV-negative healthy controls (HIVNC, n=41). Samples were analyzed for 92 markers of inflammation, sCD14, sCD163, and telomere length. Several statistical tests were performed to compare the groups under study. Multivariate linear regression was used to investigate the associations. Despite a median duration of eight years of successful ART, sCD14 (p<0.001) and sCD163 (p=0.04) levels continued to be significantly elevated in ART group as compared to HIVNC. Eleven inflammatory markers, including 4E-BP1, ADA, CCL23, CD5, CD8A, CST5, MMP1, NT3, SLAMF1, TRAIL and TRANCE, were found to be significantly different (p<0.05) between the groups. Many of these markers are associated with age-related co-morbidities including cardiovascular disease, neurocognitive decline and some of these markers are being reported for the first time in the context of HIV-induced inflammation. Linear regression analysis showed a significant negative association between HIV-1-positivity and telomere length (p<0.0001). In ART-group CXCL1 (p=0.048) and TGF- (p=0.026) have a significant association with increased telomere length and IL-10RA was significantly associated with decreased telomere length (p=0.042). This observation warrants further mechanistic studies to generate evidence to highlight the need for enhanced treatment monitoring and special interventions in HIV-infected individuals.

immunology↗