Biology subjects

Smirnov, I.

Publications and source records attributed to Smirnov, I..

8 recordsLinked to original sources

bioRxiv2026

Assay coverage reshapes metabolic diagnosis and the interpretation of pathway disturbance

Metabolic profiles are used to quantify disturbance, classify disease and infer biochemical function, yet these endpoints retain different information. We combine secondary analysis of 386 metabolites in six Arabidopsis thaliana mutation accumulation lines, known-disease classification in 129 public human metabolic-disease profiles, and an analytically solvable kinetic model. A conditional occupancy model separates annotation-bin breadth from hit count and measured bin sizes: the plant low-versus-high fitness comparison changes from a two-sided exact permutation p = 0.10 to p = 0.30 after calibration. Unsigned metabolite profiles achieve mean macro recall of 0.911 and 0.895 in separate EDTA and heparin subsets, compared with 0.624 and 0.382 for a burden baseline. However, controlled loss of 50% of held-out measurements reverses representation ranking in heparin, giving signed profiles a recall advantage of 0.108 with a conditional bootstrap interval of 0.063-0.155. A spectral decomposition identifies the within-pathway contrasts attenuated by smoothing. The kinetic model then shows that lower concentration and faster relaxation can coexist with reduced desired product flux, while a null-space criterion states when observations identify a metabolic task. The results connect assay coverage, diagnostic information and functional identifiability. Human performance is internally validated, and the kinetic predictions remain uncalibrated to patients.

systems biology↗

bioRxiv2026

The brain-meningeal interface functions as a reservoir and entry site for brain parenchymal macrophages

Microglia are regarded as self-maintaining brain parenchymal macrophages without contribution from adult hematopoiesis. Nevertheless, peripheral macrophage engraftment into the brain has been reported, but the biological variables governing central nervous system (CNS) macrophage niche access remain unclear. We show that CNS macrophage engraftment is determined by the balance between tissue-resident macrophage (TRM) self-renewal and the temporal alignment of niche opening with the availability of engraftment-competent cells and proximity to the vacated niche, rather than prolonged niche vacancy. Fate mapping revealed that monocytes entering the subdural space undergo border-associated macrophage (BAM)-like differentiation, clonal expansion, and transpial migration into the parenchyma, whereas mature BAMs directly repopulate selectively vacated parenchymal niches. We further identify a parenchymal macrophage population with a peripheral BAM-like transcriptional program in aged and neurodegenerative human brains, challenging the dogma of MG-exclusivity. Together, these findings establish a predictive framework for interpreting macrophage maintenance and replacement and for developing macrophage-based therapies.

neuroscience↗

bioRxiv2024

COMPARATIVE CHARACTERISTICS OF THE ACCUMULATION OF DIFFERENT VARIANTS OF THE SARS-COV-2 VIRUS (WUHAN, DELTA, OMICRON) IN THE ORGANS OF MODEL ANIMALS

BackgroundThe genotypic variability of the SARS-CoV-2 virus has proven to be extremely high, and the emergence of new strains raises concerns about their possible high virulence, transmissibility, and ability to bypass responses of the bodys immune system induced by previous infection or vaccination. Therefore, one of the main tasks is to study the pathogenesis of various variants of the virus using experimental animal biomodels of SARS-CoV-2 to quickly find methods and approaches to fighting new viruses. Methods60 humanized mice of the C57BL/6-Tgtn (CAG-human AEC2-IRES-Luciferase-WPRE-polyA) line (hACE2) were used. Mice were infected intranasally at different doses with three variants of the SARS-CoV-2 virus: Wuhan, Delta and Omicron. ResultsWe showed that humanized hACE2 mice, when infected with all three variants of the SARS-CoV-2 virus, showed typical pathological changes in lung consistency comparable to those found in COVID-19 in humans. All mice developed interstitial pneumonia, characterized by inflammatory cell infiltration and thickening of the alveolar septa, characteristic of vascular damage. ConclusionsAt a dose of 4 lg plaque-forming unit (PFU), all variants showed 100% mortality. A dose-dependent effect was established only for the Wuhan and Delta variants. In a comparative assessment of different variants of the SARS-CoV-2 virus in a humanized mouse model of hACE2, it was found that the Delta variant leads to more severe damage compared to Wuhan or Omicron.

pathology↗

bioRxiv2024

Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Identities from Microglia

Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206+ microglia precursors in the YS. We found that brain-engrafted MDMs exhibit transcriptional and epigenetic characteristics akin to meningeal macrophages, likely due to environmental imprinting within the meningeal space. Utilizing parabiosis and skull transplantation, we demonstrated that monocytes from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains. Our results reveal the heterogeneous origins and cellular dynamics of brain parenchymal macrophages at baseline and in models of microglia depletion.

immunology↗

bioRxiv2021

Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota

The commensal microflora is a source for multiple antigens that may induce cross-reactive antibodies against host proteins and pathogens. However, whether commensal bacteria can induce cross-reactive antibodies against SARS-CoV-2 remains unknown. Here we report that several commensal bacteria contribute to the generation of cross-reactive IgA antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. We identified SARS-CoV-2 unexposed individuals with RBD-binding IgA antibodies at their mucosal surfaces. Conversely, neutralising monoclonal anti-RBD antibodies recognised distinct commensal bacterial species. Some of these bacteria, such as Streptococcus salivarius, induced a cross-reactive anti-RBD antibodies upon supplementation in mice. Conversely, severely ill COVID-19 patients showed reduction of Streptococcus and Veillonella in their oropharynx and feces and a reduction of anti-RBD IgA at mucosal surfaces. Altogether, distinct microbial species of the human microbiota can induce secretory IgA antibodies cross-reactive for the RBD of SARS-CoV-2.

microbiology↗

bioRxiv2021

GABAergic neuronal IL-4R mediates T cell effect on memory

Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying effects of T cells on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long term potentiation. Severe combined immune-deficient (SCID) mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. This rescue was mediated via IL-4 receptors (IL-4R) expressed on neurons. Exploration of snRNAseq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways and genes regulated by immune cells and molecules. IL-4R knockout in inhibitory neurons impaired contextual fear memory, suggesting participation of an IL-4-associated switch in regulating synaptic function and promoting contextual fear memory. These findings provide insights into neuroimmune interactions at the transcriptional and functional levels in neurons.

neuroscience↗

bioRxiv2020

Single cell BCR and transcriptome analysis after respiratory virus infection reveals spatiotemporal dynamics of antigen-specific B cell responses.

B cell responses are a critical component of anti-viral immunity. However, a comprehensive picture of antigen-specific B cell responses, differentiation, clonal proliferation and dynamics in different organs after infection is lacking. Here, we combined single-cell RNA sequencing with single-cell B cell receptor (BCR) characterization of antigen-specific cells in the draining lymph nodes, spleen and lungs after influenza infection. We identify several novel B cell subpopulations forming after infection and find organ-specific differences that persist over the course of the response. We discover important transcriptional differences between memory cells in lungs and lymphoid organs and describe organ-restricted clonal expansion. Strikingly, by combining BCR mutational analysis, monoclonal antibody expression and affinity measurements we find no differences between germinal center (GC)-derived memory and plasmacells, at odds with an affinity-based selection model. By linking antigen-recognition with transcriptional programming, clonal-proliferation and differentiation, these finding provide important advances in our understanding of antiviral B cell immunity.

immunology↗

bioRxiv2019

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

neuroscience↗