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Sergei Smirnov

Publications and source records attributed to Sergei Smirnov.

5 recordsLinked to original sources
PubMed2026

Engineering controllable CAR T-cell therapies: from binary safety switches to programmable immunity.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionised cancer gene therapy, yet its expansion into solid tumours is hindered by a critical vulnerability: the autonomous, "always-on" nature of conventional CAR constructs. This unregulated activity drives severe toxicities, including cytokine release syndrome (CRS) and on-target/off-tumour damage, while constitutive signalling in hostile tumour microenvironments (TMEs) accelerates T-cell exhaustion. Early safety strategies relied on irreversible genetic "kill switches," which sacrifice the therapeutic cell population entirely. This review traces the conceptual evolution of CAR T-cell controllability from binary elimination towards platforms enabling graded, reversible, and spatiotemporally precise regulation. We examine the transition from calibrated signalling architectures and small-molecule-regulated split-CARs to advanced optogenetic and sonogenetic controllers, detailing the biophysics of photoreceptor pairs and their preclinical efficacy. Furthermore, we explore complementary architectures, including autonomous logic-gated receptors. Finally, we propose that the optimal next-generation CAR T product will integrate calibrated signalling, external control, and context-dependent armouring to achieve truly programmable, safe, and durable cellular immunotherapy.

Humans↗
PubMed2003

The COG database: an updated version includes eukaryotes.

BACKGROUND: The availability of multiple, essentially complete genome sequences of prokaryotes and eukaryotes spurred both the demand and the opportunity for the construction of an evolutionary classification of genes from these genomes. Such a classification system based on orthologous relationships between genes appears to be a natural framework for comparative genomics and should facilitate both functional annotation of genomes and large-scale evolutionary studies. RESULTS: We describe here a major update of the previously developed system for delineation of Clusters of Orthologous Groups of proteins (COGs) from the sequenced genomes of prokaryotes and unicellular eukaryotes and the construction of clusters of predicted orthologs for 7 eukaryotic genomes, which we named KOGs after eukaryotic orthologous groups. The COG collection currently consists of 138,458 proteins, which form 4873 COGs and comprise 75% of the 185,505 (predicted) proteins encoded in 66 genomes of unicellular organisms. The eukaryotic orthologous groups (KOGs) include proteins from 7 eukaryotic genomes: three animals (the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and Homo sapiens), one plant, Arabidopsis thaliana, two fungi (Saccharomyces cerevisiae and Schizosaccharomyces pombe), and the intracellular microsporidian parasite Encephalitozoon cuniculi. The current KOG set consists of 4852 clusters of orthologs, which include 59,838 proteins, or approximately 54% of the analyzed eukaryotic 110,655 gene products. Compared to the coverage of the prokaryotic genomes with COGs, a considerably smaller fraction of eukaryotic genes could be included into the KOGs; addition of new eukaryotic genomes is expected to result in substantial increase in the coverage of eukaryotic genomes with KOGs. Examination of the phyletic patterns of KOGs reveals a conserved core represented in all analyzed species and consisting of approximately 20% of the KOG set. This conserved portion of the KOG set is much greater than the ubiquitous portion of the COG set (approximately 1% of the COGs). In part, this difference is probably due to the small number of included eukaryotic genomes, but it could also reflect the relative compactness of eukaryotes as a clade and the greater evolutionary stability of eukaryotic genomes. CONCLUSION: The updated collection of orthologous protein sets for prokaryotes and eukaryotes is expected to be a useful platform for functional annotation of newly sequenced genomes, including those of complex eukaryotes, and genome-wide evolutionary studies.

Animals↗
PubMed2002

Unusual role of oxygen in electron-transfer processes.

Molecular oxygen's unique involvement in electron-transfer processes is demonstrated on a series of dyads between porphyrin derivatives and fullerene C60. It has been shown for the first time that oxygen can serve as an inhibitor of back electron transfer by enhancing intersystem crossing of a singlet radical ion pair into its triplet state. The effect is observed only when energy of the charge-separated state is lower than that of the locally excited triplet states. Due to the spin statistics, the reverse intersystem crossing is less efficient, allowing use of oxygen and other paramagnetic species for impeding charge recombination in various electron-transfer systems.

Carbon↗
PubMed2002

Spontaneous epileptiform activity mediated by GABA(A) receptors and gap junctions in the rat hippocampal slice following long-term exposure to GABA(B) antagonists.

Recent evidence suggests that excessive GABA(A) receptor-mediated transmission can lead to neuronal hyperexcitability and hypersynchrony. We show now that exposure of a rat hippocampal slice to GABA(B) receptor antagonists (CGP 55845A and CGP 35348) in the absence of ionotropic glutamatergic transmission leads to a progressive synchronization of spontaneous interneuronal activity. In about 30% of over 200 slices examined, the GABA(A)-mediated spontaneous activity produced field responses in the CA1 soma region with a positive-going phase of up to 5 mV, followed by a long-lasting negative deflection with a simultaneous extracellular K(+) transient. These bicarbonate-dependent GABAergic ictal-like events (GIEs) were associated with biphasic (hyperpolarizing/depolarizing) intracellular responses and with synchronous bursting of the pyramidal neurons. The GIEs could not be reversed by wash-out of the GABA(B) receptor antagonists or by baclofen, but they were inhibited by agonists acting on presynaptic mu-opioid and cannabinoid (CB1) receptors pointing to a down-regulation of presynaptic GABA(B) receptors. GIEs were dependent on intracellular carbonic anhydrase, and potentiated by maneuvers that increase intracellular pH. They were blocked by the Cx36-specific gap-junction (gj) blocker, quinine/quinidine, as well as by the broad-spectrum gj blocker, octanol. These data suggest that enhanced GABAergic activity with functional interneuronal connectivity via gjs is sufficient to trigger epileptiform activity in the absence of ionotropic glutamatergic transmission.

2-Amino-5-phosphonovalerate↗