Biology subjects

Toth, K.

Publications and source records attributed to Toth, K..

At least 19 recordsLinked to original sources

bioRxiv2026

The 'false transience' hypothesis: Do we need to reconsider the seed persistence classifications of soil seed bank studies?

Background and Aims Seed bank persistence data is typically indirect, inferred from the presence and distribution of seeds in the soil. However, this approach frequently underestimates seed longevity, because dormant and low-abundance seeds can remain undetected. Here, we introduce and test the 'false transience' hypothesis which proposes that a subset of species classified as having transient seeds based on soil seed bank (SSB) studies actually possess the capacity for long-term persistence. Their perceived transience stems from methodological limitations and ecological filters, rather than physiological constraints. We also aimed to assess how the seed mass and seed production of 'false transient' species compare to the full range of tested species. Methods We focused on species considered to have transient seeds based on SSB studies. We conducted a germination experiment with 103 species using dry-stored seeds aged 10-29 years. We then assessed how the seed mass and seed number of germinating species relate to the full range of tested species. Key Results From the 103 tested species, eight species (~8%) germinated. The majority of species germinating after >10 years had large seeds and low seed numbers compared to the full range of species, and all germinating species had seed numbers below the median of the tested species. Conclusions Our results provide partial support for the proposed 'false transience' hypothesis, showing that nearly 10% of supposedly transient species can persist after more than a decade of ex situ storage. Our results also suggest that 'false transients' are frequently large-seeded with low seed production, therefore being more likely to be missed in SSB studies and erroneously classified as transient. We can conclude that relying solely on field SSB data to infer seed persistence can be misleading, suggesting that the widely observed negative relationship between seed size and persistence may also require reconsideration.

ecology↗

bioRxiv2026

Thermoplastic polyurethane as a base material for soft, high-density neural interfaces

Polymers used as substrate and encapsulation for implantable devices are typically deposited layer-by-layer, leaving polymer-polymer interfaces that adhere poorly and become a critical failure point. Thermoplastic polyurethane (TPU) elastomers combine four properties not found together in any other candidate: decades of clinical use in long-term implants and availability in medical grade, a stiffness well below that of polyimide and parylene C, compatibility with microfabrication, and thermoplastic self-fusion, which removes the polymer-polymer interface entirely. This work introduces TPU as a base material for soft, high-density neural interfaces and demonstrates one route to realizing them. Gold is patterned on a sacrificial copper sheet by maskless lithography and transferred into TPU by vacuum lamination, giving conformally coated tracks down to 15 um at 30 um pitch within a single, merged polymer body. An additional electroplating step produces a nanostructured pinecone gold surface that increases the electrochemically active area of the electrodes, approximately doubling the charge injection capacity. Daisy-chain silicon chips were also embedded within the soft polymer body. The films transmit up to 88% at 470 nm, a wavelength commonly used for optogenetics. TPU showed no cytotoxicity towards differentiated SH-SY5Y cells and only a mild tissue response after 9.5 months of subcutaneous implantation in rats.

bioengineering↗

bioRxiv2026

Cortical isolation separates rhythmic synchrony from network integration in the human neocortex.

Human cortical activity reflects interactions between local recurrent circuits and distributed brain-wide inputs, but how these contributions shape cortical dynamics remains unclear. We compared oscillatory and single unit activity in laminar recordings from the same human cortical regions in eight patients across wakefulness, NREM sleep, and acute slices after surgical isolation. Gamma-band spike-field synchronization increased from wakefulness to sleep and isolated cortex, whereas population coupling, putative connectivity, network integration, and dynamical dimensionality declined. Laminar gamma sink-source organization persisted in isolation, indicating the presence of local gamma-generating mechanisms. Integration with histological data showed preserved tissue architecture, while neuronal density predicted population integration in vivo but not after isolation. Removing long-range inputs thus did not suppress cortical activity but shifted its organization toward stronger rhythmic coordination and reduced integration. Our findings suggest that neocortical microcircuits intrinsically generate coherent gamma activity, whereas network embedding supports the diverse, high-dimensional dynamics of the intact cortex.

neuroscience↗

bioRxiv2026

Functional Continuum of GABAergic Synaptic Dynamics Reflects Genetic Identities

The language of the brain is articulated by temporal patterns of neuronal activity, which individual synapses interpret through distinct forms of synaptic dynamics. While glutamatergic synapses have been proposed to use a handful of functionally distinct types of short-term plasticity (STP) that loosely align with genetic identities, the functional organization of GABAergic synaptic dynamics remains ambiguous. Here, we ask whether the diversity of GABAergic dynamics also clusters into discrete functional types or instead forms a continuum, and whether this functional organization also aligns with genetic identities. Using a combination of machine learning and synaptic modeling on the Allen Institute Synaptic Physiology Dataset, we present evidence that inhibitory dynamics organize into a functional continuum with overlapping modes corresponding to different genetic identities. This continuum spans Parvalbumin (Pvalb) to Vasoactive Intestinal Peptide (VIP) presynaptic neurons, with Somatostatin (Sst) neurons forming an intermediate class. Across the three classes, most inhibitory synapses showed either strong depression or a biphasic form of plasticity that is facilitating at higher stimulation frequencies and depressing at lower ones. However, a higher proportion of Sst and VIP synapses, compared to Pvalb synapses, exhibited either depression restricted to high frequencies or consistent facilitation. When paired with functional subtypes of excitatory synaptic dynamics, this inhibitory continuum completes a unified framework for understanding information flow in the cortical microcircuit, advancing long-standing efforts to explain circuit function by investigating the organization of its components.

neuroscience↗

bioRxiv2026

Flightless I and LRRFIP work together to regulate lateral growth of the sarcomeres in Drosophila

Myofibrils are structurally highly conserved elements of the cardiac and striated muscles. The striking commonalities in their basic organization principles emerge during myofibrillogenesis when the initially formed premyofibrils grow in length and width to attain their final dimensions, characteristic of each muscle type. Although the molecular composition of the myofibrils is well known, the mechanisms governing their growth remain poorly understood, particularly those driving peripheral thickening. Here, we show that two cardiac disease associated proteins, Flightless I and LRRFIP, are required for lateral integration of the myofilaments that is essential for circumferential myofibril growth in the Drosophila flight muscle. Genetic and biochemical analysis reveal that these proteins form multimeric complexes enriched at the barbed end of the actin filaments. Furthermore, we found that the Flightless I/LRRFIP complex acts in a formin dependent manner. Together, our findings demonstrate that Flightless I and LRRFIP cooperate to promote the spatially controlled integration of peripheral actin filaments at the Z-disc, uncovering a key step in myofibril maturation.

cell biology↗

bioRxiv2026

Preserved functions with profound morphological reorganization in human organotypic cultures

Human organotypic slice cultures provide experimental access to adult human neuronal circuits ex vivo, yet it remains unclear whether these networks preserve function or undergo fundamental reorganization following the profound perturbation of slice preparation. Here, we combined extracellular population and single-unit electrophysiology, longitudinal calcium imaging, and quantitative histology to track the changes of human cortical slice cultures over several weeks in vitro. Early phases were marked by pronounced variability and instability, with reduced firing rates, increased burst propensity in principal cells, elevated discharge irregularity, and heterogeneous recruitment during population activity. These functional changes coincided with substantial structural remodeling, including considerable neuronal loss, disruption of laminar architecture, reactive gliosis, and selective vulnerability of inhibitory interneurons. Strikingly, despite this progressive structural degradation, neuronal activity did not diverge but instead converged. By the fourth week in culture, electrophysiological properties, cell-type-specific firing patterns, and population-event recruitment became stable and highly consistent across patients. Calcium imaging revealed persistent, spatially confined regions of synchronous activity, indicating the preservation of structured network dynamics. These events remained within physiological regimes and lacked features of epileptiform discharges. Thus, human neuronal circuits exhibit a robust capacity for self-organization, transitioning from heterogeneous, injury-driven dynamics to stable and homogeneous functional states. This dissociation between structural deterioration and functional convergence establishes human organotypic slice cultures as a reproducible and translationally relevant platform for studying human brain network dynamics ex vivo.

neuroscience↗

bioRxiv2025

Soluble, but not precursor EGF induces intracrine signaling of the EGFR

EGFR is a transmembrane receptor tyrosine kinase regulating growth and survival in epithelial tissues. Its ligand, the epidermal growth factor (EGF), is produced as a membrane-anchored precursor (preEGF) that is proteolytically cleaved to release soluble EGF (sEGF). EGFR overexpression can convert it from a physiological regulator into an oncogenic driver. Therapeutic strategies targeting EGFR include monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). Although mAbs such as cetuximab initially block EGFR activity, tumors often develop resistance. Recent findings indicate that sEGF can activate EGFR within intracellular vesicles, promoting intracrine signaling that sustains proliferation despite extracellular inhibition. Here, we investigated the mechanism of intracrine EGFR signaling in the Golgi apparatus using confocal microscopy, FRET and fluorescence correlation spectroscopy. sEGF, but not preEGF, bound and induced EGFR dimerization and phosphorylation. Erlotinib, a membrane permeable TKI, effectively blocked phosphorylation, whereas extracellular cetuximab did not. These findings imply sEGF-induced intracrine EGFR signaling in the Golgi. Our results may shed light on a potential resistance mechanism to antibody treatment.

biophysics↗

bioRxiv2025

Unintentional seed dispersal via container-grown garden plants: Seed density and composition vary among exporter countries

The global ornamental plant trade is well-known as an important source of alien plants, but the unintentional dispersal of seeds as contaminants of this trade is rarely considered and largely understudied. We sampled the substrate of imported container-grown plants in several garden centres in Hungary to answer the following questions: (i) What species seeds are present in the substrate of imported garden plants and in what quantity? (ii) Do the substrates of plants imported from different countries contain seeds in different density and composition? (iii) Do characteristics of the host garden plants affect the number and diversity of seeds found in their substrate? We detected altogether 2,181 seeds of 80 taxa in the substrates. On average, 1 litre of substrate contained 36 seeds of five species. Most species were alien in Hungary and considered invasive in Europe. The majority of samples contained at least one seed of a species invasive in Europe. We found that the substrate of plants imported from different countries contained seeds in different number, diversity, and composition. Thus, the structure of the horticultural trade network can shape the alien flora of importing countries. Furthermore, the substrate of needle-leaved ornamental species contained more seeds than the substrate of broad-leaved ornamentals. Our findings demonstrate that the ornamental plant trade can disperse a large number of seeds of numerous species and introduce alien species into the importing countries. We conclude that this introduction pathway deserves greater attention in invasion biology and more studies of this phenomenon are urgently needed.

ecology↗

bioRxiv2025

Inconsistent relationships detected between seed size, shape, and persistence for different plant functional groups in the Pannonian flora

Background and AimsKnowledge on seed persistence is vital from both theoretical and practical considerations but directly collecting seed persistence data for many species is rather unfeasible. Therefore, there is a need to identify traits that can predict seed persistence, but studies about the effects of seed size and shape on persistence yielded results varying across regions. We studied 392 species of the Pannonian flora (Central Europe) to asses (i) how seed mass and shape affect seed persistence, (ii) whether this effect is consistent across plant functional groups, and (iii) whether seed mass and shape are correlated in different functional groups? MethodsWe collected data on the seed mass and persistence of species and we performed measurements to calculate their Seed Shape Index, which quantifies deviation from sphericity. We analysed how seed mass and Seed Shape Index affect persistence in all herbaceous species and separately in four plant functional groups. We also tested whether and how seed mass and shape are related to each other in these groups. Key ResultsAcross all species, both seed mass and Seed Shape Index negatively affected seed persistence. The same relationship was observed separately for perennials, short-lived species, and forbs, but only seed shape affected persistence in the graminoid group. Larger seeds also tended to be less spherical in graminoid species, in contrast to all studied species and to other functional groups, where we observed inverse or no relationship between seed mass and shape. ConclusionsConsistent with many studies in other floras, both seed mass and shape negatively affected seed persistence in the Pannonian flora. However, only seed shape influenced persistence in graminoid species, suggesting that different factors may be at play in forbs and graminoids. Therefore, future studies of this relationship may need to treat and analyse graminoids separately.

ecology↗

bioRxiv2025

A myofilament lattice model of Drosophila flight muscle sarcomeres based on multiscale morphometric analysis during development

The indirect flight muscle is a widely used model for studying sarcomere structure and muscle development due to its extremely regular architecture. Nevertheless, precise measurement of the basic sarcomeric parameters remains a challenge even in this greatly ordered tissue. In this study, we identified several factors affecting measurement reliability and developed a software tool for precise, high-throughput measurement of sarcomere length and myofibril width. The accuracy of this new tool was validated against simulated images and blinded manual measurements. To extend the scope of this morphometric analysis to the sub-sarcomeric scale, we used electron and super-resolution microscopy to quantify myofilament number and filament length during myofibrillogenesis. These results provided novel insights into the dynamics of sarcomere growth, and enabled us to construct a refined model of sarcomere growth reaching to the level of individual myofilaments and providing a spatial framework for interpreting molecular localization data. These findings enhance our understanding of sarcomere assembly and offer a foundation for future studies of muscle development and function. SUMMARY STATEMENTThis study identifies factors influencing sarcomere size measurements, introduces a validated tool for precise analysis, and presents a comprehensive model of Drosophila flight muscle sarcomere growth during muscle development.

developmental biology↗

bioRxiv2025

In vitro and in vivo Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxvirus and African Swine Fever Virus Replication

Poxviruses are double-stranded DNA viruses including relevant zoonotic pathogens with high morbidity. Although African swine fever virus (ASFV) belongs to the Asfarviridae family and is not strictly classified as a member of the Poxviridae, both fall within the same class of Pokkesviricetes that replicate in the cytoplasm, and some poxviruses pose potential biological warfare threats. Among compounds targeting these viruses, acyclic nucleoside phosphonate prodrugs are nucleoside analogues inhibitors of viral DNA polymerases that have been identified as promising agents. However, some limitations related to their toxicity and the rapid emergence of resistance highlight the need for new antiviral molecules. In this study, the new nucleoside analogue LAVR-289 was shown to effectively inhibit the viral replication by intervening early in the viral replication step, targeting a specific domain of the poxvirus DNA polymerase. Using monkeypox virus models, the subcutaneous or oral administration of LAVR-289 demonstrates protective efficacy in infected animal models without toxicity or behavioral modification. The stability in vivo, long shelf-life and efficacy make LAVR-289 a promising candidate for further development and stockpiling as a medical countermeasure against dsDNA virus outbreaks. Its broad-spectrum efficacy is a real asset in a context of recurrent viral epidemics, risk of bioterrorism and emergence of resistance strains in the population. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug targeting viral DNA polymerases. C_LIO_LILAVR-289 displays antiviral activity against dsDNA viruses, ASFV and poxviruses. C_LIO_LIFirst report of in vivo evaluation of LAVR-289 against MPXV by subcutaneous and oral administration. C_LIO_LILAVR-289 reduces clinical signs and increase survival in animal models. C_LI

microbiology↗

bioRxiv2025

LAVR-289, a New Orally Bioavailable Inhibitor of Adenovirus Replication in vitro and in vivo.

Adenoviruses are responsible for a range of pathologies, including respiratory infections in children, accounting for 5-10% of such cases. Although most adenovirus infections are self-resolving, they can cause serious illness, particularly in immunocompromised individuals. There is currently no approved treatment for adenovirus infections, although various therapeutic approaches are under investigation, including nucleoside analog inhibitors of replication. However, these treatments have shown limited efficacy. In this study, we report on the antiviral activity of LAVR-289, a broad-spectrum acyclonucleoside phosphonate exhibiting potent in vitro efficacy against several adenovirus serotypes, comparable to that of brincidofovir. LAVR-289 specifically inhibits viral replication, blocking the formation of viral replication centers and preventing late protein expression without affecting viral entry or delivery of viral genomes to the nucleus. In vivo using immunocompromised Syrian hamsters infected with HAdV-C6, oral administration of LAVR-289 resulted in 100% animal survival. These results suggest that LAVR-289 holds promise as a potential therapy for adenovirus infections, particularly in immunocompromised patients. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug. C_LIO_LILAVR-289 displays antiviral activity against Adenovirus with an EC50 of about 100 nM against HAdV-C5 ANCHOR. C_LIO_LILAVR-289 inhibits viral replication by targeting viral DNA polymerase, preventing DBP clustering and replication center formation. C_LIO_LIIn immunosuppressed Syrian hamsters, LAVR-289 is well tolerated and ensures 100% survival while effectively stopping virus replication. C_LIO_LILAVR-289's broad-spectrum activity positions it as a promising treatment for immunocompromised patients facing multiple viral infections. C_LI

microbiology↗

bioRxiv2024

Synthesis of USC-093 and comparison with its promoiety enantiomer USC-093D against adenovirus in vitro and in a Syrian hamster model

Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. At present, no drug has been approved by FDA for the treatment of adenovirus infections. A current treatment of such infections is off-label use of an antiviral acyclic nucleotide phosphonate, cidofovir (CDV, (S)-HPMPC), which requires i.v. administration and has dose-limiting kidney toxicity. We recently reported that USC-093, a homoserinamide analogue of the tyrosinamide (S)- HPMPA prodrug USC-087, was orally effective at a 10 mg/kg against disseminated human adenovirus infection (HAdV-C6) in a Syrian hamster model, although their efficacy was marginal after respiratory infection. Neither prodrug manifested GI toxicity. Unlike USC-087, USC-093 showed no significant nephrotoxicity at the effective dose. Here, we describe in detail the synthesis of USC-093 and also its D-homoserinamide analogue, USC-093D, in four steps (20-40% overall yield) starting from Boc-protected L-homoserine or D-homoserine lactone, respectively. The two stereoisomeric prodrugs had EC50 30-70 nM vs. Ad5 or 1-6 nM vs. Ad6 in HFF cells, with USC-093D giving the lower values. The prodrugs were 30-59x more potent vs. Ad5 and 82-332x more potent than Ad6 relative to the positive control, CDV. To ascertain whether D-chirality in the promoiety could enhance the performance of the prodrug in vivo, USC-093D and USC-093 were compared in the Syrian hamster model (treated from day 1 q.d at an experimentally determined maximum tolerated oral dose of 20 mg/kg)). In this study, the hamsters were instilled i.n. with vehicle or 4X1010 PFU/kg of HAdV-C6 to promote lung infection. Oral valganciclovir (VGCV) at 200 mg/kg b.i.d. was used as the positive control. The body weights were recorded daily, and at 3 days post challenge, gross pathological observation was performed. Lung samples were collected, and the virus burden was determined by TCID50 assay. The results show that altering homoserine stereochemistry did not markedly improve the efficacy of the orally administered prodrug, consistent with the premise that its mechanism of transport is likely not dependent on stereoselective pathways, such as hPEPT1-mediated uptake.

biochemistry↗

bioRxiv2024

Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential

Non-muscle myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal synaptic plasticity, has substantial therapeutic potential. However, translating this potential to in vivo use has been hampered by the lack of selective tools. The most prototypical non-selective inhibitor, blebbistatin inactivates both NMII and cardiac myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that improve tolerability by selectively targeting NMII over CMII, including MT-228, which has excellent properties such as high brain penetration and efficacy in preclinical models of stimulant use disorder, which has no current FDA-approved therapies. The structure of MT-228 bound to myosin II provides insight into its 17-fold selectivity for NMII over CMII. MT-228s broad therapeutic window opens the door to new disease treatments and provides valuable tools for the scientific community, along with promising leads for future medication development. HighlightsO_LIResearch suggests numerous indications, from axon regeneration and cancer, would benefit from a small molecule inhibitor of non-muscle myosin II, a molecular motor that regulates the actin cytoskeleton. C_LIO_LICurrent chemical probe options are very limited and lack sufficient safety for in vivo C_LIO_LIstudies, which we show is primarily due to potent inhibition of cardiac myosin II. C_LIO_LIRational design that focused on improving target selectivity over the pan-myosin II inhibitor, blebbistatin, led to the identification of MT-228, a small molecule inhibitor with a wide therapeutic window. C_LIO_LIHigh-resolution structure of MT-228 bound to myosin II reveals that selectivity results from a different positioning compared to blebbistatin and an important sequence difference between cardiac and non-muscle myosin II in the inhibitor binding pocket. C_LIO_LIA single administration of MT-228 shows long-lasting efficacy in animal models of stimulant use disorder, a current unmet and rapidly escalating need with no FDA-approved treatments. C_LI

cell biology↗

bioRxiv2024

Longevity of Implantable Silicon-ICs for Emerging Neural Applications: Evaluation of Bare Die and PDMS-Coated ICs After Accelerated Aging and Implantation Studies

Silicon integrated circuits (ICs) are central to the next-generation miniature active neural implants, whether packaged in soft polymers for flexible bioelectronics or implanted as bare die for neural probes. These emerging applications bring the IC closer to the corrosive body environment, raising reliability concerns, particularly for long-term clinical use. Here, we evaluated the long-term electrical and material stability of silicon-ICs from two foundries, after one-year accelerated in vitro and in vivo animal studies. The ICs featured various custom-designed test structures and were partially PDMS coated, creating two regions on each chip, uncoated "bare die" and "PDMS-coated". During the accelerated in vitro study, ICs were electrically biased and periodically monitored. Results demonstrated stable electrical performance for at least a year, suggesting that bare die ICs can function in the body for months. Despite electrical stability, material analysis revealed chemical and electrically driven degradation of the IC passivation in the bare die regions. In contrast, PDMS-coated regions revealed no such degradation, making PDMS a highly suitable encapsulant for ICs intended for years-long implantation. Based on the new insights, guidelines are proposed that may enhance the longevity of implantable ICs, significantly broadening their applications in the biomedical field.

neuroscience↗

bioRxiv2023

Soybean RIN4 represents a mechanistic link between plant immune and symbiotic signaling

The legume-rhizobium symbiosis represents a unique and beneficial interaction between legumes and nitrogen-fixing soil bacteria, called rhizobia. The initiation and development of this symbiosis is complex and begins with recognition of key molecular signals, produced by the plant and its symbiont, which determine symbiotic compatibility. Current data suggest that the invading symbiont initially triggers plant immune responses that are subsequently suppressed. Hence, there is growing evidence that features of plant immunity may be relevant to symbiotic establishment. RIN4 is a key immune regulator in plants, regulating basal immunity and it is also targeted by pathogen effector proteins that either confer susceptibility or resistance, depending on the presence of the appropriate resistance protein. Surprisingly, we found that RIN4 was rapidly phosphorylated upon rhizobial inoculation of soybean root hairs. RNAi silencing and mutant studies indicate that RIN4 expression is essential for effective nodulation of soybean. RIN4 phosphorylation occurs within a fifteen amino acid motif, which is highly conserved within the Fabales (legumes) and Rosales orders, which comprise species capable of nitrogen-fixing endosymbiosis with rhizobia. RIN4 proteins mutated in this conserved phosphorylation site failed to support efficient soybean nodulation. Phosphorylation of this site is mediated by the symbiotic receptor-like kinase, SymRK, a well-studied member of the symbiotic signaling pathway. The data implicate RIN4 phosphorylation as a key mediator of rhizobial compatibility, interconnecting symbiotic and immune signaling pathways. SignificanceThe nitrogen fixing legume-rhizobium symbiosis is a cornerstone of sustainable agriculture, with ongoing efforts to transfer this unique ability to non-leguminous crop plants. Plants are surrounded by a myriad of microbes in the soil, and, therefore, require constant surveillance in order to distinguish between a pathogen or symbiont. Plants monitor for specific molecular signals that indicate pathogen or symbiont presence. We show that RIN4, a key immune regulator, plays an essential role in promoting the development of the symbiotic nitrogen-fixing relationship between soybean and its compatible symbiont Bradyrhizobium japonicum. Therefore, RIN4 is likely a key player in mediating the appropriate response upon infection by friend or foe.

plant biology↗

bioRxiv2023

Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states

COVID-19 is associated with diverse neurological abnormalities, which predict poor outcome in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies in COVID-19 are unclear. We hypothesized that microglia, the resident immune cells of brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy-, protein- and mRNA data sets in post-mortem mirror blocks of brain and peripheral organ samples from COVID-19 cases. Nanoscale microscopy, single-cell RNA sequencing and analysis of inflammatory and metabolic signatures revealed distinct mechanisms of microglial dysfunction associated with cerebral SARS-CoV-2 infection. We observed focal loss of microglial P2Y12R at sites of virus-associated vascular inflammation together with dysregulated microglia-vascular-astrocyte interactions, Cx3Cr1-fractalkine axis deficits and mitochondrial failure in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction occurs at sites of excessive synapse- and myelin phagocytosis and loss of glutamatergic terminals. While central and systemic viral load is strongly linked in individual patients, the regionally heterogenous microglial reactivity in the brain correlated with the extent of central and systemic inflammation related to IL-1 / IL-6 via virus-sensing pattern recognition receptors (PRRs) and inflammasome activation pathways. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

immunology↗

bioRxiv2023

Functional Subtypes of Synaptic Dynamics in Mouse and Human

Synapses show preferential responses to particular temporal patterns of activity. Across individual synapses, there is a large degree of response heterogeneity that is informally or tacitly separated into classes, and typically only two: facilitating and depressing short-term plasticity. Here we combined a kernel-based model and machine learning techniques to infer the number and the characteristics of functionally distinct subtypes of short-term synaptic dynamics in a large dataset of glutamatergic cortical connections. To this end, we took two independent approaches. First, we used unsupervised techniques to group similar synapses into clusters. Second, we used supervised prediction of cell subclasses to reveal features of synaptic dynamics that characterized cellular genetic profiles. In rodent data, we found five clusters with a remarkable degree of convergence with the transgenic-associated subtypes. Two of these clusters corresponded to different degrees of facilitation, two corresponded to depression with different degrees of variability and one corresponded to depression-then-facilitation. Strikingly, the application of the same clustering method in human data inferred highly similar clusters to those observed in rodents, supportive of a stable clustering procedure and suggesting a homology of functional subtypes across species. This nuanced dictionary of functional subtypes shapes the heterogeneity of cortical synaptic dynamics and provides a lens into the basic motifs of information transmission in the brain.

neuroscience↗