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Receptor clustering tunes and sharpens the selectivity of multivalent binding
The immune system exploits a wide range of strategies to combine sensitivity with selectivity for optimal response. We propose a generic physical mechanism that allows tuning the location and steepness of the response threshold of cellular processes activated by multivalent binding. The mechanism is based on the possibility to modulate the attraction between membrane receptors. We use theory and simulations to show how tuning interreceptor attraction can enhance or suppress the binding of multivalent ligand-coated particles to surfaces. The changes in the interreceptor attraction less than the thermal energy k B T can selectively switch the receptor-clustering and activation on or off in an almost step-wise fashion, which we explain by near-critical receptor density fluctuations. We also show that the same mechanism can efficiently regulate the onset of endocytosis for, e.g. , drug delivery vehicles.
4D sensor perception in relativistic image processing
Abstract This article introduces the 4D sensor perception in relativistic image processing as a novel way of position and depth estimation. Relativistic image processing extends conventional image processing in computer vision to include the theory of relativity and combines temporal sensor and image data. In consideration of these temporal and relativistic aspects, we process diverse types of information in a novel model of 4D space through 10 different degrees of freedom consisting of 4 translations and 6 rotations. In this way, sensor and image data can be related and processed as a causal tensor field. This enables the temporal prediction of a user’s own position and environmental changes as well as the extraction of depth and sensor maps by related sensors and images. The dynamic influences and cross-sensor dependencies are incorporated into the metric calculation of spatial distances and positions, opening up new perspectives on numerous fields of application in mobility, measurement technology, robotics, and medicine.
Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling
The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in neuronal signaling throughout the nervous system. Its implication in neurological disorders and inflammation has spurred the development of numerous compounds that enhance channel activation. However, the therapeutic potential of these compounds has been limited by the characteristically fast desensitization of the α7 receptor. Using recent high-resolution structures from cryo-EM, and all-atom molecular dynamic simulations augmented by Markov state modeling, here we explore the mechanism of α7 receptor desensitization and its implication on allosteric modulation. The results provide a precise characterization of the desensitization gate and illuminate the mechanism of ion-pore opening/closing with an agonist bound. In addition, the simulations reveal the existence of a short-lived, open-channel intermediate between the activated and desensitized states that rationalizes the paradoxical pharmacology of the L247T mutant and may be relevant to type-II allosteric modulation. This analysis provides an interpretation of the signal transduction mechanism and its regulation in α7 receptors.
Phenotypic and genotypic characterization of Aeromonas hydrophila isolated from freshwater fishes at Middle Upper Egypt
Abstract Aeromonas hydrophila is a common fish pathogen and a significant foodborne pathogen of increasing public health concern. This study was conducted in Middle Upper Egypt to determine the prevalence of A. hydrophila among the diseased Oreochromis niloticus (n = 100) and Clarias gariepinus (n = 100) at Assiut and Sohag Governorates. A. hydrophila isolates (n = 44) were assessed for antimicrobial susceptibility and biofilm production. Moreover, PCR was performed to analyze the incidence of some genes in 20 isolates of A. hydrophila. The results showed that 24% and 20% of the examined O. niloticus and C. gariepinus were infected with A. hydrophila respectively, with all (100%) showing a variety of clinical signs of septicemia. A. hydrophila isolates were all biofilm producers, with varied degrees of biofilm production. 79.5% of the isolates were multidrug-resistant and had a high multiple antimicrobial resistance index > 0.2. PCR analysis revealed that all isolates carried act and blaTEM genes but not carried int2 gene. Additionally, sul1, aer, tetA, int1, and qnrA genes were present in 75%, 60%, 55%, 55% and 45% of them, respectively. This study highlights the high incidence of multidrug-resistant pathogenic A. hydrophila in the infected fishes, posing a serious risk to humans and fish.
A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression
All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that “cancer outgrows its blood supply,” we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53 fl/fl PTEN fl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow–derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.
Linear regressive weighted Gaussian kernel liquid neural network for brain tumor disease prediction using time series data
Identification of a protective antigen reveals the trade-off between iron acquisition and antigen exposure in a global fungal pathogen
Systemic infections caused by Cryptococcus claim over 161,000 lives annually, with global mortality rate close to 70% despite antifungal therapies. Currently, no vaccine is available. To develop an effective multivalent vaccine against this free-living opportunistic eukaryotic pathogen, it is critical to identify protective antigens. We previously discovered ZNF2 oe strains elicit protective host immune responses and increase the abundance of antigens present in the capsule, which is required for its immunoprotection. Capsule is a defining feature of Cryptococcus species and composed of polysaccharides and mannoproteins. Here, we found increased levels of exposed mannoproteins in ZNF2 oe cells. As mannoproteins are the primary components recognized by anticryptococcal cell-mediated immune responses and few have been characterized, we systemically screened all 49 predicted GPI-mannoproteins in Cryptococcus neoformans for enhanced host recognition. We identified those highly present in ZNF2 oe cells and found Cig1 to be a protective antigen against cryptococcosis either as a recombinant protein vaccine or an mRNA vaccine. Cig1 is induced by iron limitation and is highly expressed by this fungus in infected mice and in patients with cryptococcal meningitis. Remarkably, iron restriction by the host induces cryptococcal cells to express iron-uptake proteins including Cig1, which act as cryptococcal antigens and in turn enhance host detection. Our results highlight an arms race between the pathogen and the host centered on iron competition, and the trade-off between cryptococcal iron acquisition and antigen exposure. These findings demonstrate the potential of leveraging this host–pathogen interaction for vaccine development.
Example dependent cost sensitive learning based selective deep ensemble model for customer credit scoring
Interconnecting fragmented forests: Small and mobile birds are cornerstones in the plant–frugivore meta-network
Habitat fragmentation is causing the collapse of seed dispersal interactions and ecosystem functioning. When management and conservation strategies aim to sustain ecosystem functioning of fragmented forests, species’ traits and functional performance are critical in guiding decisions. However, to date, we lack a quantitative understanding of the role of frugivores’ body size and dispersal ability in ecosystem sustainability among fragmented forests. Focusing on avian frugivory and seed dispersal in a multi-island setting, we address the data gap by recording more than 20,000 frugivory events in an artificial insular fragmented landscape constructed in 1959 and nearby unfragmented forests on the mainland. We show that large-bodied and dispersal-limited frugivorous birds are largely confined to large islands and the unfragmented mainland, whereas on small islands, small-bodied and highly mobile birds predominantly engage in frugivory interactions. The plant–frugivore meta-network exhibits a distinct compartmentalization, driven by island area and bird mobility. Birds with smaller size and greater mobility have higher topological importance, and the presence of small-bodied birds significantly enhances meta-network robustness. These results suggest that among insular fragmented forests where frugivory interactions are degraded, small-bodied and highly mobile birds disproportionately contribute to meta-community cohesion and ecosystem functioning because of the lack of large-bodied and dispersal-limited birds. We thus advocate for the restoration of landscapes to facilitate seed dispersal and functional connectivity, ensuring the presence of large patches along with small patches as stepping-stones. Meanwhile, we recommend prioritizing conservation on small-bodied and highly mobile birds in fragmented landscapes, a subset of underappreciated species that yet play crucial roles in ecosystem functioning.
Parent-of-origin testing of prenatal copy number variations: a retrospective study of 167 family cases
SNORD80-guided 2’-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses
The introns of the gene encoding the long noncoding RNA (lncRNA) GAS5 host up to 10 C/D box small nucleolar RNAs (snoRNAs). However, whether there is a regulatory and functional relationship between these snoRNAs and GAS5 is unknown. Here, we show that the expression of SNORD80, but not the other snoRNAs, parallels GAS5 expression and is regulated alongside GAS5 in response to cellular stress. The 2′-O-methylation at the A496 site, located within a segment of GAS5 complementing the conserved RNA-binding region on SNORD80, promotes GAS5 stability and consequent upregulation. This methylation requires SNORD80, as it is diminished by knockdown of SNORD80 and increased by SNORD80 overexpression, similar to the effects of manipulating the expression of fibrillarin, the methyltransferase of the box C/D small nucleolar ribonucleoprotein particle (snoRNP). The upregulation of SNORD80 in response to cellular stress is due to an enhancement in its stability, which is associated with an increase in its interaction with fibrillarin. Collectively, these results identify a role for SNORD80 in guiding 2′-O-methylation to stabilize GAS5. This uncovers a feedforward regulatory loop at the GAS5 gene locus in response to cellular stress and sheds light on posttranscriptional mechanisms governing lncRNA expression.
Study on polarization-insensitive splitter by combining symmetrical structure with matching layer
Raver1 links <i>Ripk1</i> RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance
Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1 -deficient mice exhibit altered splicing of Ripk1 . As a result, Raver1 -deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1 . Consequently, Raver1 -deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.
Kernel-based response extraction approach for efficient configurable ring oscillator PUF
Photopic flicker optoretinography captures the light-driven length modulation of photoreceptors during phototransduction
In this study, we used an inhibitor of phosphodiesterase 6 (PDE6) to examine the impact of changes in the conformation of the PDE6 protein on the light-induced process responsible for altering the length of the outer segments of photoreceptor cells in both human and rodent eyes. We employed a imaging method called spatiotemporal optical coherence tomography, which ensures high contrast and phase stability within the strongly scattering photoreceptor– Retinal Pigment Epithelium complex. Using this approach, we recorded nanometer-scale changes in human cones and rods in response to photopic flicker stimulation and observed length changes in rodent rods under scotopic conditions following a single pulse of light, in the absence or presence of sildenafil, which inhibits the catalytic activity of PDE6. Our findings are consistent with the interpretation that during phototransduction conformational changes in PDE6 structure, which occur on an angstrom scale, are amplified to the nanometer scale due to the unique structure of the photoreceptor outer segments and sequential stimulation. This finding opens up possibilities for the informed use of photopic flicker optoretinography measurements as a diagnostic tool, as the observed nanometer-scale changes in rod and cone dimensions as a function of light stimulus can now be directly linked to molecular events involved in the phototransduction pathway.
Author Correction: Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance
Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources ( http://www.genetictargets.com/MALL ), provide a framework for the metabolism-centered management of ALL.
Waking rest during retention facilitates memory consolidation, but so does social media use
Abstract A short period of post-encoding waking rest has been shown to benefit subsequent memory performance. For example, past research suggests that waking rest after learning Icelandic-German word pairs boosts subsequent recall relative to an equally long period of social media use. Such findings are typically interpreted as evidence in favor of diversion retroactive interference. According to this account, non-specific cognitive processing inhibits consolidation and thus impairs storage of information encoded previously. However, the effect might alternatively be explained by similarity retroactive interference according to which retrieval is hampered by information processed during retention. Here, we report two experiments that shed light on the mechanisms underlying the waking rest effect. In both experiments, participants either wakefully rested, used social media, or engaged in additional Norwegian-German vocabulary learning after the original learning phase. We performed multinomial processing tree (MPT) analyses to disentangle latent storage and retrieval contributions to cued recall and recognition performance. We did not find any memory differences between the waking rest and social media conditions in either experiment. Moreover, storage, but not retrieval, was reliably impaired in the vocabulary condition. Thereby, the present research provides direct behavioral evidence for a dominant role of consolidation in the waking rest effect.
The MutRS quorum-sensing system controls lantibiotic mutacin production in the human pathogen <i>Streptococcus mutans</i>
Microbes use quorum-sensing systems to respond to ecological and environmental changes. In the oral microbiome, the pathogenic bacterium Streptococcus mutans uses quorum-sensing to control the production of bacteriocins. These antimicrobial peptides kill off ecological competitors and allow S. mutans to dominate the microenvironment of dental plaques and form dental caries. One class of bacteriocins produced by S. mutans , the lantibiotic mutacins, are particularly effective at killing due to their broad spectrum of activity. Despite years of study, the regulatory mechanisms governing production of lantibiotic mutacins I, II, and III in S. mutans have never been elucidated. We identified a distinct class of quorum-sensing system, MutRS, that regulates mutacins and is widespread among the streptococci. We demonstrate that MutRS systems are activated by a short peptide pheromone (Mutacin Stimulating Peptide) and show that MutRS controls production of three separate lantibiotic mutacins in three different strains of S. mutans . Finally, we show that paralogous MutRS systems participate in inter- and intrastrain crosstalk, providing further evidence of the interplay between quorum-sensing systems in the oral streptococci.