Browse Articles

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.

Cyclic mechanical loading of photopolymerized methacrylated hydrogels for probing interdependent effects of strain, stiffness, and substrate composition in pulmonary fibrogenesis

Photoreceptor-induced LHL4 protects the photosystem II monomer in <i>Chlamydomonas reinhardtii</i>

Photosynthesis, the fundamental process using light energy to convert carbon dioxide to organic matter, is vital for life on Earth. It relies on capturing light through light-harvesting complexes (LHC) in photosystem I (PSI) and PSII and on the conversion of light energy into chemical energy. Composition and organization of PSI and PSII core complexes are well conserved across evolution. PSII is particularly sensitive to photodamage but benefits from a large diversity of photoprotective mechanisms, finely tuned to handle the dynamic and ever-changing light conditions. Light Harvesting Complex protein family members (LHC and LHC-like families) have acquired a dual function during evolution. Members of the LHC antenna complexes of PS capture light energy, whereas others dissipate excess energy that cannot be harnessed for photosynthesis. This process mainly occurs through nonphotochemical quenching (NPQ). In this work, we focus on the Light Harvesting complex-Like 4 (LHL4) protein, a LHC-like protein induced by ultraviolet-B (UV-B) and blue light through UV Resistance locus 8 (UVR8) and phototropin photoreceptor-activated signaling pathways in the model green microalgae Chlamydomonas reinhardtii . We demonstrate that alongside established NPQ effectors, LHL4 plays a key role in photoprotection, preventing singlet oxygen accumulation in PSII and promoting cell survival upon light stress. LHL4 protective function is distinct from that of NPQ-related proteins, as LHL4 specifically and uniquely binds to the transient monomeric form of the core PSII complex, safeguarding its integrity. LHL4 characterization expands our understanding of the interplay between light harvesting and photoprotection mechanisms upon light stress in photosynthetic microalgae.

Hybrid Greylag Goose deep learning with layered sparse network for women nutrition recommendation during menstrual cycle

Spatial profiling of the interplay between cell type- and vision-dependent transcriptomic programs in the visual cortex

How early sensory experience during “critical periods” of postnatal life affects the organization of the mammalian neocortex at the resolution of neuronal cell types is poorly understood. We previously reported that the functional and molecular profiles of layer 2/3 (L2/3) cell types in the primary visual cortex (V1) are vision-dependent [S. Cheng et al. , Cell 185 , 311–327.e24 (2022)]. Here, we characterize the spatial organization of L2/3 cell types with and without visual experience. Spatial transcriptomic profiling based on 500 genes recapitulates the zonation of L2/3 cell types along the pial–ventricular axis in V1. By applying multitasking theory, we suggest that the spatial zonation of L2/3 cell types is linked to the continuous nature of their gene expression profiles, which can be represented as a 2D manifold bounded by three archetypal cell types. By comparing normally reared and dark reared L2/3 cells, we show that visual deprivation-induced transcriptomic changes comprise two independent gene programs. The first, induced specifically in the visual cortex, includes immediate-early genes and genes associated with metabolic processes. It manifests as a change in cell state that is orthogonal to cell-type-specific gene expression programs. By contrast, the second program impacts L2/3 cell-type identity, regulating a subset of cell-type-specific genes and shifting the distribution of cells within the L2/3 cell-type manifold. Through an integrated analysis of spatial transcriptomics with single-nucleus RNA-seq data, we describe how vision patterns cortical L2/3 cell types during the critical period.

Integrated patterns of residence and movement create testable hypotheses about fish feeding migrations