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The ERAD pathway mediates cross talk between two control points in cholesterol synthesis: HMG CoA reductase and squalene monooxygenase
Two key enzymes, HMG CoA reductase (HMGCR) and squalene monooxygenase (SM), are subjected to distinct endoplasmic reticulum–associated degradation (ERAD) pathways to maintain cholesterol homeostasis. HMGCR catalyzes conversion of HMG CoA to mevalonate, the first rate-limiting step in cholesterol synthesis. Sterols accelerate ERAD of HMGCR by promoting its binding to Insig proteins, which recruit E3 ubiquitin ligases for ubiquitination and degradation. Downstream, SM catalyzes oxygenation of squalene, committing intermediates to sterol synthesis. Cholesterol stimulates ERAD of SM, but through an Insig-independent mechanism mediated by the E3 ligase MARCH6. Here, we report a mechanism of posttranslational regulation involving a stable complex between HMGCR and SM in sterol-deprived cells. The two enzymes physically interact within ER membranes in an Insig-independent manner, and this interaction protects both proteins from ERAD. Loss of either enzyme destabilizes the other, indicating a costabilization mechanism. These findings uncover a layer of coordination in cholesterol synthesis, suggesting HMGCR and SM function as an integrated complex to ensure synchronization of early and late steps of the pathway.
Strength behaviour of Clayey Soil modified with processed periwinkle shell ash
Stromal and endothelial transcriptional changes during progression from MGUS to myeloma and after treatment response
Abstract Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is accompanied by profound remodeling of the bone marrow microenvironment (BME), yet the contribution of its non-immune compartment remains unclear. Using single-cell RNA sequencing in genetically engineered mouse models that recapitulate disease evolution, we transcriptionally profile endothelial cells (EC) and mesenchymal stem cells (MSC). EC adopt a stress-associated program at MGUS that precedes angiogenesis in MM, while MSC undergo early and sustained loss of differentiation capacity. We identify a coordinated interferon (IFN)-driven program across EC and MSC that defines MM in the BIcγ1 model but is absent in the more aggressive MI cγ1 model. Treatment with bortezomib, lenalidomide, and dexamethasone suppresses this IFN signature, promotes endothelial adaptation, and restores osteogenic potential in MSC. Validation in patient samples reveals enrichment of this IFN-signature across disease stages. These findings define dynamic and targetable alterations in the non-immune BME during myeloma progression.
Structural insights into RNA recognition by the <i>Staphylococcus aureus</i> exoribonuclease YhaM
Bacterial ribonucleases regulate gene expression in response to environmental stress and host interactions. In Staphylococcus aureus , the hibernation-promoting factor (Hpf) induces the formation of RNase R-resistant 100S ribosomes. We previously showed that the 3’-5’ exoribonuclease YhaM cleaves the hpf transcript, reducing Hpf synthesis and leading to ribosome degradation. No structure of any YhaM homolog bound to RNA is available, and biological investigations of YhaM remain limited. Here, we find that deletion of yhaM attenuates S. aureus virulence in a Galleria mellonella infection model. We further determined electron cryomicroscopy structures of YhaM–RNA complexes. YhaM adopts a hexameric complex arranged in a ring, with its N-terminal oligonucleotide/oligosaccharide-binding (OB) domains positioned on both sides of the ring while the catalytic histidine/aspartate-rich (HD) domain active sites are buried within the interior. The OB-1’’ domains recognize the hpf hairpin by the formation of complementary minor groove interactions. RNA binding by two YhaM OB domains is mediated through engagement of both the backbones and nucleobases of the RNA substrate, where stacking of aromatic residues and nucleobases likely contributes to substrate recognition. Structures of YhaM bound to a single-stranded RNA reveal how the 3’ ends of two RNAs are positioned within the HD domain poised for catalysis. Although six YhaM active sites are present, only two engage in RNA cleavage and further point to the importance of the remaining YhaM monomers as structural scaffolds for guiding RNA to the active site. In summary, these findings provide insights into the unique assembly of an understudied bacterial RNase.
Role of β-adrenergic signaling in the development of Porphyromonas gingivalis lipopolysaccharide-induced cardiac dysfunction in mice
Sustainable trans-scale fibrous membranes for stable ultra-protective air filtration
Abstract Disposable fibrous air filtration media represent one of the most convenient and effective approaches for personal health protection. Nevertheless, restricted by the technical bottlenecks of spinning technologies in fabricating ultrafine nanofibers and designing topological filtration networks, current filters cannot realize reliable ultra-protection against ultrafine particulate matter (PM). Moreover, non-degradable waste from excessive filter use imposes severe environmental burdens. Herein, we report a universal multi-level splitting electrospinning strategy for fabricating a variety of biodegradable trans-scale fiber membranes (TSFM). The hierarchical interweaving and stacking of ultrafine nanofibers, nanofibers, and submicron fibers endow the lightweight TSFM with tortuous interception networks and abundant mass and energy transport channels. Consequently, they can achieve a stable ultra-efficient PM 0.3 removal, low air resistance, great breathability, and reduce polymer consumption by 99% relative to commercial N95 respirators. This work may boost the iterative upgrading of advanced spinning technologies and the development of high-performance, sustainable filtration and separation materials.
The physiological relevance of downstream effectors of p53 activity
The TP53 tumor suppressor encodes a transcription factor that regulates the expression of hundreds of target genes. Previous mouse studies have identified a conserved p53-dependent transcriptional signature that includes Cdkn1A (p21) , Gtse1 ( G2 and S-phase expressed 1 ), and Eda2r . In this study, we investigated the physiological roles of these three genes, along with Bbc3 (Puma), a p53 target involved in apoptosis, as effectors of p53 activity. We generated alleles of Gtse1 and Eda2r . In contrast to previously reported Cdkn1A-null and Bbc3-null mice which do not exhibit any overt phenotypes, mice expressing N-terminal deletions of Gtse1 ( Gtse1Δ7 ) and Eda2r ( Eda2rΔ11 ) displayed defects in spermatogenesis and liver abnormalities, respectively. We crossed these mice to an Mdm2 -deletion model that constitutively activates p53 resulting in multiple phenotypes and lethality. Notably, loss of p21 rescued the lethality associated with constitutive p53 activation in vivo, whereas the Gtse1Δ7 mutant partially rescued this effect; no rescue was observed with Eda2rΔ11 or Bbc3 loss. These findings indicate that cell cycle regulators, rather than apoptosis-related genes, are the main drivers of sustained p53-induced gastrointestinal defects and lethality.
Impulsive intervention strategies for temperature and rainfall-dependent visceral leishmaniasis transmission dynamics
FRAME: Fine-Resolution Asymmetric Migration Estimation
Phenolic profiling, synergistic antibacterial and antioxidant potentials of various honey combinations: in vitro and in silico study
Abstract This study investigated the synergistic interactions within binary combinations of ten Algerian honey samples, focusing on their phytochemical profiles and bioactivities. Ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) profiling identified 22 phenolic compounds, with quinic acid, gallic acid, naringenin, and acacetin predominant across samples. The antioxidant (DPPH, ABTS, FRAP) and antibacterial activities against Staphylococcus aureus (S. aureus) , Pseudomonas aeruginosa (P. aeruginosa) , and Escherichia coli (E. coli) were evaluated using both in vitro assays and in silico molecular docking. Results revealed significant synergistic effects; specifically, combinations involving Bunium mauritanicum honey (M3) exhibited superior antioxidant capacity, while samples M 2 , M 5 , and M 8 showed enhanced antibacterial efficacy. Molecular docking confirmed strong interactions between major phenolics and target protein active sites, which yielded favorable binding scores. These findings highlight the enhanced therapeutic as well as nutritional potential of Algerian honey combinations as potent natural sources of synergistic bioactive compounds.
Sterically protected π-electron systems for efficient solid-state photon upconversion
Abstract A solid-state visible-to-ultraviolet triplet–triplet annihilation-based photon upconversion system driven by low-intensity light at sunlight levels is developed. Realizing such a solid-state photon upconversion system has been challenging because it is difficult to achieve high fluorescence quantum yield and fast triplet exciton diffusion simultaneously, which requires methodologies to precisely control interactions among chromophores and suppress quenching of both singlet and triplet excited states. Here, we report that a group of dihydroindeno[2,1- a ]indene derivatives functionalized with alkyl chains above and below the π-plane satisfies all these requirements. Among three derivatives investigated, we identify the optimal emitter structure that exhibits the highest photon upconversion quantum yield in both solution and crystalline states. The solid-state system is less affected by crystalline defects, exhibiting high photoluminescence quantum yield, long triplet lifetime, and fast triplet diffusion, with an absolute photon upconversion quantum yield of 1.9% and a low threshold excitation intensity of 1.2 mW cm −2 .
Canonical EDS1/PAD4 small-molecule binding sites are required for LRR-RP-mediated pattern-triggered immunity
Pattern-triggered immunity (PTI) is a key plant defense mechanism initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by cell-surface receptors, including leucine-rich repeat receptor proteins (LRR-RPs). Upon PAMP perception, LRR-RPs associate with SOBIR1 and recruit SERK coreceptors, such as BAK1, into the receptor complex to initiate PTI. The lipase-like protein EDS1 and PAD4 are central components of effector-triggered immunity (ETI). Small molecule (SM) phosphoribosyl-AMP/ADP, generated by TIR-domain NADase activity, promotes the recruitment of helper NLRs of the ADR1 family into the EDS1–PAD4 complex to execute ETI. This ETI signaling branch, known as the EDS1–PAD4–ADR1 node, is associated with SOBIR1 and is essential for LRR-RP-mediated PTI. To elucidate the molecular mechanism by which EDS1–PAD4 contributes to PTI, we show that PTI initiation mediated by BAK1 recruitment to LRR-RP complexes is unaffected in eds1-2 or pad4-1 mutants but is abolished in the sobir1-12 mutant, highlighting the essential role of SOBIR1 in surface immune receptor complex formation. Furthermore, we demonstrate that SM binding to EDS1 and PAD4, in addition to its role in ETI, is also critical for LRR-RP-mediated PTI, as SM-binding-deficient mutants fail to restore PTI responses. Moreover, de novo SM synthesis is required for late PTI responses, including PR1 expression and bacterial resistance, but not for early responses such as reactive oxygen species and ethylene production. Finally, the TNL SADR1 functions specifically in late PTI responses. Together, these findings indicate that a preformed EDS1–PAD4–ADR1 complex is essential for PTI and reveal a two-tiered role for TIR-domain proteins in PTI signaling.
Frequency-domain multi-scale hybrid attention for pathological image classification
Global current systems in the magnetosphere of Mercury
Abstract The global current systems of a planet represent electrodynamic interactions between its different parts, and between its magnetosphere and the ambient solar wind. Although some local currents of Mercury’s magnetosphere have already been revealed by previous observational studies, the global picture of current systems in Mercury’s magnetosphere remains unknown. Here we reconstruct the global current systems in the Mercury’s magnetosphere, using five years magnetic field and plasma measurements made by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft. It reveals a complex picture: a magnetopause current, cross-tail current, inner and outer equatorial ring currents and an unexpected polar ring current. The equatorial ring currents and the polar ring current agree with the prediction of the plasma drifting model in a region with a pressure gradient. These ring currents could reshape Mercury’s magnetosphere and reveal new dynamics and energy transfer processes in Mercury.
Epithelial cells fire voltage spikes
Bioelectric signaling is well characterized in neurons and cardiomyocytes but remains largely unexplored in epithelia. Using multielectrode arrays, we demonstrate that localized laser injury to epithelial monolayers (primary human keratinocytes and MDCK cells) triggers voltage spikes in the range of 4 to 12 per min for over 60 min postinjury. These spikes exhibit depolarization, repolarization, and hyperpolarization phases lasting 1 to 2 s, a timescale three orders of magnitude slower than neuronal action potentials. Spike amplitudes and frequencies detected at 740 μm from the injury site (the maximum distance measured) are comparable to those at 140 μm and exhibit a nonmonotonic spatial profile, arguing against simple radial propagation from the wound. Calcium chelation with ethylenediaminetetraacetic acid abolishes spiking entirely, and inhibition of myosin II with blebbistatin produces equivalent suppression, indicating that calcium influx and actomyosin contractility are both required. The mechanosensitive channel modifier GsMTx4 partially suppresses spiking, implicating the role of stretch-activated ion channels. Most strikingly, pharmacological activation of the mechanosensitive channel TRPV4 and Piezo1 generates high-amplitude spikes (1 to 10 mV) even in the absence of injury, demonstrating that mechanosensitive channel activation is sufficient to drive epithelial electrical excitability. These findings reveal that epithelia, long thought to lack action-potential-like dynamics, possess intrinsic bioelectric excitability gated by mechanical stress, challenging the classical distinction that electrical signaling is exclusive to specialized tissues like neurons and muscles and suggesting a signaling modality for coordinating collective cellular responses across tissue-scale distances.
The ITM2B-associated retinal dystrophy mutation modifies BRI23 peptide interactions in the human retina
Varifocal Alvarez metalens array for adaptive light-field imaging
Abstract Metalens arrays hold great promise for compact light-field imaging systems owing to their compactness and wavefront shaping capabilities. However, their fixed focal lengths fundamentally limit depth-of-field modulation and axial scanning, restricting their adaptability to diverse light-field imaging scenarios. Here, we demonstrate adaptive light-field imaging using a varifocal Alvarez metalens array. The array is composed of two closely bonded metasurfaces, each patterned with 24 × 20 cubic-phase sub-regions. Through relative lateral displacement, the Alvarez metalens array achieves continuous focal length tuning from 3.33 mm to 4.50 mm. Integrated into a plenoptic imaging system, the proposed metalens array enables dynamic focusing and an expanded depth range. We further introduce a MultiLensFusion algorithm that combines these multi-focus captures into high-resolution, all-in-focus renderings. This work offers a compact and versatile platform for next-generation light-field imaging systems with dynamically tunable optical response.
Correlated gene copy number changes in a seminal fluid protein network in <i>Drosophila</i>
In Drosophila melanogaster , the male seminal fluid protein Sex Peptide regulates persistent postmating changes in female physiology and behavior. The persistence of long-term postmating responses in females requires Sex Peptide binding to sperm, which is mediated by a network of other seminal fluid proteins. A recent study documented substantial copy number variation of Sex Peptide genes in Drosophila species. We hypothesized that, due to shared selective pressures and compensatory changes to maintain functionality, members of the Sex Peptide network should exhibit correlated patterns of gene duplication or loss. Using a computational pipeline pairing iterative genome searches with phylogenetic clustering to resolve homology relationships, we annotated among-species copy number variation of Sex Peptide network genes. We found that these genes are present in the common ancestor of Drosophila species and in many cases predated the origin of Sex Peptide itself. Furthermore, we observed statistically significant correlations in gene duplication or loss events among network members. Our results suggest that selection acting on copy number variation is an additional source of among-species variation of reproductive genes, and that this selection contributes to the maintenance of reproductive gene interactions. Using patterns of shared gene loss across the genus, we also identified and experimentally validated a network member, suggesting the utility of using correlated loss to identify functionally related genes. In contrast to the Sex Peptide seminal fluid network, female-derived proteins that modulate functions downstream of sperm bound Sex Peptide showed no correlation of gene turnover events with Sex Peptide network members.
Heavy metal concentrations and inter-metal relationships in commercially available hair dyes of different colours: a chemometric evaluation
Abstract Cosmetic hair colouring products may contain trace inorganic contaminants introduced through pigments, raw materials, manufacturing processes, or packaging. Repeated use may contribute to low-level human and environmental exposure. This study determined the concentrations of seven heavy metals (Cr, Co, Cu, Pb, Cd, Ni, and Fe) in 21 commercially available hair dyes representing seven colour categories obtained from retail outlets in Ibadan, Nigeria. Samples were digested using a nitric acid–hydrogen peroxide mixture and analysed by flame atomic absorption spectrometry. Method reliability was verified using procedural blanks, replicate analysis, and spike recovery (95–104%). Metal concentrations (mg/kg) exhibited colour-dependent variability. Chromium ranged from 0.230 ± 0.245 mg/kg in green dyes to 2.53 ± 0.12 mg/kg in blue dyes, while copper showed the highest variability, reaching 7.03 ± 4.67 mg/kg in red dyes. Lead and nickel also varied across colour categories, with relatively higher nickel concentrations observed in blue dyes. Multivariate analyses (principal component analysis and hierarchical clustering) revealed partial grouping patterns and inter-metal associations, suggesting potential common sources linked to formulation components. Although concentrations were generally within available guidance ranges, the co-occurrence of multiple metals suggests the need for continued monitoring of cosmetic products as a screening-level indication of potential contamination concerns. Given the limited sample size and market scope, the findings should be interpreted as exploratory baseline data for cosmetic surveillance and environmental monitoring rather than definitive health risk characterization.