Search Results (716)

Conventionally designed piezoelectric micro-electro-mechanical systems (MEMS) speakers with thin-film-type, piston-type, and cantilever-type vibration membranes still adopt a Si supporting layer, which not only hinders the improvement of sound pressure level (SPL) but also lacks characterization of reliability. In this paper, we propose a fixed-end beam–cantilever piezoelectric MEMS speaker with a flexible supporting layer, achieving an SPL comparable to that of traditional three types of piezoelectric MEMS speakers with a Si supporting layer, and displaying good reliability. The measured results performed on encapsulated prototypes mounted to an acoustic test adaptor demonstrate that under a driving voltage of 1 V_rms, the SPL exceeds 51.6 dB in the human audible frequency range of 20 Hz–20 kHz, the total harmonic distortion (THD) remains below 3.4% above 430 Hz, satisfying the basic requirements for human auditory perception. Moreover, further experiments also prove its reliability by revealing no abnormal sound output, no fracture after being dropped from heights of 1 to 5 m, and the retention of over 92% SPL following 100 h of continuous music playback. This fixed-end beam–cantilever piezoelectric MEMS speakers with a flexible supporting layer provide researchers and enterprises with brand-new design ideas and a fresh perspective, which may potentially promote their development and practical application. Full article

Background/Objectives: Maresin-1 (MaR1), a specialized pro-resolving mediator (SPM) derived from omega-3 fatty acids, has demonstrated potent anti-inflammatory and pro-resolving properties. However, its effects on depression-like behaviors and the associated dynamics of neuroinflammation, particularly in the context of chronic stress, are not yet fully understood. This study aimed to investigate the therapeutic potential of MaR1 in a chronic unpredictable stress (CUS) model and to monitor its dynamic effects on neuroimmune activity using longitudinal in vivo imaging. Methods: Adolescent male C57BL/6J mice were subjected to a 5-week CUS protocol. Mice exhibiting stable anhedonia were randomized to receive intraperitoneal injections of either MaR1 (5 µg/kg) or vehicle every other day for 4 weeks. During this period, CUS procedures were maintained. Depression-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Dynamic changes in neuroinflammation were monitored via longitudinal [18F]DPA-714 positron emission tomography (PET) scans at baseline and after 2 and 4 weeks of treatment. Ex vivo analyses included immunofluorescence quantification of hippocampal microglia (ionized calcium-binding adaptor molecule 1, Iba1), astrocytes (glial fibrillary acidic protein, GFAP), and 18 kDa translocator protein (TSPO) co-expression, alongside quantitative polymerase chain reaction (qPCR) and Western blotting for inflammatory markers (IL-1β, IL-4, TSPO). Results: MaR1 treatment selectively alleviated depression-like behaviors, significantly reversing CUS-induced anhedonia in the SPT and improving locomotor activity, while its effect on despair-like behavior (TST) was not statistically significant. Longitudinal PET imaging revealed a biphasic neuroimmune response, characterized by an initial increase in [18F]DPA-714 standardized uptake value (SUV) at 2 weeks, followed by a return toward baseline at 4 weeks. Histologically, MaR1 reversed CUS-induced hippocampal microglial loss, resulting in a rebound of microglial numbers, and normalized astrocytic activation. At the molecular level, MaR1 dynamically modulated cytokine expression, culminating in a significant upregulation of the pro-resolving marker IL-4 and TSPO at 4 weeks. Conclusions: These findings indicate that Maresin-1 treatment is associated with behavioral improvement and dynamic modulation of glial activity and TSPO PET signals in the hippocampus. This study highlights the value of TSPO PET imaging for monitoring dynamic glial changes during therapeutic intervention and provides supportive evidence for targeting neuroimmune pathways in depression. Full article

Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a clathrin adaptor essential for clathrin-mediated endocytosis. Genome-wide association studies (GWAS) have consistently identified PICALM as one of the most significant genetic susceptibility loci for late-onset sporadic Alzheimer’s disease (AD). However, the functional impact of the most validated AD-associated variant, rs3851179, remains unclear. Here, we examined PICALM mRNA and protein expression in post-mortem AD brains with reference to rs3851179 genotype. We found that PICALM mRNA levels were significantly increased in AD brains compared with controls, and that the protective rs3851179T allele was associated with reduced PICALM mRNA levels relative to the non-protective rs3851179C allele. In contrast, PICALM levels were significantly reduced in AD brain lysates compared with controls. PICALM expression did not significantly differ between carriers of the protective and non-protective alleles. Analysis of the mRNA-to-protein ratio revealed a significant dissociation between transcript and protein levels, suggesting relatively reduced protein expression efficiency in cases carrying the non-protective CC genotype. To assess whether reduced PICALM levels influence tau pathology, we used Picalm heterozygous knockout (Picalm+/−) mice, which express approximately 50% of the wild-type Picalm protein. Following stereotaxic injection of pathological tau extracted from AD brains, both wild-type and Picalm+/− mice developed tau pathology; however, the extent of tau accumulation did not significantly differ between genotypes. Together, these findings indicate that although PICALM protein level is reduced in AD, this reduction does not appear to affect tau propagation in this model. Therefore, the AD susceptibility associated with PICALM variant likely arises from mechanisms other than tau spread, possibly involving other aspects of autophagy, endocytic or vascular function. Full article

Methyl farnesoate (MF) is a sesquiterpenoid hormone that controls a variety of physiological processes in crustaceans, including morphogenesis, development, reproduction, and molting. MF action is mediated by a transcriptional signaling cascade consisting of Methoprene-tolerant (Met), Steroid receptor coactivator (Src), Krüppel homolog 1 (Kr-h1), and Ecdysone response gene 93 (E93) transcription factors (TFs), and transcriptional co-regulators CREB-binding protein (CBP) and C-terminal-binding protein (CtBP). Phylogenetic and sequence analyses revealed that these genes were highly conserved across pancrustacean species. Met and Src were characterized as basic helix-loop-helix, Period (Per)-Aryl Hydrocarbon Nuclear Translocator (ARNT)-Single-minded (Sim) protein (bHLH-PAS) TFs; Kr-h1 was characterized as a C₂H₂ zinc finger TF with seven zinc finger motifs; E93 was characterized as a helix-turn-helix, pipsqueak (HTH_Psq) TF. CBP was identified by several zinc finger-binding regions with Transcription Adaptor Zinc Finger 1 and 2, Really Interesting New Gene, Plant homeodomain, and Z-type zinc finger domains; the Kinase-inducible Domain Interacting-transcription factor docking site; the Bromodomain-acetylated lysine recognition and binding site; the histone acetyltransferase domain; and a C-terminal CREB-binding region containing a nuclear receptor co-activator-binding domain. CtBP had a dehydrogenase domain with arginine-glutamate-histidine catalytic triad. 81 Met contigs, 45 Src contigs, 136 Kr-h1 contigs, 66 E93 contigs, 60 CBP contigs, and 172 CtBP contigs were identified across pancrustacean taxa, including decapod crustaceans. Bioinformatic identification and annotation of these TFs and co-regulators in brachyuran Y-organ (YO) transcriptomes suggests that MF signaling influences YO ecdysteroidogenesis; functional tests in the YO are needed to establish causality. Full article

The concept of individual cellular intelligence reframes cells as dynamic entities endowed with sensory, reactive, adaptive, and memory-like capabilities, enabling them to navigate lifelong metabolic and extrinsic stressors. A likely vital component of this intelligence system is stress-responsive G protein-coupled receptor (GPCR) networks, interconnected by common signaling adaptors. These stress-regulating networks orchestrate the detection, processing, and experience retention of environmental cues, events, and stressors. These networks, along with other sensory mechanisms such as receptor-mediated signaling and DNA damage detection, allow cells to acknowledge and interpret stressors such as oxidative stress or nutrient scarcity. Reactive responses, including autophagy and apoptosis, mitigate immediate damage, while adaptive strategies, such as metabolic rewiring, receptor expression alteration and epigenetic modifications, enhance long-term survival. Cellular experiences that are effectively translated into ‘memories’, both transient and heritable, likely rely on GPCR-induced epigenetic and mitochondrial adaptations, enabling anticipation of future insults. Dysregulation of these processes and networks can drive pathological states, shaping resilience or susceptibility to chronic diseases like cancer, neurodegeneration, and metabolic disorders. Employing molecular evidence, here, we underscore the presence of an effective cellular intelligence, supported by multi-level sensory GPCR networks. The quality of this intelligence acts as a critical determinant of somatic health and a promising frontier for therapeutic innovation. Future research leveraging single-cell omics and systems biology may unravel the molecular underpinnings of these capabilities, offering new strategies to prevent or reverse stress-induced pathologies. Full article

Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)–Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of Parkin-independent alternative pathways. The mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) acts as a key effector in such pathways, yet its regulatory mechanisms remain incompletely understood. Here, we identify Ubiquitination Factor E4B (UBE4B) as an E3 ubiquitin ligase for NIPSNAP1 and demonstrate that it catalyzes NIPSNAP1 ubiquitination in both Human Embryonic Kidney 293 cells (HEK293T) and HeLa cells. Under mitochondrial depolarization, UBE4B not only promotes NIPSNAP1 ubiquitination and subsequent lysosome-dependent degradation, but also significantly enhances its interaction with the autophagy adaptors Nuclear Dot Protein 52 kDa (NDP52) and Sequestosome 1 (p62/SQSTM1). Notably, while Parkin does not ubiquitinate NIPSNAP1, UBE4B-mediated ubiquitination facilitates mitophagy in Parkin-null HeLa cells by strengthening the binding between NIPSNAP1 and NDP52. Collectively, this study unveils a novel mitophagy pathway regulated by the UBE4B-NIPSNAP1 axis, offering new insights into mitochondrial quality control. Full article

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), poses a severe threat to global wheat production. The adaptor protein complex AP-1 plays a crucial role in vesicular trafficking, yet its function in rust fungi remains poorly understood. In this study, a gene encoding an AP-1 σ subunit, designated PsAP1, was identified in Pst. The expression of PsAP1 was highly induced during the early infection stage. Heterologous expression of PsAP1 in a Fusarium graminearum mutant partially restored its pathogenic defects. Subcellular localization analysis revealed that PsAP1 localizes to the plasma membrane, cytoplasm, and nucleus. Silencing PsAP1 in wheat using Barley stripe mosaic virus-mediated host-induced gene silencing (BSMV-HIGS) significantly attenuated Pst pathogenicity, reducing hyphal growth by 6.7% (colony diameter), sporulation by 61.6% (lesion length), and pathogen biomass by 66%, along with enhanced accumulation of host reactive oxygen species. Transcriptomic analysis further demonstrated that silencing PsAP1 disrupted multiple pathways, including MAPK signaling, glutathione metabolism, and carbohydrate metabolism. These findings indicate that PsAP1 facilitates Pst infection by modulating vesicular trafficking, suppressing host immunity, and reprogramming host metabolism. This study provides novel insights into the pathogenic mechanisms of rust fungi and suggests a potential target for disease control. Full article

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Recent studies support that hematopoietic stem cell (HSC)-derived myeloid dendritic cells, monocytes/macrophages (Mo/Mϕ), and osteoclast precursors (OCps) share common progenitor(s) during development. This occurs mainly through receptor activator of NF-κB ligand (RANKL) signaling via its cytoplasmic adaptor protein complex (TRAF6) to subsequent osteoclastogenesis for bone loss and/or remodeling. Presently, mounting new evidence suggests that erythro-myeloid progenitor (EMP)-derived macrophages (Mϕ) and HSC-derived monocytes (Mo) produce embryonic, fetal, and postnatal OCp pools (i.e., primitive OCp), pinpointing a complex network of multiple OCp developmental origins. However, their ontogenic developments, lineage interactions, and contributions to the alternative osteoclastogenesis—in contrast to overall bone remodeling or loss—remain elusive. Interestingly, studies have also elucidated the contributions of immature CD11c⁺ myeloid DC-like OCps to osteoclastogenesis, with or without the classical so-called Mo/Mϕ-derived OCp subsets, and described that CD11c⁺ myeloid DCs (mDCs) develop into functionally active OCs; meanwhile, the cytokine TGF-β mediates a stepwise regulation of de novo immature mDCs/OCps through distinct crosstalk(s) with IL-17, an unrecognized interaction featuring TRAF6^(−/−)CD11c⁺ mDDOCps that coexist and proficiently colocalize in the local environment to drive a bona fide route for alternative osteoclastogenesis in vivo. Collectively, new findings—critically hinged on progenitor osteoclastogenic pathways (primitive OCps, mDCs/OCps, osteomorphs, etc.) and involving classical and/or alternative routes to inflammation-induced bone loss—are discussed via the illustrated schemes. This review highlights plausible ontogenic vs. principal or alternative developmental paths and their consequential downstream effects. Full article

Emerging evidence highlights a strong association between cerebrovascular accident (CVA) and major depressive disorder (MDD), mediated by immune dysregulation. Elevated levels of proinflammatory cytokines, reduced adaptive immune responses, altered immune cell composition, and increased microglial activation characterize this bidirectional relationship. Microglial activation appears to be a central molecular mechanism linking CVA and MDD, underscoring the immune system’s crucial role in disease pathogenesis. This interplay suggests that immune-driven processes not only exacerbate neurological damage but also contribute to psychiatric manifestations. Based on current literature, the role of proinflammatory processes, particularly microglial activation, in the relationship between CVA and MDD warrants special attention. In this context, the participation of myeloid differentiation factor 88 (MyD88), a cytosolic adaptor protein, appears to play a key role in proinflammatory signaling pathways driving microglial activation. Thus, focusing on MyD88 emerges as a promising complementary strategy for future research and for advancing our understanding of the mechanisms underlying microglial homeostasis dysregulation and its link to the pathophysiology of MDD and CVA. Full article

Background/Objectives: Facial expressions are central to nonverbal communication and social cognition, and their recognition is shaped not only by facial features but also by contextual cues and prior experience. In high-threat contexts, rapid and accurate decoding of others’ emotions is adaptively advantageous. Grounded in neurocognitive models of face processing and vigilance, we tested whether brief perceptual adaptation to emotionally salient scenes, real-world disaster exposure, and pre-traumatic stress reactions enhance facial-emotion categorization. Methods: Fifty healthy adults reported prior direct exposure to catastrophic events (present/absent) and completed the Pre-Traumatic Stress Reactions Checklist (Pre-Cl; low/high). In a computerized task, participants viewed a single adaptor image for 5 s—negative (disaster), positive (pleasant environment), or neutral (phase-scrambled)—and then categorized a target face as emotional (fearful, angry, happy) or neutral as quickly and accurately as possible. Performance was compared across adaptation conditions and target emotions and examined as a function of disaster exposure and Pre-Cl. Results: Emotional adaptation (negative or positive) yielded better performance than neutral adaptation. Higher-order interactions among adaptation condition, target emotion, disaster exposure, and Pre-Cl indicated that the magnitude of facilitation varied across specific facial emotions and was modulated by both experiential (exposed vs. non-exposed) and dispositional (low vs. high Pre-Cl) factors. These effects support a combined influence of short-term contextual tuning and longer-term experience on facial-emotion categorization. Conclusions: Brief exposure to emotionally salient scenes facilitates subsequent categorization of facial emotions relative to neutral baselines, and this benefit is differentially shaped by prior disaster exposure and pre-traumatic stress. The findings provide behavioral evidence that short-term perceptual adaptation and longer-term experiential predispositions jointly modulate a fundamental communicative behavior, consistent with neurocognitive accounts in which context-sensitive visual pathways and salience systems dynamically adjust to support adaptive responding under threat. Full article

Human transmembrane proteins Serinc3 and Serinc5 are antiviral restriction factors that inhibit HIV-1 infectivity. In the absence of viral antagonism, Serinc3 and Serinc5 incorporate into the envelopes of nascent virions and inhibit the fusion of virions to the target cells. The HIV-1 virus counteracts the restriction of Serinc3 by downregulating it from the cell surface and thus excluding it from budding virions. This is orchestrated by the viral accessory protein Nef and involves hijacking of the clathrin adaptor protein complex 2 (AP2)-dependent endocytosis. The mechanistic details of Nef-mediated Serinc3 downregulation, however, have been enigmatic. In this work, we investigated and revealed the molecular determinants of Serinc3 modulation by Nef. Our results show that Nef recruits Serinc3 by binding to its N-terminal cytosolic tail. Furthermore, Nef residues important for Serinc3-binding in vitro, and for the exclusion of Serinc3 from virions, overlap with those required for Nef-mediated CD4 downregulation, suggesting great mechanistic similarities between the two functions of Nef. In addition to shedding light on the mechanism of Serinc3 antagonism, our work also highlights the conserved substrate-binding pocket of Nef as a molecular hotspot for inhibitor development and antiretroviral drug discovery. Full article

Activation through the T cell receptor (TCR) initiates a signaling cascade in T cells that induces extensive molecular and cellular changes. The adaptor protein Linker for Activation of T cells (LAT) plays an essential role in transducing activation and regulatory signals downstream of the TCR. Phosphorylation of LAT tyrosine residues recruits multiple signaling proteins, leading to the assembly of the LAT signalosome, which is crucial for relaying signals that regulate T cell development and function. We previously showed that substitution of a negatively charged amino acid segment preceding the fifth tyrosine residue of LAT (Tyr127 in humans or Tyr132 in mouse LAT) enhances some early TCR signaling events, whereas downstream responses, such as Ca²⁺ influx and Erk phosphorylation, are partially inhibited. To investigate the physiological relevance of this segment in vivo, we generated a new LAT knock-in mouse strain (Lat^NIL) in which the negatively charged segment was replaced with a non-charged sequence. Unexpectedly, this mutation led to an alternative splicing event in the Lat gene that excluded exons 6 and 7, resulting in a frameshift, a premature stop codon at residue 145, and the loss of the six C-terminal tyrosine residues of LAT. Homozygous Lat^NIL/NIL mice showed a phenotype similar to that of LAT-knockout and Lat^4YF mice (in which the four C-terminal tyrosines had been mutated to phenylalanine). Interestingly, homozygous Lat^NIL/NIL mice exhibited a distinct population of γδ T cells in lymphoid organs, which has not been observed in LAT-KO or Lat^4YF mice. These γδ T cells expressed higher levels of CD27 compared to those in wild-type and LAT-KO mice, suggesting altered activation or differentiation states. Together, these data highlight how subtle alterations in LAT structure can profoundly impact T cell signaling and lineage composition. Full article

Leveraging the complementary strengths of handcrafted radiomics and data-driven deep learning, this work develops and rigorously benchmarks three modeling streams (Models A, B and C) for pancreatic ductal adenocarcinoma (PDAC) detection on multiphase abdominal Computed Tomography (CT) scans. Model A distills hundreds of PyRadiomics descriptors to sixteen interpretable features that feed a gradient-boosted machine learning model, achieving discrimination (external AUC ≈ 0.99) with excellent calibration. Model B adopts a 3-D CBAM-ResNet-18 trained under weighted cross-entropy and mixed precision; although less accurate in isolation, it yields volumetric Grad-CAM maps that localize the tumor and provide explainability. Model C explores two fusion strategies that merge radiomics and deep embeddings: (i) a two-stage “frozen-stream” variant that locks both feature extractors and learns only a lightweight gating block plus classifier, and (ii) a full end-to-end version that allows the CNN’s adaptor layer to co-train with the fusion head. The frozen approach surpasses the single stream, whereas the end-to-end model reports external AUC of 0.987, balanced sensitivity/specificity above 0.93, and a Brier score below 0.05, while preserving clear Grad-CAM alignment with radiologist-drawn masks. Results demonstrate that a carefully engineered deep-radiomic fusion pipeline can deliver accurate, well-calibrated and interpretable PDAC triage directly from routine CT. Our contributions include a stability-verified 16-feature radiomic signature, a novel deep-radiomic fusion design that improves robustness and interpretability across vendors and a fully guideline-aligned, openly released pipeline for reproducible PDAC detection on routine CT. Full article

Despite the groundbreaking impact of currently approved CAR T-cell therapies, substantial unmet clinical needs remain. This highlights the need for CAR T treatments that are easier to tune, combine, and program with logic rules, in oncology and autoimmunity. Modular CAR T cells use a two-part system: the CAR on the T cell binds an adaptor molecule (AM), and that adaptor binds the tumour-associated antigen (TAA). This design separates recognition of the target antigen and activation of the T cells, resulting in a cellular therapy concept with better control, flexibility, and safety compared to established direct-targeting CAR T-cell systems. The key advantage of the system is the adaptor molecule, often an antibody-based reagent, that targets the TAA. Adaptors can be swapped or combined without re-engineering the T cells, enabling straightforward multiplexing and logic-gated control. The CAR itself is designed to recognise the AM via a unique tag on the adaptor. Only when the CAR, AM, and antigen-positive target cell assemble correctly is T-cell effector function activated, leading to cancer cell lysis. This two-component system has several features that need to be considered when designing a modular CAR: First, the architecture of the CAR, i.e., how the binding domain and the backbone are designed, can influence tonic signalling and activation/exhaustion parameters. Second, the affinity of CAR–AM and AM–TAA will mostly define the engagement kinetics of the system. Third, the valency of the AM has an impact on exhaustion and non-specific activation of CAR T cells. And lastly, the architecture of the AM, especially the size, defines the pharmacokinetics and, consequently, the dosing scheme of the AM. The research conducted on direct-targeting CAR T cells have generated in-depth knowledge of the advantages and disadvantages of the technology in its current form, with remarkable clinical success in relapsed/refractory disease and long-term survival in otherwise difficult-to-treat patient populations. On the other hand, CAR T-cell therapy poses the risk of severe adverse events and antigen loss coupled with antigen-negative relapse which remains the main reason for failed therapies. Addressing these issues in the traditional setting of one CAR targeting one antigen will always be difficult due to the heterogeneous nature of most oncologic diseases, but the flexibility to change target antigens and the modulation of CAR T response by dosing the AM in a modular CAR system might be pivotal to mitigate these hurdles of direct CAR T cells. Since the first conception of modular CARs in 2012, there have been more than 30 constructs published, and some of those have been translated into phase I/II clinical trials with early signs of success, but whether these will progress into a late-stage clinical trial and gain regulatory approval remains to be seen. Full article