We investigated the role of SIRT1 in linear growth and bone structure, focusing on the response of the epiphyseal growth plate (EGP) to nutritional manipulation. A ColX-Cre driver was used to target hypertrophic chondrocytes (HZ), and generate hypertrophic specific Sirt1 knockout (CKO) mice. We found that Sirt1 deletion in hypertrophic chondrocytes markedly impaired growth in males, with a 33% reduction in body weight and 10-11% shorter long bones and EGP height (P<0.05). In females, effects were milder (12% reduction in weight, 5-7% shorter long bones; P<0.05 in both) but EGP height was reduced similarly to the males. These mice were next tested in a catch-up (CU) growth model involving food restriction followed by refeeding. Under CU conditions, male CKO mice showed an unexpected exaggerated response, surpassing the weight and bone length of normally fed CKO. We therefore conclude that targeted Sirt1 deletion in the hypertrophic zone revealed a strong sex-dependent effect on skeletal growth and bone quality. Both male and female CKO mice exhibited growth impairment under normal conditions compared to littermate control (CTL), however while male showed hyper-responsiveness to refeeding, females CKO showed only moderate alterations. This targeted approach uncovers sex-dependent role for SIRT1 in regulating growth and bone quality, moving beyond its generally understood functions in cartilage and bone development. The distinct responses to both basal conditions and nutritional stress between sexes represent a significant new finding, extending its known role beyond general cartilage and bone development.
To accurately characterize the nonlinear hyper-viscoelastic mechanical behavior of rubber materials under large deformation and stress relaxation conditions, this study investigates fluororubber (FKM) and hydrogenated nitrile rubber (HNBR) with different hardness levels through uniaxial mechanical tests and stress relaxation experiments. A constitutive parameter identification method based on hyperelastic models and the parallel rheological framework (PRF) model is established. First, several representative hyperelastic models, including the Neo-Hookean, Mooney-Rivlin, Yeoh, Ogden, Arruda-Boyce, and Van der Waals models, are comparatively evaluated. The results show that the Ogden model with (N = 3) provides the highest fitting accuracy for the large-deformation responses of FKM and HNBR with different hardness levels, with coefficients of determination (R2) ranging from 0.9879 to 0.9948. Subsequently, the Prony series parameters are identified from the stress relaxation data and converted into the initial parameters of the linear PRF model. To overcome the limitations of the linear PRF model in predicting nonlinear relaxation behavior, the PRF parameters are further optimized using the Isight data matching method combined with the Hooke-Jeeves algorithm. Finite element validation demonstrates that the optimized nonlinear PRF model can accurately predict the stress relaxation behavior of both FKM and HNBR. The mean absolute percentage errors of FKM60, FKM70, and FKM80 are 2.67%, 1.57%, and 2.56%, respectively, while those of HNBR60, HNBR70, and HNBR80 are 2.16%, 2.72%, and 2.58%, respectively. These results indicate that the combination of the Ogden (N = 3) hyperelastic model and the optimized nonlinear PRF model can effectively describe the large-deformation and time-dependent viscoelastic responses of rubber materials, providing a reliable constitutive modeling basis for finite element analysis and parameter calibration of rubber sealing structures.
Objective: Diabetes mellitus (DM) is a major metabolic disorder associated with hyper-glycemia and oxidative stress. Traditional medicinal plants remain important sources of bioactive compounds with potential antidiabetic activity. Salacia reticulata and Caralluma tuberculata are two important medicinal plants that have been reported to have antidiabetic effects. The growing burden of type 2 diabetes and the need for therapies that address both hyperglycemia and oxidative stress underscore the necessity to investigate these two medicinal plants. Therefore, the current study evaluated the antihyperglycemic, antioxidant, and protective effects of Salacia reticulata and Caralluma tuberculata in an alloxan-induced diabetic female rat model. Methods: Ethanolic extracts of S. reticulata and C. tuberculata were characterized by total phenolic content (TPC), total flavonoid content (TFC), DPPH radical-scavenging assay, and UPLC-MS/MS metabolite profiling. Female Wistar rats (n = 42) were randomly assigned to seven groups (n = 6/group), including normal control, diabetic control, extract-treated non-diabetic groups, diabetic extract-treated groups, and a metformin-treated diabetic group. Diabetes was induced by alloxan (130 mg/kg), followed by oral treatment for 8 days with extracts or metformin (500 mg/kg/day). Fasting blood glucose, oral glucose tolerance, serum malondialdehyde (MDA), antioxidant markers (SOD1, GSH, and CAT), and liver and kidney histopathology were assessed. Results: Both plant extracts significantly reduced fasting blood glucose compared with baseline, with S. reticulata showing a greater reduction (22.8%) than C. tuberculata (12.3%), and a response comparable to metformin (27.4%). Diabetic rats exhibited increased MDA and reduced antioxidant enzyme activities. C. tuberculata significantly lowered MDA levels and increased SOD1 activity, suggesting moderate antioxidant effects, whereas S. reticulata showed higher phenolic and flavonoid contents and the highest DPPH scavenging activity. UPLC-MS/MS identified 33 compounds in S. reticulata and 24 in C. tuberculata. Histopathological findings supported improvement of diabetes-associated renal and hepatic damage. Conclusions: Within the eight-day experimental period, both extracts demonstrated significant acute antidiabetic and antioxidant effects with distinct redox-metabolic profiles. However, further long-term studies are recommended to evaluate their sustained efficacy, safety, and potential as complementary therapeutic agents for diabetes management.
Contemporary electrophysiology experiments often involve massively parallel recordings of neuronal activity using multi-electrode arrays. While researchers have been aware of artifacts arising fromelectric cross-talk between channels in setups for such recordings, systematic and quantitative assessment of the effects of those artifacts on the data quality has never been reported. Here we present, based on examination of electrophysiology recordings from multiple laboratories, that multi-electrode recordings of spiking activity commonly contain extremely precise (at the data sampling resolution) spike coincidences far above the chance level. The recordings analyzed here were obtained from two rhesus macaques (Macaca mulatta; one male, one female) and one male mouse (C57BL/6J).We derive, throughmodeling of the electric cross-talk, a systematic relation between the amount of such hyper-synchronous events (HSEs) in channel pairs and the correlation between the raw signals of those channels in the multi-unit activity frequency range (500-7500 Hz). We show that whitening the band-pass filtered raw signals removes the above chance HSEs; strongly suggesting they originate from linear mixing of signals. Whitening should therefore be performed prior to spike sorting and any further analysis of precise spike correlation, otherwise analysis results may be considerably affected.Significance statement Artifacts are widespread in electrophysiological recordings. To mitigate their impact, these artifacts need to be detected and they should be removed from the data without impacting the quality of the data. This work presents measures to identify and quantify the amount of artifacts within a multichannel recording by evaluating the occurrence of hyper-synchronous events i.e., spikes that are synchronous on a sub-millisecond time scale, and further introduces zero-phase component analysis (ZCA) as a method to remove these artifacts from the data. Thus, we recommend to use ZCA as a general preprocessing for electrophysiological recordings.
Persistent sensory hypersensitivity is a common but under-recognized feature of post-concussion syndrome (PCS) following mild traumatic brain injury (mTBI), and may contribute to chronic cognitive complaints. However, the mechanistic relationship between long-term sensory dysregulation and cognitive dysfunction after repeat concussion remains poorly understood. Here, we used an experimental repeated closed-head injury (rCHI-5x), in young adult mouse model targeting the frontal cortex at 8-weeks of age to test whether chronic sensory processing abnormalities contribute to cognitive impairment under increased sensory load chronically at 8-10 weeks post-injury (4-months old). rCHI mice exhibited significant sensory dysfunction across multiple modalities, including increased tactile sensitivity, tactile avoidance, and impaired habituation to auditory startle, despite the absence of gross structural brain damage and preserved learning and memory under low-demand conditions. While spatial learning and working memory in the Barnes maze were intact, rCHI mice displayed increased perseveration and reduced cognitive flexibility. However, these cognitive deficits emerged only when auditory and tactile sensory distractors were introduced during testing, unmasking impairments that were not evident under baseline conditions. Within-animal statistical analyses found strong associations between the severity of sensory hypersensitivity, impaired sensory habituation, and deficits in cognitive flexibility in rCHI mice, but not in sham controls. These findings indicate that chronic sensory dysregulation following repeat mild concussion is not merely a secondary symptom, but a primary contributor to cognitive impairment under conditions of increased sensory load. Together, this work identifies persistent sensory processing and gating dysfunction as a key driver of PCS-related cognitive deficits and reveals that targeting sensory circuitry for therapeutic neuromodulation may offer functional rescue across multiple domains, extending beyond sensory symptoms to improve higher-order cognitive performance.
Neuronal hyper-excitability in glioma environments has been reported long before and recent research has clarified that glioma cells are inducing the enhanced excitability of surrounding neurons. Furthermore, the direct interaction between neuron and glioma is also found to be a special characteristic within glioma progression. However, neurovascular unit (NVU) consists of various types of cells and are known to modulate the neuronal activity directly and indirectly. Among different cells constituting the NVU, microglia are recently found to be modulating neuronal activity through negative feedback via purinergic signaling while its modulating function is relatively unknown in glioma environment. In this review, we focus on the role of microglia in controlling neuronal activity and its loss-of-function contributing to the neuronal hyper-excitability within glioma environment.
Polycythemia vera (PV) is a JAK2-associated clonal myeloproliferative neoplasm characterized by erythroid hyperplasia. To the best of our knowledge, this is the first reported case of acute hyper-viscosity encephalopathy as the initial manifestation of suspected PV in a resident of extreme high altitude-a diagnosis frequently mistaken for altitude-induced secondary polycythemia in this population. A 37-year-old Tibetan man, lifelong resident at 4,100 m, presented with acute encephalopathy characterized by altered consciousness, gait ataxia, and headache. Neurological examination confirmed higher cortical dysfunction. Laboratory studies showed marked erythrocytosis (hemoglobin 229 g/L, hematocrit 77.4%) with paradoxically suppressed serum erythropoietin (EPO, 1.2 mIU/mL). Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) revealed acute bilateral frontoparietal and centrum semiovale diffusion-restricted lesions. Neurological symptoms resolved rapidly after osmotic therapy for intracranial hypertension. These findings were consistent with suspected PV based on WHO diagnostic criteria. This case suggests that acute infection may trigger life-threatening hyper-viscosity syndrome in suspected PV at extreme altitudes. EPO assessment and JAK2 mutational analysis are recommended to be included in the diagnostic algorithm to distinguish malignant PV clones from compensatory polycythemia and to prevent catastrophic neurological outcomes in high-altitude residents.
Accurate fault diagnosis is critical to ensuring the reliable operation of equipment. However, traditional deep learning methods typically rely on a predefined set of known fault types, limiting their ability to identify unknown faults. Thus, this paper proposes an open set fault diagnosis method based on Hyper-opinion Dual Branch Evidential Deep Learning with Distance Perception (HDEDL-DP). Firstly, a dual-branch framework is proposed to capture sharp evidence supporting single proposition and vague evidence supporting composite propositions via hyper-opinion modeling. A projection mechanism converts the vague evidence into sharp evidence for model inference. Secondly, mahalanobis distance is used to provide distance perception. Finally, an OOD score integrating uncertainty estimation and distance perception is designed to identify unknown fault classes. Two case studies validate the effectiveness of HDEDL-DP.
Autism spectrum disorder (ASD) is characterized by widespread aberrations in brain scalp-level synchronization. Phase-amplitude coupling (PAC), which reflects cross-frequency neuronal oscillatory interactions, serves as a crucial metric for assessing functional brain integration. However, the specific patterns of PAC at both intra-region and inter-region scalp levels in young children with ASD, as well as their precise associations with clinical symptoms, remain unclear. This study enrolled 237 children with ASD aged 3-9 years and 201 age-matched typically developing (TD) children. Resting-state electroencephalography (EEG) data were acquired from all participants. The analysis systematically examined low-frequency oscillation phase (δ, θ, α) modulation of high-frequency oscillation amplitude (β and low γ) from both intra-region and inter-region dimensions. The PAC strength was quantified using the modulation index (MI). Multiple comparisons were corrected using the Bonferroni method. Finally, correlations between PAC metrics and Autism Behavior Checklist (ABC) scores were analyzed. Compared to the control group, children with ASD exhibited significant frequency-specific PAC abnormalities: (1) Multi-regional γ hyper-coupling: There was a significant enhancement in the modulation of γ amplitude by δ/θ/α phase across the measured scalp regions, suggesting abnormal high-frequency synchronization. (2) Dissociated β modulation patterns: The ASD group showed increased δ-β coupling (predominantly in frontal, temporal, and occipital lobes) alongside significantly reduced α-β coupling (localized to frontal and central regions). This reflects both an abnormal locking of slow-wave activity to the β band and a diminished regulatory role of α oscillations. (3) Clinical correlation: Notably, abnormally elevated PAC strength (particularly in the δ/θ/α-γ bands) showed a negative correlation with clinical symptom severity-that is, stronger coupling was associated with lower scores on the ABC. Leveraging a large-sample dataset, this study characterizes the landscape of aberrant cross-frequency interactions in young children with ASD. Our findings indicate that the neuroelectrical activity in ASD goes beyond mere connectivity anomalies by demonstrating altered PAC strength at both the intra-region and inter-region levels. Notably, the strength of this aberrant intra-region PAC is correlated with clinical symptoms.
Systemic sclerosis (SSc) is a progressive autoimmune disease characterized by fibrosis, vasculopathy, and immune dysregulation. Emerging evidence indicates that SSc shares multiple hallmarks of accelerated biological aging, including genomic instability, telomere attrition, mitochondrial dysfunction, cellular senescence, and chronic innate immune activation. This review summarizes recent advances published during the last 18 months supporting the concept of SSc as a disorder of maladaptive or 'hyper-aging'. Recent epigenetic clock studies, including DunedinPACE and other DNA methylation-based aging models, demonstrate accelerated biological aging in SSc, particularly in patients with interstitial lung disease and severe organ involvement. Gene expression meta-analysis has confirmed that aging and senescence signatures are markedly enriched in SSc-ILD lung tissue. Multiple aging-associated mechanisms contribute to disease progression, including telomere shortening, mitochondrial dysfunction, micronuclei formation, and chromosomal instability. Cytosolic DNA derived from damaged nuclei or mitochondria activates the cGAS-STING pathway, sustaining type I interferon signaling, inflammaging, and fibrotic remodeling. Recent transcriptomic and spatial studies further support a close relationship between metabolic collapse, mitochondrial stress, immune dysregulation, and tissue fibrosis in SSc. Current evidence supports the concept that SSc represents a state of accelerated and dysregulated biological aging involving persistent innate immune activation, mitochondrial stress, and defective genome surveillance. Therapeutic strategies targeting aging-associated pathways, particularly mitochondrial dysfunction, cGAS-STING signaling, and cellular senescence, may provide new opportunities to modulate fibrosis, inflammation, and immune imbalance in SSc.
In this paper, we introduce the space-air-ground integrated low-altitude aerial vehicular networks (SAG-LAAVN) that deliver ubiquitous intelligent connectivity for three-dimensional intelligent transportation systems (ITS). Built upon an innovative hyper-converged architecture that unifies Data, Operation, Information, and Communication Technologies (DOICT), SAG-LAAVN aims to address the stringent connectivity requirements imposed by the rapid evolution of low-altitude aerial vehicles, offering seamless coverage, enhanced resilience, and improved quality of experience across diverse scenarios. Three key scientific challenges in the SAG-LAAVN are discussed. Besides, we present three potential technologies: intelligent networking approach, multi-dimensional resource management, and virtual-physical dynamic collaboration. Implemented via the fully decoupled radio access network (FD-RAN), a case study is presented to demonstrate that SAG-LAAVN can provide ubiquitous, high-quality services that meet the evolving needs of the low-altitude economy.
Fluorinated liquid crystal monomers (FLCMs) have been identified as emerging organic pollutants because of their persistence, bioaccumulation potential, and toxicity. They have been observed in various environmental matrices and have attracted significant public concern. However, research on the development of functional materials and reliable methods for the highly efficient extraction and sensitive determination of FLCMs for assessing the risk levels in soil remains limited. Herein, two types of pentadecafluorooctanoyl (PF)-functionalized hyper-crosslinked polymers (HCPs), namely HCPPF-TPB and HCPPF-TPC, were synthesized by a facile and cost-effective Friedel-Crafts reaction. HCPPF-TPB demonstrated superior extraction performance and was selected to prepare fiber coating for the efficient solid-phase microextraction (SPME) of FLCMs. In addition, the underlying adsorption mechanism was systematically revealed through experiments and density functional theory (DFT) calculations. Under optimal SPME conditions, HCPPF-TPB coated SPME fiber combined with gas chromatography-mass spectrometry (GC-MS) method was proposed for sensitive detection of nine FLCMs in soil, affording high enrichment factors (1091-1760), wide linear range (0.05-100 μg kg-1), and low detection limits (0.010-0.028 μg kg-1). This work provides a simple strategy for the synthesis of perfluoroalkyl-functionalized HCPs and offers a reliable method for the efficient extraction and sensitive quantification of FLCMs in complex environmental matrices, thus promoting the resolution of FLCMs critical problems in the environment.
Understanding how plants adjust to salinity is essential for the sustainable management of arid ecosystems. This study aims to examine the anatomical, ionic, physiological, and biochemical responses of Tamarix aphylla across various desert habitats. T. aphylla demonstrates adaptive strategies to survive under hyper-saline conditions. Three habitats were chosen: sand dunes, sandy plains, and saline areas. Five locations per habitat were sampled using 10 × 10 m quadrats, and soil and mature plants were collected for analysis. The findings showed that under saline circumstances, vascular bundle area (2170.97 μm²), cortical thickness (610.03 μm), and sclerenchyma thickness (120.39 μm) all attained their maximum values (p < 0.05). Ionic contents showed increased accumulation of Na⁺ (38.93 mg g⁻¹ DW), Cl⁻ (33.15 mg g⁻¹ DW), K⁺ (8.66 mg g⁻¹ DW), and Ca²⁺ (1.74 mg g⁻¹ DW) in plant roots under saline conditions. Physiological traits decreased in saline environments, with lower amounts of carotenoids (0.039 mg g⁻¹ FW), chlorophyll a (0.842 mg g⁻¹ FW), and chlorophyll b (0.312 mg g⁻¹ FW). However, contents of proline (396.12 µg g⁻¹ FW), total soluble sugars (32.62 mg g⁻¹ DW), and total soluble proteins (1946.4 µg g⁻¹ FW), as well as phenolics (9.56 µg g⁻¹ FW) and flavonoids (3.5 mg g⁻¹ DW), showed increased under saline conditions. Strong significant correlations (r > 0.9) between root ionic concentrations and important metabolic characteristics were also shown by Mantel test analysis. Overall results suggested that T. aphylla demonstrates a comprehensive adaptation strategy that includes biochemical defense, ionic homeostasis, and structural strengthening, allowing it to survive and thrive in extremely salty environments.
Genuine accumulation of metals/metalloids in bryophytes is limited and highly susceptible to surficial contamination with soil particles. Washing with an apolar solvent removes most surficial contamination prior to elemental analysis. Bryophytes are often the first colonisers of soils toxic from metals/metalloids derived from natural mineralisation or mining wastes. They are ostensibly highly tolerant to the prevailing high concentrations of metals and metalloids in the substrate, but little is known about their ability to (hyper)accumulate these metals/metalloids. Terrestrially growing bryophytes were collected from arsenic-thallium mineralised soils at the Allchar site in North Macedonia. Samples were analysed for elemental concentrations using monochromatic X-ray fluorescence analysis (MXRF) after stringent washing with an apolar solvent and subjected to synchrotron micro-X-ray fluorescence (µXRF) elemental imaging. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) were additionally used to assess extraneous contamination and test the efficiency of the washing procedure. The results show that surficial contamination with soil particles is a major challenge for assessing metal and metalloid concentrations in (terrestrial) bryophytes from metalliferous soils. Washing with an apolar solvent (hexane) removes most surficial contamination prior to elemental analysis, indicating some potential for elemental accumulation, as found in Rhynchostegium megapolitanum for thallium. Genuine accumulation of arsenic and thallium is relatively low despite the ability to grow on extremely arsenic-thallium enriched soils. Measured elemental concentrations in bryophyte samples are strongly affected by the washing procedure, highlighting the importance of appropiate sample preparation.
In arid and hyper-arid regions, agriculture depends heavily on irrigation, making crop type monitoring important for water allocation, monitoring crop management policies, and providing the information required to forecast food supply. However, field labels are often scarce, and crop calendars can shift due to locally managed planting, harvest, and irrigation decisions, complicating mapping at field-scale. We present a seasonal crop type mapping approach applied to Wadi Al-Dawasir, Saudi Arabia, generating maps for 2020-2024 from biweekly optical and radar satellite time series. The method learns representations from unlabeled imagery through self-supervised pretraining and fine-tunes a segmentation model using a small set of field observations with pseudo-label augmentation from unsupervised clustering. We mapped four classes: fallow, cereal, vegetables, and forage, and evaluated performance using overall accuracy, F1-score, and mean intersection-over-union (mIoU). The configuration combining self-supervised pretraining, pseudo-label augmentation, and optical-radar inputs achieved an mIoU of 0.80, an F1-score of 0.88, and an overall accuracy of 0.97. In contrast, using optical information alone substantially reduced accuracy, with an mIoU of 0.35, an F1-score of 0.32, and an overall accuracy of 0.64. Fallow and forage produced the highest mapping accuracies, with mIoU values of 0.97 and 0.85, respectively, while vegetables had the lowest accuracy among the four crop groups, with an mIoU of 0.52. These results show that self-supervised temporal pretraining combined with pseudo-label augmentation can support efficient multi-season, field-scale crop mapping using limited labels in irrigation-driven arid regions. The lower accuracy for vegetables highlights the continued challenge of mapping heterogeneous crop groups with overlapping phenological patterns.
 Hyper-IgE Syndrome (HIES) is a rare immunodeficiency predisposing patients to infections, inflammation, and occasional neoplasia. We report a 17-year-old boy with HIES who presented with severe right thigh pain. FDG-PET/CT demonstrated a right adrenal mass (SUVmax=5.4), multiple pulmonary nodules, and a lytic-sclerotic femoral lesion (SUVmax=4.6), initially suggesting disseminated malignancy. Biopsy confirmed acute osteomyelitis and a benign spindle cell tumor of the adrenal gland. Two months later, persistent fever and elevated ESR prompted re-evaluation, revealing intense FDG uptake in the thoracic aorta (SUVmax=20.5) consistent with large vessel vasculitis, later confirmed by angiography. The combination of infection, benign tumor, and vasculitis illustrates the broad FDG uptake spectrum in HIES and the risk of misdiagnosis as malignancy. Integration of clinical, imaging, and histopathologic data was critical for accurate diagnosis. This case highlights FDG-PET/CT's value in detecting inflammatory vascular disease and monitoring therapy, while reinforcing the importance of biopsy for definitive diagnosis. In immunodeficient patients, a multimodal diagnostic approach is essential to distinguish between malignant and benign FDG-avid lesions.
The oxygen reduction reaction (ORR) remains a pivotal process in sustainable energy conversion and electrochemical synthesis. However, the development of efficient and cost-effective metal-free catalysts remains a challenge. In the last few years, it has become clear that polymers are a promising option. However, relatively easy-to-synthesize porous materials, such as non-metalated, non-pyrolyzed hyper-crosslinked polymers (HCPs), remain unexplored for the ORR. Here, we have focused on the ORR performance of HCPs synthesized by solvent knitting of triphenylamine (TPA) and triphenylbenzene (TPB) using different catalysts: FeCl3 (Fe-TPBA) and AlCl3 (Al-TPBA). Both polymers exhibit a hierarchical pore structure, with the latter showing a predominant contribution from micropores. HCP particles were immobilized in a Nafion® film deposited on the electrode surface, and their electrocatalytic activity towards the ORR was evaluated in both acidic and alkaline electrolytes. Both HCPs exhibit a catalytic effect and promote the 2-electron ORR. It was found that oxygen is preconcentrated in the catalyst film, contributing to the increase in its flux as compared to the bulk electrolyte, thereby increasing the ORR current. Three-phase junctions (electrode|nonconductive polymeric catalyst|ionomer filled with aqueous electrolyte) are suggested as the reaction site. DFT quantum chemical calculations indicate a weak interaction between HCPs' molecular motifs and O2, making it a suitable O2 flux promoter. Moreover, the calculations indicate that the presence of nitrogen-containing TPA units enhances the oxygen reduction rate as compared to TPB. This study paves the way for exploration of other non-metalated HCPs prepared from a wide array of precursors for ORR electrocatalysis.
The cytoplasm is a crowded and dynamic fluid within which cellular building blocks such as mRNA, proteins, or organelles undergo transport and mixing. Although small things like proteins can eventually mix through diffusion, the high viscosity of cytoplasm means that it should be difficult to obtain significant mixing for structures in the size range of mRNA, multi-protein complexes or organelles. In large amoeboid cells, the cytoplasm undergoes active streaming coupled to cell motility, but this streaming is laminar flow which should not be effective for mixing. In this work we used a combination of live cell tracking of injected beads and computational analysis of motion and mixing in giant amoeba Chaos carolinensis with the initial goal of testing the possibility that large-scale cellular deformations during pseudopod formation might implement chaotic mixing by a Baker-transform like process. Instead, we found that Chaos carolinensis accelerates cytoplasmic mixing using a novel cytoplasmic gel state capture and release strategy. While it was previously thought that the amoeba sol to gel state transitions only occur at the trailing and leading edge of the cell body, our work indicates that these transitions occur frequently throughout the mid-cell region, driving the cytoplasmic mixing of beads and organelles. These results indicate that amoeba achieves nearly complete mixing between 1 and 2 cytoplasmic stream/flow cycle, effectively approximating the Bernoulli mixing regime and thus representing one of the theoretically fastest possible mixers.
Transcriptional reprogramming under genotoxic stress is essential for the survival and pathogenesis of Candida albicans. While many DNA damage response (DDR) genes are well-characterized, the functions of pathogen-specific, stress-inducible genes remain poorly understood. Here, we characterized GEI1 (Orf19.3109), a gene significantly induced by genotoxic agents and oxidative stress, which lacks a clear ortholog in Saccharomyces cerevisiae. Interestingly, although GEI1 expression is triggered by DNA damage stress, its deletion does not impair genotoxin tolerance. Instead, the gei1Δ mutant shows increased resistance to oxidative stress, characterized by reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, loss of GEI1 leads to hyper-secretion of extracellular aspartyl proteases (Saps) and results in a hypervirulence phenotype in the Galleria mellonella infection model. Transcriptomic profiling and CRISPR-interference (CRISPRi) assays revealed that loss of GEI1 function triggers the hyperactivation of antioxidant defenses and protease secretion. We demonstrate that the hypervirulence of the gei1Δ mutant is primarily driven by the transcriptional derepression of SAP1, SAP3, SAP5 and the putative alcohol dehydrogenase ADH4. Repression of these downstream effectors in the gei1Δ background reduced protease secretion and restored virulence to wild-type levels. Overall, our findings uncouple transcriptional induction from conventional DNA repair functions and reveal a novel regulatory checkpoint where GEI1 links genotoxic stress signaling to the suppression of key pathogenic traits, highlighting a complex strategy by which C. albicans balances stress adaptation and virulence control.
Persistently elevated serum immunoglobulin M (IgM) is commonly interpreted as a marker of acute infection, autoimmune activity, or lymphoproliferation. Sustained IgM elevation may represent an underrecognized marker of underlying primary immunodeficiency disorders (PIDs), especially those associated with class-switch recombination defects or immune dysregulation. This article aims to highlight the diagnostic value of persistently elevated IgM levels in pediatric PIDs and to propose a practical clinical framework for the evaluation of children with unexplained IgM elevation. We performed a case-based narrative review of the literature on primary immunodeficiencies associated with elevated serum IgM, focusing on pathogenic mechanisms, clinical phenotypes, and diagnostic implications. The review was complemented by two pediatric cases from our practice in which persistent IgM elevation served as a clue to the diagnosis of distinct primary immunodeficiencies. Persistently increased IgM levels in PIDs may reflect impaired class-switch recombination, impaired germinal center maturation, or chronic immune activation. The two presented cases, ataxiatelangiectasia with a hyper-IgM phenotype and BENTA disease, illustrate how elevated IgM associated with frequent and severe infections, lymphoproliferation, growth impairment, or syndromic features may guide clinicians toward immunological and genetic evaluation. Persistent IgM elevation should be interpreted in its clinical context and should not be dismissed as a nonspecific laboratory abnormality. A structured diagnostic approach may help distinguish secondary causes, classic hyper-IgM syndromes, and hyper-IgM phenotypes. Persistently elevated serum IgM should not be dismissed as a transient abnormality in children with recurrent infections or immune dysregulation. When interpreted in its clinical context, it may serve as a practical indicator for further immunological investigation and diagnosis of PIDs.