Structural Basis for Gating and Activation of RyR1.

The type-1 ryanodine receptor (RyR1) is an intracellular calcium (Ca(2+)) release channel required for skeletal muscle contraction. Here, we present cryo-EM reconstructions of RyR1 in multiple functional states revealing the structural basis of channel gating and ligand-dependent activation. Binding sites for the channel activators Ca(2+), ATP, and caffeine were identified at interdomain interfaces of the C-terminal domain. Either ATP or Ca(2+) alone induces conformational changes in the cytoplasmic assembly ("priming"), without pore dilation. In contrast, in the presence of all three activating ligands, high-resolution reconstructions of open and closed states of RyR1 were obtained from the same sample, enabling analyses of conformational changes associated with gating. Gating involves global conformational changes in the cytosolic assembly accompanied by local changes in the transmembrane domain, which include bending of the S6 transmembrane segment and consequent pore dilation, displacement, and deformation of the S4-S5 linker and conformational changes in the pseudo-voltage-sensor domain.

Structural insights into the regulation of RyR1 by S100A1.

S100A1, a small homodimeric EF-hand Ca2+-binding protein (~21 kDa), plays an important regulatory role in Ca2+ signaling pathways involved in various biological functions including Ca2+ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca2+ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca2+. Ca2+-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca2+-binding, S100A1 undergoes a conformational change resulting in the exposure of the hydrophobic pocket known to serve as a major interaction site of S100A1. Through interactions of the hydrophobic pocket with RyR1, Ca2+-bound S100A1 intrudes deeper into the RyR1 structure beneath BSol than the apo-form and induces sideways motions of the C-terminal BSol region toward the adjacent RyR1 protomer resulting in tighter interprotomer contacts. Interestingly, the second hydrophobic pocket of the S100A1-dimer is largely exposed at the hydrophilic surface making it prone to interactions with the local environment, suggesting that S100A1 could be involved in forming larger heterocomplexes of RyRs with other protein partners. Since S100A1 interactions stabilizing BSol are implicated in the regulation of RyR-mediated Ca2+ release, the characterization of the S100A1 binding site conserved between RyR isoforms may provide the structural basis for the development of therapeutic strategies regarding treatments of RyR-related disorders.

Olfactory threat extinction in the piriform cortex: An age-dependent employment of NMDA receptor-dependent long-term depression.

Extinction of threat memory is a measure of behavioral flexibility. In the absence of additional reinforcement, the extinction of learned behaviors allows animals and humans to adapt to their changing environment. Extinction mechanisms and their therapeutic implications for maladaptive learning have been extensively studied. However, how aging affects extinction learning is much less understood. Using a rat model of olfactory threat extinction, we show that the extinction of olfactory threat memory is impaired in aged Sprague-Darley rats. Following extinction training, long-term depression (LTD) in the piriform cortex (PC) was inducible ex vivo in aged rats and was NMDA receptor (NMDAR)-independent. On the other hand, adult rats acquired successful olfactory threat extinction, and LTD was not inducible following extinction training. Neuronal cFos activation in the posterior PC correlated with learning and extinction performance in rats. NMDAR blockade either systemically or locally in the PC during extinction training prevented successful extinction in adult rats, following which NMDAR-dependent LTD became inducible ex vivo. This suggests that extinction learning employs NMDAR-dependent LTD mechanisms in the PC of adult rats, thus occluding further LTD induction ex vivo. The rescue of olfactory threat extinction in aged rats by D-cycloserine, a partial NMDAR agonist, suggests that the impairment in olfactory threat extinction of aged animals may relate to NMDAR hypofunctioning and a lack of NMDAR-dependent LTD. These findings are consistent with an age-related switch from NMDAR-dependent to NMDAR-independent LTD in the PC. Optimizing NMDAR function in sensory cortices may improve learning and flexible behavior in the aged population.

Dual-Ligand Europium-Organic Gels as a Highly Efficient Anodic Annihilation Electrochemiluminescence Emitter for Ultrasensitive Detection of MicroRNA.

In this study, a novel europium dual-ligand metal-organic gel (Eu-D-MOGs) with high-efficient anodic annihilation electrochemiluminescence (ECL) was synthesized as an ECL emitter to construct a biosensor for ultrasensitive detection of microRNA-221 (miR-221). Impressively, compared to the ECL signal of europium single-ligand metal-organic gels (Eu-S-MOGs), the ECL signal of Eu-D-MOGs was significantly improved since the two organic ligands could jointly replace the H2O and coordinate with Eu3+, which could remarkably reduce the nonradiative vibrational energy transfer caused by the coordination between H2O and Eu3+ with a high coordination demand. In addition, Eu-D-MOGs could be electrochemically oxidized to Eu-D-MOGs•+ at 1.45 V and reduced to Eu-D-MOGs•- at 0.65 V to achieve effective annihilation of ECL, which overcame the side reaction brought by the remaining emitters at negative potential. This benefited from the annihilation ECL performance of the central ion Eu3+ caused by its redox in the electrochemical process. Furthermore, the annihilation ECL signal of Eu3+ could be improved by sensitizing Eu3+ via the antenna effect. In addition, combined with the improved rolling circle amplification-assisted strand displacement amplification strategy (RCA-SDA), a sensitive biosensor was constructed for the sensitive detection of miR-221 with a low detection limit of 5.12 aM and could be successfully applied for the detection of miR-221 in the lysate of cancer cells. This strategy offered a unique approach to synthesizing metal-organic gels as ECL emitters without a coreactant for the construction of ECL biosensing platforms in biomarker detection and disease diagnosis.

Therapeutic potential and mechanisms of Rifaximin in ameliorating iron overload-induced ferroptosis and liver fibrosis in vivo and in vitro.

Liver fibrosis could progress to liver cirrhosis with several contributing factors, one being iron overload which triggers ferroptosis, a form of regulated cell death. Rifaximin, a non-absorbable antibiotic, has shown promise in mitigating fibrosis, primarily by modulating gut microbiota. This study investigated the effects and mechanisms of rifaximin on iron overload-related hepatic fibrosis and ferroptosis. In an iron overload-induced liver fibrosis model in mice and in ferric ammonium citrate (FAC)-stimulated primary hepatocytes, treatment with rifaximin showed significant therapeutic effects. Specifically, it ameliorated the processes of ferroptosis triggered by iron overload, reduced liver injury, and alleviated fibrosis. This was demonstrated by decreased iron accumulation in the liver, improved liver function, and reduced fibrotic area and collagen deposition. Rifaximin also modulated key proteins related to iron homeostasis and ferroptosis, including reduced expression of TFR1, a protein facilitating cellular iron uptake, and increased expression of Fpn and FTH, proteins involved in iron export and storage. In the context of oxidative stress, rifaximin treatment led to a decrease in lipid peroxidation, evidenced by reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and an increase in the reduced glutathione (GSH) and decrease in oxidized glutathione (GSSG). Notably, rifaximin's potential functions were associated with the TGF-ß pathway, evidenced by suppressed Tgfb1 protein levels and ratios of phosphorylated to total Smad2 and Smad3, whereas increased Smad7 phosphorylation. These findings indicate rifaximin's therapeutic potential in managing liver fibrosis by modulating the TGF-ß pathway and reducing iron overload-induced damage. Further research is required to confirm these results and explore their clinical implications.

Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio associated with 28-day all-cause mortality in septic patients with coronary artery disease: a retrospective analysis of MIMIC-IV database.

BACKGROUND: High Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), Platelet-to-Lymphocyte Ratio (PLR) were associated with worse prognosis of patients with sepsis. In-hospital mortality has been reported to be higher in patients with coronary artery disease (CAD) and sepsis than those with sepsis alone. However, the relationship between NLR, MLR, PLR and mortality in septic patients with coronary artery disease (CAD) remains unclear. The study aimed to explore the association between NLR, MLR, PLR and 28-day all-cause mortality in septic patients with CAD. METHODS: We performed an observational cohort study of septic patients with CAD from the Medical Information Mart for Intensive Care (MIMIC)-IV database between 2008 and 2019. The patients were categorized by three group (Q1: low levels, Q2: medium levels, Q3: high levels) based on tertiles of NLR, MLR, and PLR. The associations between NLR, MLR, PLR and 28-day all-cause mortality were examined using the Cox proportional hazards model. Subsequently, we applied receiver operating characteristic (ROC) analysis for predicting 28-day mortality in septic patients with CAD by combining NLR, MLR and PLR with the modified sequential organ failure assessment (mSOFA) scores. RESULTS: Overall 1,175 septic patients with CAD were included in the study. Observed all-cause mortality rates in 28 days were 27.1%. Multivariate Cox proportional hazards regression analysis results showed that 28-day all-cause mortality of septic patients with CAD was significantly related to rising NLR levels (adjusted hazard ratio [aHR]: 1.02; 95% confidence interval [CI]: 1.01-1.02; P < 0.001), MLR levels (aHR: 1.29; 95%CI: 1.18-1.41; P < 0.001), and PLR levels (aHR: 1.0007; 95%CI: 1.0004-1.0011; P < 0.001). Meanwhile, the higher levels (Q3) group of NLR, MLR, and PLR also had a higher risk of 28-day all-cause mortality than the lower (Q1) group. The area under the ROC curve of NLR, MLR, PLR, and mSOFA score were 0.630 (95%CI 0.595-0.665), 0.611 (95%CI 0.576-0.646), 0.601 (95%CI 0.567-0.636) and 0.718 (95%CI 0.689-0.748), respectively. Combining NLR, MLR, and PLR with mSOFA scores may improve ability of predicting 28-day mortality (AUC: 0.737, 95%CI 0.709-0.766). CONCLUSION: Higher levels of NLR, MLR and PLR were associated with 28-day all-cause mortality in septic patients with CAD. Further investigation will be needed to improve understanding of the pathophysiology of this relationship.

Aging differentially affects LTCC function in hippocampal CA1 and piriform cortex pyramidal neurons.

Aging is associated with cognitive decline and memory loss in humans. In rats, aging-associated neuronal excitability changes and impairments in learning have been extensively studied in the hippocampus. Here, we investigated the roles of L-type calcium channels (LTCCs) in the rat piriform cortex (PC), in comparison with those of the hippocampus. We employed spatial and olfactory tasks that involve the hippocampus and PC. LTCC blocker nimodipine administration impaired spontaneous location recognition in adult rats (6-9 months). However, the same blocker rescued the spatial learning deficiency in aged rats (19-23 months). In an odor-associative learning task, infusions of nimodipine into either the PC or dorsal CA1 impaired the ability of adult rats to learn a positive odor association. Again, in contrast, nimodipine rescued odor associative learning in aged rats. Aged CA1 neurons had higher somatic expression of LTCC Cav1.2 subunits, exhibited larger afterhyperpolarization (AHP) and lower excitability compared with adult neurons. In contrast, PC neurons from aged rats showed higher excitability and no difference in AHP. Cav1.2 expression was similar in adult and aged PC somata, but relatively higher in PSD95- puncta in aged dendrites. Our data suggest unique features of aging-associated changes in LTCCs in the PC and hippocampus.

Barriers to using eHealth/mHealth platforms and perceived beneficial eHealth/mHealth platform features among informal carers of persons living with dementia: a qualitative study.

BACKGROUND: New technologies have brought about a new age of technology-enabled aids that can equip informal carers with the relevant resources for better care. These include but are not limited to facilitating access to healthcare providers, knowledge of caring for persons living with dementia, and sources of support for carers' well-being. This qualitative study explores barriers to using eHealth/mHealth platforms and perceived beneficial eHealth/mHealth platform features among informal carers of persons living with dementia. METHODS: An exploratory qualitative study design was employed. Semi-structured interviews were conducted among 29 informal carers of persons living with dementia in Singapore recruited via convenience and snowball sampling. The interviews were audio-recorded and transcribed verbatim. Thematic analysis was used to analyse the data. RESULTS: The participants in this study identified several barriers to using eHealth/mHealth platforms, including personal preference, apprehension, poor user experience and lack of skills. On the other hand, knowledge of dementia, caring for persons living with dementia and self-care, a list of resources, social support, location monitoring and alert systems, and the ability to manage appointments and transactions were valuable features for eHealth/mHealth platforms. CONCLUSIONS: Despite the underutilisation of eHealth/mHealth platforms, carers expressed a keen interest in using them if they are functional and capable of reducing their care burden. The findings from this study can contribute to developing content and features for eHealth/mHealth interventions aimed at lightening carers' burden in their day-to-day caring routine.

Improved diagnostic yield of peripheral pulmonary malignant lesions with emphysema using a combination of radial endobronchial ultrasonography and rapid on-site evaluation.

BACKGROUND: This is a retrospective cohort study from a single center of Chest Medical District of Nanjing Brain Hospital Affiliated to Nanjing Medical University, Jiangsu Province, China. It was aim to evaluate the diagnostic value of radial endobronchial ultrasound (R-EBUS) combination with rapid on-site evaluation (ROSE) guided transbronchial lung biopsy (TBLB) for peripheral pulmonary lesions in patients with emphysema. METHODS: All 170 patients who underwent PPLs with emphysema received an R-EBUS examination with or without the ROSE procedure, and the diagnostic yield, safety, and possible factors influencing diagnosis were analyzed between the two groups by the SPSS 25.0 software. RESULTS: The pooled and benign diagnostic yields were not different in the two groups (P = 0.224, 0.924), but the diagnostic yield of malignant PPLs was significantly higher in the group with ROSE than the group without ROSE (P = 0.042). The sensitivity of ROSE was 79.10%, the specificity, 91.67%, the positive predictive value, 98.15%, and the negative predictive value, 84.62%. The diagnostic accuracy, was 95.52%. In the group of R-EBUS + ROSE, the procedural time and the number of times of biopsy or brushing were both significantly reduced (all P<0.05). The incidence of pneumothorax (1.20%) and bleeding (10.84%) in the group of R-EBUS + ROSE were also less than those in the group of R-EBUS (P<0.05). The lesion's diameter ≥ 2 cm, the distance between the pleura and the lesion ≥ 2 cm, the positive air bronchograms sign, the location of the ultrasound probe within the lesion, and the even echo with clear margin feature of lesion ultrasonic image, these factors are possibly relevant to a higher diagnostic yield. The diagnostic yield of PPLs those were adjacent to emphysema were lower than those PPLs which were away from emphysema (P = 0.048) in the group without ROSE, however, in the group of R-EBUS + ROSE, there was no such difference whether the lesion is adjacent to emphysema or not (P = 0.236). CONCLUSION: Our study found that the combination of R-EBUS and ROSE during bronchoscopy procedure was a safe and effective modality to improve diagnostic yield of PPLs with emphysema, especially for malignant PPLs. The distance between the pleura and the lesion ≥ 2 cm, the positive air bronchograms sign, the location of the ultrasound probe within the lesion, and the even echo with clear margin feature of lesion ultrasonic image, these factors possibly indicated a higher diagnostic yield. Those lesions' position is adjacent to emphysema may reduce diagnostic yield but ROSE may make up for this deficiency.

A Survey of Deep Learning Road Extraction Algorithms Using High-Resolution Remote Sensing Images.

Roads are the fundamental elements of transportation, connecting cities and rural areas, as well as people's lives and work. They play a significant role in various areas such as map updates, economic development, tourism, and disaster management. The automatic extraction of road features from high-resolution remote sensing images has always been a hot and challenging topic in the field of remote sensing, and deep learning network models are widely used to extract roads from remote sensing images in recent years. In light of this, this paper systematically reviews and summarizes the deep-learning-based techniques for automatic road extraction from high-resolution remote sensing images. It reviews the application of deep learning network models in road extraction tasks and classifies these models into fully supervised learning, semi-supervised learning, and weakly supervised learning based on their use of labels. Finally, a summary and outlook of the current development of deep learning techniques in road extraction are provided.

Direct Position Determination of Non-Gaussian Sources for Multiple Nested Arrays: Discrete Fourier Transform and Taylor Compensation Algorithm.

This paper delves into the problem of direct position determination (DPD) for non-Gaussian sources. Existing DPD algorithms are hindered by their high computational complexity from exhaustive grid searches and a disregard for the received signal characteristics by multiple nested arrays (MNAs). To address these issues, the paper proposes a novel DPD algorithm for non-Gaussian sources with MNAs: the Discrete Fourier Transform (DFT) and Taylor compensation algorithm. Initially, the fourth-order cumulant matrix of the received signal is computed, and the vectorizing method is applied. Subsequently, a computationally efficient DPD cost function is proposed by leveraging a normalized DFT matrix to reduce complexity. Finally, first-order Taylor compensation is utilized to enhance the accuracy of the localization results. The superiority of the proposed algorithm is demonstrated through numerical simulation results.

A micropeptide TREMP encoded by lincR-PPP2R5C promotes Th2 cell differentiation by interacting with PYCR1 in allergic airway inflammation.

BACKGROUND: Allergic asthma is largely dominated by Th2 lymphocytes. Micropeptides in Th2 cells and asthma remain unmasked. Here, we aimed to demonstrate a micropeptide, T-cell regulatory micropeptide (TREMP), in Th2 cell differentiation in asthma. METHODS: TREMP translated from lincR-PPP2R5C was validated using Western blotting and mass spectrometry. TREMP knockout mice were generated using CRISPR/Cas9. Coimmunoprecipitation revealed that TREMP targeted pyrroline-5-carboxylate reductase 1 (PYCR1), which was further explored in vitro and in vivo. The levels of TREMP and PYCR1 in Th2 cells from clinical samples were determined by flow cytometry. RESULTS: TREMP, encoded by lincR-PPP2R5C, was in the mitochondrion. The lentivirus encoding TREMP promoted Th2 cell differentiation. In contrast, Th2 differentiation was suppressed in TREMP-/- CD4+ T cells. In the HDM-induced model of allergic airway inflammation, TREMP was increased in pulmonary tissues. Allergic airway inflammation was relieved in TREMP-/- mice treated with HDM. Mechanistically, TREMP interacted with PYCR1, which regulated Th2 differentiation via glycolysis. Glycolysis was decreased in Th2 cells from TREMP-/- mice and PYCR1-/- mice. Similar to TREMP-/- mice, allergic airway inflammation was mitigated in HDM-challenged PYCR1-/- mice. Moreover, we measured TREMP and PYCR1 in asthma patients. And we found that, compared with those in healthy controls, the levels of TREMP and PYCR1 in Th2 cells were significantly increased in asthmatic patients. CONCLUSIONS: The micropeptide TREMP encoded by lincR-PPP2R5C promoted Th2 differentiation in allergic airway inflammation by interacting with PYCR1 and enhancing glycolysis. Our findings highlight the importance of neglected micropeptides from noncoding RNAs in allergic diseases.

Distributed Identity Authentication with Lenstra-Lenstra-Lovász Algorithm-Ciphertext Policy Attribute-Based Encryption from Lattices: An Efficient Approach Based on Ring Learning with Errors Problem.

In recent years, research on attribute-based encryption (ABE) has expanded into the quantum domain. Because a traditional single authority can cause the potential single point of failure, an improved lattice-based quantum-resistant identity authentication and policy attribute encryption scheme is proposed, in which the generation of random values is optimized by adjusting parameters in the Gaussian sampling algorithm to improve overall performance. Additionally, in the key generation phase, attributes are processed according to their shared nature, which reduces the computational overhead of the authorization authority. In the decryption phase, the basis transformation of the Lenstra-Lenstra-Lovász (LLL) lattice reduction algorithm is utilized to rapidly convert shared matrices into the shortest vector form, which can reduce the computational cost of linear space checks. The experimental results demonstrate that the proposed method not only improves efficiency but also enhances security compared with related schemes.

The 'a, b, c's of pretangle tau and their relation to aging and the risk of Alzheimer's Disease.

Braak has described the beginnings of Alzheimer's Disease as occurring in the locus coeruleus. Here we review these pretangle stages and relate their expression to recently described normal features of tau biology. We suggest pretangle tau depends on characteristics of locus coeruleus operation that promote tau condensates. We examine the timeline of pretangle and tangle appearance in locus coeruleus. We find catastrophic loss of locus coeruleus neurons is a late event. The strong relationship between locus coeruleus neuron number and human cognition underscores the utility of a focus on locus coeruleus. Promoting locus coeruleus health will benefit normal aging as well as aid in the prevention of dementia. Two animal models offering experimental approaches to understanding the functional change initiated by pretangles in locus coeruleus neurons are discussed.

Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation.

Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause several diseases called laminopathies, the most common of which is dilated cardiomyopathy with muscular dystrophy. The role of Ca2+ regulation in these diseases remain poorly understood. We now show biochemical remodeling of the ryanodine receptor (RyR)/intracellular Ca2+ release channel in heart samples from human subjects with LMNA mutations, including protein kinase A-catalyzed phosphorylation, oxidation and depletion of the stabilizing subunit calstabin. In the LmnaH222P/H222P murine model of Emery-Dreifuss muscular dystrophy caused by LMNA mutation, we demonstrate an age-dependent biochemical remodeling of RyR2 in the heart and RyR1 in skeletal muscle. This RyR remodeling is associated with heart and skeletal muscle dysfunction. Defective heart and muscle function are ameliorated by treatment with a novel Rycal small molecule drug (S107) that fixes 'leaky' RyRs. SMAD3 phosphorylation is increased in hearts and diaphragms of LmnaH222P/H222P mice, which enhances NADPH oxidase binding to RyR channels, contributing to their oxidation. There is also increased generalized protein oxidation, increased calcium/calmodulin-dependent protein kinase II-catalyzed phosphorylation of RyRs and increased protein kinase A activity in these tissues. Our data show that RyR remodeling plays a role in cardiomyopathy and skeletal muscle dysfunction caused by LMNA mutation and identify these Ca2+ channels as a potential therapeutic target.

Fine particulate matter (PM2.5) induces inhibitory memory alveolar macrophages through the AhR/IL-33 pathway.

Fine particulate matter (PM2.5) concentrations have decreased in the past decade. The adverse effects of acute PM2.5 exposure on respiratory diseases have been well recognized. To explore the long-term effects of PM2.5 exposure on chronic obstructive pulmonary disease (COPD), mice were exposed to PM2.5 for 7 days and rest for 21 days, followed by challenges with lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). Unexpectedly, PM2.5 exposure and rest alleviated the disease severity and airway inflammatory responses in COPD-like mice. Although acute PM2.5 exposure increased airway inflammation, rest for 21 days reversed the airway inflammatory responses, which was associated with the induction of inhibitory memory alveolar macrophages (AMs). Similarly, polycyclic aromatic hydrocarbons (PAHs) in PM2.5 exposure and rest decreased pulmonary inflammation, accompanied by inhibitory memory AMs. Once AMs were depleted, pulmonary inflammation was aggravated. PAHs in PM2.5 promoted the secretion of IL-33 from airway epithelial cells via the aryl hydrocarbon receptor (AhR)/ARNT pathway. High-throughput mRNA sequencing revealed that PM2.5 exposure and rest drastically changed the mRNA profiles in AMs, which was largely rescued in IL-33-/- mice. Collectively, our results indicate that PM2.5 may mitigate pulmonary inflammation, which is mediated by inhibitory trained AMs via IL-33 production from epithelial cells through the AhR/ARNT pathway. We provide the rationale that PM2.5 plays complicated roles in respiratory disease.

Comprehensive analysis of the effects of magnetic field gradient on the performance of the SERF co-magnetometer.

The magnetic field gradient affects the improvement of sensitivity and magnetic field suppression ability of the spin-exchange relaxation-free co-magnetometer. This paper proposes a response model of a co-magnetometer considering magnetic field gradient based on state-space method. The effects of transverse and longitudinal magnetic field gradients on the system's scale factor, bandwidth and magnetic field response are analyzed. The analysis shows that transverse gradient affects the whole frequency band of system response, including steady-state and dynamic performance, while longitudinal gradient only affects steady-state response. With the increase of the gradient, the effect becomes more significant. The test results are in agreement with the theory, proving the accuracy of the theoretical analysis. The rotational sensitivity at 1 Hz decreases from 6.51 ×10-6 °/s/Hz1/2 to 5.05×10-5 °/s/Hz1/2 in the presence of a magnetic field gradient of -40 nT/cm, so the effect of the magnetic field gradient is critical. This work provides an accurate model for evaluating the effects of magnetic field gradients and provides a method for suppressing gradients using gradient coils, which are important for improving the sensitivity and accuracy of co-magnetometers.

CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis.

Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.

MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation.

Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). MyD88 controls the expression of several key modifier genes in liver tumorigenesis; however, whether and how MyD88 in myofibroblasts contributes to the development of fibrosis-associated liver cancer remains elusive. Here, we used an established hepatocarcinogenesis mouse model involving apparent liver fibrogenesis in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient (Fib-MyD88 KO) mice developed significantly fewer and smaller liver tumor nodules. MyD88 deficiency in myofibroblasts attenuated liver fibrosis and aerobic glycolysis in hepatocellular carcinoma tissues. Mechanistically, MyD88 signaling in myofibroblasts increased the secretion of CCL20, which promoted aerobic glycolysis in cancer cells. This process was dependent on the CCR6 receptor and ERK/PKM2 signaling. Furthermore, liver tumor growth was greatly relieved when the mice were treated with a CCR6 inhibitor. Our data revealed a critical role for MyD88 in myofibroblasts in the promotion of hepatocellular carcinoma by affecting aerobic glycolysis in cancer cells and might provide a potential molecular therapeutic target for HCC. © 2021 The Pathological Society of Great Britain and Ireland.

Bio-inspired synaptic behavior simulation in thin-film transistors based on molybdenum disulfide.

Synaptic behavior simulation in transistors based on MoS2 has been reported. MoS2 was utilized as the active layer to prepare ambipolar thin-film transistors. The excitatory postsynaptic current phenomenon was simulated, observing a gradual voltage decay following the removal of applied pulses, ultimately resulting in a response current slightly higher than the initial current. Subsequently, ±5 V voltages were separately applied for ten consecutive pulse voltage tests, revealing short-term potentiation and short-term depression behaviors. After 92 consecutive positive pulses, the device current transitioned from an initial value of 0.14 to 28.3 mA. Similarly, following 88 consecutive negative pulses, the device current changed, indicating long-term potentiation and long-term depression behaviors. We also employed a pair of continuous triangular wave pulses to evaluate paired-pulse facilitation behavior, observing that the response current of the second stimulus pulse was ∼1.2× greater than that of the first stimulus pulse. The advantages and prospects of using MoS2 as a material for thin-film transistors were thoroughly displayed.