A network of acetyl phosphate-dependent modification modulates c-di-AMP homeostasis in Actinobacteria.

Cyclic purine nucleotides are important signal transduction molecules across all domains of life. 3',5'-cyclic di-adenosine monophosphate (c-di-AMP) has roles in both prokaryotes and eukaryotes, while the signals that adjust intracellular c-di-AMP and the molecular machinery enabling a network-wide homeostatic response remain largely unknown. Here, we present evidence for an acetyl phosphate (AcP)-governed network responsible for c-di-AMP homeostasis through two distinct substrates, the diadenylate cyclase DNA integrity scanning protein (DisA) and its newly identified transcriptional repressor, DasR. Correspondingly, we found that AcP-induced acetylation exerts these regulatory actions by disrupting protein multimerization, thus impairing c-di-AMP synthesis via K66 acetylation of DisA. Conversely, the transcriptional inhibition of disA was relieved during DasR acetylation at K78. These findings establish a pivotal physiological role for AcP as a mediator to balance c-di-AMP homeostasis. Further studies revealed that acetylated DisA and DasR undergo conformational changes that play crucial roles in differentiation. Considering the broad distribution of AcP-induced acetylation in response to environmental stress, as well as the high conservation of the identified key sites, we propose that this unique regulation of c-di-AMP homeostasis may constitute a fundamental property of central circuits in Actinobacteria and thus the global control of cellular physiology.IMPORTANCESince the identification of c-di-AMP is required for bacterial growth and cellular physiology, a major challenge is the cell signals and stimuli that feed into the decision-making process of c-di-AMP concentration and how that information is integrated into the regulatory pathways. Using the bacterium Saccharopolyspora erythraea as a model, we established that AcP-dependent acetylation of the diadenylate cyclase DisA and its newly identified transcriptional repressor DasR is involved in coordinating environmental and intracellular signals, which are crucial for c-di-AMP homeostasis. Specifically, DisA acetylated at K66 directly inactivates its diadenylate cyclase activity, hence the production of c-di-AMP, whereas DasR acetylation at K78 leads to increased disA expression and c-di-AMP levels. Thus, AcP represents an essential molecular switch in c-di-AMP maintenance, responding to environmental changes and possibly hampering efficient development. Therefore, AcP-mediated posttranslational processes constitute a network beyond the usual and well-characterized synthetase/hydrolase governing c-di-AMP homeostasis.

GluR2 can Drive Neuroinflammation and Cognitive Impairments Following Peripherally Repeated Lipopolysaccharide Exposures.

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

A study on the physical aging characteristics of the older people over 70 years old in China.

Aim: In China, with the increase of life expectancy and the decrease of fertility rate, the aging problem has become increasingly prominent, and the physical problems of the older people over 70 years are the key and difficult problems. Method: Based on the interactive logic between the aging problem and the older people health, in the study, a questionnaire survey and a nationwide physical fitness test were carried out on the older people over 70, to divide into different age groups (70-74 years old, 75-79 years old, 80-84 years old, 85 years old and older) and different genders. There were 8,400 valid samples, and 1,050 persons in each group. One-way ANOVA was used to compare the differences among groups of different ages, and a broken line chart was drawn to discuss the aging characteristics of various physical indexes of the older people over 70 in China. Result: (1) Body morphology: male waist circumference, male waist-to-height ratio and female BMI showed a gradual downward trend with the increase of age; (2) Physiological function: male and female vital capacity showed a decreasing trend with the increase of age, while female pulse pressure showed a gradual upward trend. (3) Physical quality: the indicators of male and female muscle strength, flexibility quality, aerobic endurance and balance showed a downward trend with the increase of age. Conclusion: Vital capacity, flexibility quality, muscle strength, aerobic endurance, balance ability and so on, decreased significantly with the growth of age. 80 years old is the inflection point of the rapid decline of various indicators. Blood pressure, silent pulse, BMI, waist-to-hip ratio, waist-to-height ratio and other indicators did not change regularly with age. Indicators such as blood pressure, BMI, waist-to-hip ratio and waist-to-height ratio were in the high-risk range of metabolic diseases and cardiovascular and cerebrovascular diseases. The study conducted physical fitness test on the older people over 70 years old in 7 geographical regions of China, which is the first nationwide physical fitness test for the older people, which is an extension and expansion of the national physical fitness monitoring system, and also shows that the test indicators involved in the "Health fitness scale" are simple and feasible. And the study added a series of test data over 70 years old, which is the basis for scientific and reasonable formulation of physical fitness evaluation standards for the older people, and is of great significance for improving the national physical fitness database and grasping the dynamic changes of national physical health status, and providing data support for scientific guidance of physical exercise for the older people.

PM2.5 exposure inhibits osteoblast differentiation by increasing the ubiquitination and degradation of Smad4.

Increasing epidemiological evidence has shown that PM2.5 exposure is significantly associated with the occurrence of osteoporosis. It has been well demonstrated that PM2.5 exposure enhanced the differentiation and function of osteoclasts by indirectly causing chronic inflammation, while the mechanism in osteoblasts remains unclear. In our study, toxic effects were evaluated by direct exposure of 20-80 µg/ml PM2.5 to MC3T3-E1 cells and BMSCs. The results showed that PM2.5 exposure did not affect cell viability via proliferation and apoptosis, but significantly inhibited osteoblast differentiation in a dose-dependent manner. Osteogenic transcription factors Runx2 and Sp7 and other biomarkers Alp and Ocn decreased after PM2.5 exposure. RNA-seq revealed TGF-ß signaling was involved in PM2.5 exposure inhibited osteoblast differentiation, which led to P-Smad1/5 and P-Smad2 reduction in the nucleus by increasing the ubiquitination and degradation of Smad4. At last, the inflammation response increased in MC3T3-E1 cells with PM2.5 exposure. Moreover, the mRNA levels of Mmp9 increased in bone marrow-derived macrophage cells treated with the conditional medium collected from MC3T3-E1 cells exposed to PM2.5. Overall, these results indicated that PM2.5 exposure inhibits osteoblast differentiation and concurrently increases the maturation of osteoclasts. Our study provides in-depth mechanistic insights into the direct impact of PM2.5 exposure on osteoblast, which would indicate the unrecognized role of PM2.5 on osteoporosis.

Red cell distribution width to total serum calcium ratio and in-hospital mortality risk in patients with acute ischemic stroke: A MIMIC-IV retrospective analysis.

We investigated the relationship among red cell distribution width (RDW), to total serum calcium (TSC) ratio (RCR), and in-hospital mortality in patients with acute ischemic stroke (AIS). This study was a retrospective analysis. The data of 2700 AIS patients was retrospectively analyzed from the Medical Information Mart for Intensive Care database (version IV). The main outcome of interest was in-hospital mortality. A Cox proportional hazards regression model was used to determine whether RCR was independently associated with in-hospital mortality. The Kaplan-Meier method was used to plot the survival curves for RCR. Subgroup analyses were performed to measure the mortality across various subgroups. The area under curve (AUC) of receiver operating characteristic curve (ROC) was calculated to ascertain the quality of RCR as a predictor of in-hospital mortality in patients with AIS. In the multivariate analysis, statistically significant differences were identified in age, ethnicity, length of ICU stay, mechanical ventilation, sequential organ failure assessment (SOFA) score, RDW, hemoglobin, RCR, whether taking anticoagulants, hyperlipidemia, and atrial fibrillation (P < .05). A threshold inflection point value of 1.83 was obtained through a two-piecewise regression model. There was a non-linear relationship between RCR and hospital mortality in patients with AIS. The hazard ratio (HR) and the 95% confidence intervals (CI) on the right and left of the inflection point were 0.93 (0.57-1.51; P = .7660) and 2.96 (1.37-6.42; P = .0060), respectively. The Kaplan-Meier curve indicated that survival rates were higher when RCR was ≤ 1.83 and lower when RDW was > 1.83 after adjustment for age, gender, BMI, ethnicity. The area under curve (AUC) of RCR was 0.715. A higher RCR was associated with an increased risk of in-hospital mortality in patients with AIS.

A dynamic light scattering inversion method based on regularization matrix reconstruction for flowing aerosol measurement.

Tikhonov regularization, or truncated singular value decomposition (TSVD), is usually used for dynamic light scattering (DLS) inversion of particles in suspension. The Tikhonov regularization method uses a regularization matrix to modify all singular values in the kernel matrix. The modification of large singular values cannot effectively reduce the variance of the estimated values but may introduce bias in the solution, resulting in poor disturbance resistance in the inversion results. The TSVD method, on the other hand, truncates all small singular values, which leads to the loss of particle size information during the inversion process. The shortcomings of the two methods mentioned above do not have a significant impact on the inversion of high signal-to-noise ratio data. However, compared to the classical DLS particle size inversion for non-flowing suspended particles, the DLS inversion of flowing aerosols is more significantly affected by noise, and the extraction of particle size information is more difficult due to the effect of flow velocity, resulting in worse inversion results with increasing aerosol flow velocity for both methods. To improve the accuracy of the particle size distribution (PSD) of flowing aerosols, we introduced a kernel matrix into the regularization matrix, and based on the principles of the two methods, the spectral information of the kernel matrix was utilized to make the modification of small singular values by the regularization matrix. Correspondingly, weak or no modification was made according to the values of large singular values to reduce the introduction of bias. The inversion results of simulated and measured data indicate that the reconstruction of the regularization matrix improves the anti-disturbance performance and avoids the loss of particle size information during the regularization inversion process, thereby significantly improving the PSD accuracy, which is affected by the dual effects of flow velocity and noise in the DLS measurement of flowing particles. The peak error and distribution error of the inversion results by reconstructing the regularization matrix are lower than those of Tikhonov regularization.

Design and implementation of automated notification systems and an electronic whiteboard for radiation therapy planning monitoring.

PURPOSE: Radiotherapy (RT) treatment and treatment planning is a complex process prepared and delivered by a multidisciplinary team of specialists. Efficient communication and notification systems among different team members are therefore essential to ensure the safe, timely delivery of treatments to patients. METHOD: To address this issue, we developed and implemented automated notification systems and an electronic whiteboard to track every CT simulation, contouring task, the new-start schedule, and physician's appointments and tasks, and notify team members of overdue and missing tasks and appointments. The electronic whiteboard was developed to have a straightforward view of current patients' planning workflow and to help different team members coordinate with each other. The systems were implemented and have been used at our center to monitor the progress of treatment-planning tasks for over 2 years. RESULTS: The last-minute plans were relatively reduced by about 40% in 2023 compared to 2021 and 2022 with a p-value < 0.05. The overdue contouring tasks of more than 1 day decreased from 46.8% in 2019 and 33.6% in 2020 to 20%-26.4% in 2021-2023 with a p-value < 0.05 after the implementation of the notification system. The rate of plans with 1-3 day planning time decreased by 20.31%, 39.32%, and 24.08% with a p-value < 0.05 and the rate of plans with 1-3 day planning time due to the contouring task overdue more than 1 day decreased by 49.49%, 56.89%, and 46.52% with a p-value < 0.05 after the implementation. The rate of outstanding appointments that are overdue by more than 7 days decreased by more than 5% with a p-value < 0.05 following the implementation of the system. CONCLUSIONS: Our experience shows that this system requires minimal human intervention, improves the treatment planning workflow and process by reducing errors and delays in the treatment planning process, positively impacts on-time treatment plan completion, and reduces the need for compressed or rushed treatment planning timelines.

New anti-inflammatory limonoids from the fruits of Melia azedarach.

The phytochemical study of the fruits of Melia azedarach (Meliaceae) led to the isolation and characterisation of two novel natural limonoids1-deoxy- 3, 20-dicinnamoyl-11-methoxy-meliacarpinin (1) and 12ß- O- methyl nimbolinin A (2), along with twelve known limonoids. Its structure was identified by 1D- and 2D-NMR, HR-ESI-MS and comparison with published data. The anti-inflammatory effect of the compounds was measured in vitro in RAW 264.7 cells by evaluating the production of NO stimulated by LPS. Compounds 1, 8 and 14 indicated significant anti-inflammatory effect with inhibition rate of 11.76, 8.45 and 6.59 µM, respectively. Limonoid 1 significantly inhibited the production of NO, TNF-α and IL-1ß in RAW 264.7 cells. Therefore, limonoid derivative may be a promising source of bioactive metabolite for inflammatory diseases.

[High Resolution Emission Inventory of Greenhouse Gas and Its Characteristics in Guangdong，China].

Based on the typical city survey data and statistics of Guangdong Province， a 2018-based 3 km×3 km gridded greenhouse gas emissions inventory was developed for Guangdong Province using the combination of top-down and bottom-up emission factor methods. The inventory covered the CO2， CH4， and N2O emissions from energy， industrial processes， agriculture， land use change and forest， waste management， and indirect sources. The results showed that estimates for CO2， CH4， and N2O in Guangdong Province for the year 2018 were 8.5×108， 1.9×106， and 1.1×105 t， respectively， and 8.5×108， 4.0×107， and 3.4×107 t by equivalent carbon dioxide， totaling 9.2×108 t. CO2 was the main greenhouse gas in Guangdong Province， accounting for 92.0% of the total emissions. Energy and indirect sources were the main emission sources， accounting for 77.9% and 7.6%， respectively， totaling 85.5%. Spatial distributions illustrated that most grids were greenhouse gas emissions， whereas some others were greenhouse gas sinks； the greenhouse gas emissions were distributed mainly in the Pearl River Delta region and had certain characteristics of distribution along the road network and channels. The greenhouse gas grids of high emission were mainly the locations of high energy-consuming enterprises such as large power plants， steel mills， and cement plants.

Material and microbial perspectives on understanding the role of biochar in mitigating ammonia inhibition during anaerobic digestion.

With the increasing adoption of carbon-based strategies to enhance methanogenic processes, there is a growing concern regarding the correlation between biochar properties and its stimulating effects on anaerobic digestion (AD) under ammonia inhibition. This study delves into the relevant characteristics and potential mechanisms of biochar in the context of AD system under ammonia inhibition. The introduction of optimized biochar, distinguished by rich CO bond, abundant defect density, and high electronic capacity, resulted in a significant reduction in the lag period of anaerobic digestion system under 5.0 g/L ammonia stress, approximately by around 63 % compared to the control one. Biochar helps regulate the community structure, promotes the accumulation of acetate-consuming bacteria, in the AD system under ammonia inhibition. More examinations show that biochar promotes direct interspecies electron transfer in AD system under ammonia inhibition, as evidenced by diminished levels of bound electroactive extracellular polymeric substances, increased abundance of electroactive bacteria, and notably, the up-regulation of direct interspecies electron transfer associated genes, including the conductive pili and Cytochrome C genes, as revealed by meta-transcriptomic analysis. Additionally, gene expression related to proteins associated with ammonium detoxification were found to be up-regulated in systems supplemented with biochar. These findings provide essential evidence and insights for the selection and potential engineering of effective biochar to enhance AD performance under ammonia inhibition.

Five degrees-of-freedom mechanical arm with remote center of motion (RCM) device for volumetric optical coherence tomography (OCT) retinal imaging.

Handheld optical coherence tomography (HH-OCT) is gaining popularity for diagnosing retinal diseases in neonates (e.g. retinopathy of prematurity). Diagnosis accuracy is degraded by hand tremor and patient motion when using commercially available handheld retinal OCT probes. This work presents a low-cost arm designed to address ergonomic challenges of holding a commercial OCT probe and alleviating hand tremor. Experiments with a phantom eye show enhanced geometric uniformity and volumetric accuracy when obtaining OCT scans with our device compared to handheld imaging approaches. An in-vivo porcine volumetric image was also obtained with the mechanical arm demonstrating clinical deployability.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial.

BACKGROUND: Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. METHODS: This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. DISCUSSION: APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. TRIAL REGISTRATION: Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Liraglutide ameliorates delirium-like behaviors of aged mice undergoing cardiac surgery by mitigating microglia activation via promoting mitophagy.

OBJECTIVE: Postoperative delirium (POD) is a prevalent complication in cardiac surgery patients, particularly the elderly, with neuroinflammation posited as a crucial contributing factor. We investigated the prophylactic effects of liraglutide, a GLP-1 analog, on delirium-like behaviors in aged mice undergoing cardiac surgery and explored the underlying mechanisms focusing on neuroinflammation, mitochondrial dysfunction, and synaptic plasticity. METHODS: Using a cardiac ischemia-reperfusion animal model to mimic cardiac surgery, we assessed delirium-like behaviors, microglial activation, NLRP3 inflammasome activation, mitophagy, synaptic engulfment, and synaptic plasticity. RESULTS: Cardiac surgery triggered delirium-like behaviors, concomitant with heightened microglial and NLRP3 inflammasome activation and impaired mitochondrial function and synaptic plasticity. Pretreatment with liraglutide ameliorated these adverse outcomes. Mechanistically, liraglutide enhanced mitophagy, thereby inhibiting NLRP3 inflammasome activation and subsequent microglial activation. Furthermore, liraglutide counteracted surgery-induced synaptic loss and impairment of synaptic plasticity. CONCLUSION: Liraglutide exerts protective effects against delirium-like behaviors in aged mice post-cardiac surgery, potentially through bolstering microglia mitophagy, curtailing neuroinflammation, and preserving synaptic integrity. This highlights the potential of liraglutide as a promising perioperative strategy for delirium prevention in cardiac surgery patients.

Etiologies and clinical characteristics of acute ataxia in a single national children's medical center.

OBJECTIVE: To analyze etiologic factors of pediatric acute ataxia and to identify the severity of its underlying causes for urgent medical intervention. METHODS: Clinical data of children diagnosed with acute ataxia between December 2015 and December 2021 from one national medical center were analyzed retrospectively. RESULTS: A total of 99 children (59 boys, 40 girls), median age at disease onset 55 (range: 12-168) months, were enrolled. The median follow period was 46 (range 6-78) months. Eighty-six (86.9 %) children were diagnosed with immune-associated acute ataxia, among which acute post-infectious cerebellar ataxia (APCA) was the most common diagnosis (50.5 %), followed by demyelinating diseases of the central nervous system (18.2 %) and Guillain-Barré syndrome (9.1 %). On cerebrospinal fluid (CSF) examination, 35/73 (47.9 %) patients had pleocytosis (>5 cells/mm3), and 18/73 (24.7 %) had elevated protein levels. Thirty-one patients (31.3 %) had an abnormal cerebral MRI. Children with other immune-associated acute cerebellar ataxia had more extracerebellar symptoms, intracranial MRI lesions, abnormal CSF results, longer hospital stay, higher recurrence rates and incidence of neurological sequelae than children with APCA. CONCLUSION: Immune-associated acute ataxia is the main cause of pediatric acute ataxia, among which APCA is the most common phenotype. However, some immune-associated diseases, especially autoantibody-mediated disease, which has a higher recurrence rate and neurological sequelae account for an increasing proportion of pediatric acute ataxia. When children present with extracerebellar symptoms, abnormal cranial MRI or CSF results, and without prodromal infection, prudent differential diagnosis is recommended.

Structure and functional divergence of PIP peptide family revealed by functional studies on PIP1 and PIP2 in Arabidopsis thaliana.

PAMP-induced secreted peptide (PIP), one of the small post-translationally modified peptides (PTMPs), plays a crucial role in plant development and stress tolerance. However, little is known about functional divergence among this peptide family. Here, we studied the evolution of the PIP family in 23 plant species (10 monocotyledons and 13 dicotyledons from 7 families) and their functional divergence in Arabidopsis. A total of 128 putative PIP precursors were identified and classified into two subfamilies through phylogenetic analysis. Functional studies on AtPIP1 which represents Clade I family and AtPIP2 which represents Clade II family have shown that AtPIP2 displayed stronger immunity induction activity but weaker root growth inhibition than AtPIP1 in Arabidopsis. Transcriptome analysis of Arabidopsis seedlings treated with AtPIP1 and AtPIP2 showed that differential genes for both polypeptides were significantly enriched in similar plant defense pathways. However, Co-expression and Protein-protein interaction (PPI) analysis showed that the functions of AtprePIP2 co-expressed genes were more enriched in plant defense pathways than AtprePIP1. Molecular docking results show that AtPIP1 binds to RLK7 receptor with a more stable free energy and less binding area than AtPIP2, while hydrogen bond transfer occurs at the SGP motif position. The above results suggest that the PIP family have undergone functional divergence during evolution. Collectively, this work illustrates the relationship between PIP structure and function using Arabidopsis PIP as an example, and provides new insights into the current understanding between growth inhibition and immune responses which may be correlated but not fully coupled.

Comparison of efficacy between subcutaneous and intravenous application of moss-aGal in the mouse model of Fabry disease.

Fabry disease (FD, OMIM 301500) is a rare X-linked inherited lysosomal storage disorder associated with reduced activities of α-galactosidase A (aGal, EC 3.2.1.22). The current standard of care for FD is based on enzyme replacement therapy (ERT), in which a recombinantly produced version of αGal is intravenously (iv) applied to Fabry patients in biweekly intervals. Though the iv application is clinically efficacious, periodical infusions are inconvenient, time- and resource-consuming and they negatively impact the patients' quality of life. Subcutaneous (sc) injection, in contrast, is an established route of administration for treatment of chronic conditions. It opens the beneficial option of self-administration, thereby improving patients' quality of life and at the same time reducing treatment costs. We have previously shown that Moss-α-Galactosidase (moss-aGal), recombinantly produced in the moss Physcomitrium patens, is efficient in degrading accumulated Gb3 in target organs of murine model of FD and in the phase I clinical study, we obtained first efficacy evidence in human patients following single iv infusion. Here, we tested the efficacy of subcutaneous administration of moss-aGal and compared it with the results observed following iv infusion in Fabry mice. The obtained findings demonstrate that subcutaneously applied moss-aGal is correctly transported to target organs and efficacious in degrading Gb3 deposits there and thus suggest the possibility of using this route of administration for therapy of Fabry disease.

Coexistence of superconductivity and charge density wave instability in A15-Nb3Sn.

A15-type compound Nb3Sn has attracted much attention due to its relatively high critical temperature and critical field of superconductivity, making it a leading material for superconducting applications. In this study, we investigate the structural instability and superconductivity of Nb3Sn under hydrostatic pressure using first-principles calculations. We determine the electronic properties, phonon dispersion, electron-phonon coupling and the superconducting gap for Nb3Sn at pressures ranging from ambient to 9 GPa. Our results show that a significant electron density is present near the Fermi level due to the van Hove singularity, indicating the strong electron-phonon coupling. The phonon dispersion of Nb3Sn exhibits Kohn anomalies at three different wave vectors at a lower temperature. Moreover, above a pressure of 6 GPa, the charge density wave (CDW) instability disappeared, suggesting that pressure inhibits the CDW phase. The superconducting temperature is predicted to be TC = 18.62 K under ambient conditions, which is well consistent with the experimental results. We find that both the CDW and superconducting orders respond to pressure, with their transition temperatures decreasing as the pressure increases below 6 GPa. Above 6 GPa, the superconducting transition temperature increases slowly with pressure. Our results suggest that the instability in Nb3Sn is driven by the softening of the phonon modes due to the CDW caused by strong electron-phonon coupling. Therefore, the CDW phase and superconducting phase of Nb3Sn coexist at low pressure.

[Clinical characteristics and prognosis in 12 children with SARS-CoV-2 Omicron variant infection-associated acute necrotizing encephalopathy]. / 12ä¾‹æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“ç›¸å ³æ€¥æ€§åæ­»æ€§è„‘ç— å„¿ç«¥çš„ä¸´åºŠç‰¹ç‚¹åŠé¢„åŽåˆ†æž.

OBJECTIVES: To study the clinical characteristics and prognosis of SARS-CoV-2 Omicron variant infection-associated acute necrotizing encephalopathy (ANE) in children. METHODS: A retrospective analysis was conducted on the medical data of 12 children with SARS-CoV-2 Omicron variant infection-associated ANE who were admitted to the Pediatric Intensive Care Unit, Qingdao Women and Children's Hospital from December 18 to 29, 2022. The children were divided into two groups based on outcomes: death group (7 cases) and survival group (5 cases). The clinical manifestations and auxiliary examination results were compared between the two groups. RESULTS: The median age of the 12 patients was 30 months, with a male-to-female ratio of 1:1. All patients presented with persistent high fever, with a median highest body temperature of 41℃. The median time from fever onset to seizure or consciousness disturbance was 18 hours. The death group had a higher proportion of neurogenic shock, coagulation dysfunction, as well as elevated lactate, D-dimer, interleukin-6, interleukin--8, and interleukin-10 levels compared to the survival group (P<0.05). CONCLUSIONS: Children with SARS-CoV-2 Omicron variant infection-associated with ANE commonly present with persistent high fever, rapidly progressing disease, and have a high likelihood of developing consciousness disorders and multiorgan dysfunction within a short period. The occurrence of neurogenic shock, coagulation dysfunction, and significantly elevated cytokine levels suggests an increased risk of mortality.