Repetitive transcranial magnetic stimulation in Alzheimer's disease: effects on neural and synaptic rehabilitation.

Alzheimer's disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis. The Alzheimer's disease brain tends to be hyperexcitable and hypersynchronized, thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life, leaving patients incapacitated. Repetitive transcranial magnetic stimulation is a cost-effective, neuro-modulatory technique used for multiple neurological conditions. Over the past two decades, it has been widely used to predict cognitive decline; identify pathophysiological markers; promote neuroplasticity; and assess brain excitability, plasticity, and connectivity. It has also been applied to patients with dementia, because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult. However, its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies. This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment, evaluate its effects on synaptic plasticity, and identify the associated mechanisms. This review essentially focuses on changes in the pathology, amyloidogenesis, and clearance pathways, given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer's disease. Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription, which are closely related to the neural regeneration process, are also highlighted. Finally, we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation, with the aim to highlight future directions for better clinical translations.

C286, an orally available retinoic acid receptor ß agonist drug, regulates multiple pathways to achieve spinal cord injury repair.

Retinoic acid receptor ß2 (RARß2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARß agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARß specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARß specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARß2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions.

Mir-150-5p distinguishes acute pulmonary embolism, predicts the occurrence of pulmonary arterial hypertension, and regulates ox-LDL-induced endothelial cell injury.

BACKGROUND: Acute pulmonary embolism (APE) is a major type of venous thromboembolism (VTE) with a high risk of mortality and disability. There is a lack of biomarkers for APE to indicate deteriorating development and predict adverse outcomes. This study evaluated the significance of miR-150-5p in APE aiming to explore a novel potential biomarker for APE. METHODS: The study enrolled APE (n = 137) and deep wein thrombosis (DVT, n = 67) patients and collected plasma samples from all study subjects. The expression of miR-150-5p was analyzed by PCR and its significance in screening APE and pulmonary arterial hypertension (PAH) was assessed by receiver operating curve (ROC) and logistic analyses. The study established oxidized low-density lipoprotein (ox-LDL)-induced human venous endothelial cells (HUVECs). Through cell transfection combined with cell counting kit-8 (CCK8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), the effect of miR-150-5p on ox-LDL-induced HUVEC injury was evaluated. RESULTS: Significant downregulation of miR-150-5p was observed in the plasma of APE patients compared with DVT patients (P < 0.0001). The plasma miR-150-5p levels in APE patients occurred PAH was much lower than in patients without PAH (P < 0.0001). Reducing miR-150-5p distinguished APE patients from DVT patients (AUC = 0.912) and was identified as a risk factor for the occurrence of PAH in APE patients (OR = 0.385, P = 0.010). In HUVECs, oxidized low-density lipoprotein (ox-LDL) caused inhibited cell proliferation, enhanced apoptosis, increased pro-inflammatory cytokines, reactive oxygen species (ROS), malondialdehyde (MDA), and decreased superoxide dismutase (SOD). Overexpressing miR-150-5p could promote proliferation, inhibit apoptosis, and alleviate inflammation and oxidative stress of ox-LDL-treated HUVECs. CONCLUSIONS: Downregulated plasma miR-150-5p served as a diagnostic biomarker for APE and predicted the predisposition of PAH in APE patients. Overexpressing miR-150-5p could alleviate ox-LDL-induced endothelial cell injury in HUVECs.

A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon.

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.

Ectoin attenuates cortisone-induced skin issues by suppression GR signaling and the UVB-induced overexpression of 11ß-HSD1.

BACKGROUND: Accelerated pace of modern work and lifestyles subject individuals to various external and psychological stressors, which, in turn, can trigger additional stress through visible signs of fatigue, hair loss, and obesity. As the primary stress hormone affecting skin health, cortisol connects to the glucocorticoid receptor (GR) to aggravate skin issues induced by stress. This activation depends on the expression of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in skin cells, which locally converts cortisone-produced by the central and peripheral hypothalamic-pituitary-adrenal axis-into its active form. METHODS: Our study delves deeper into stress's adverse effects on the skin, including the disruption of keratinocyte structural proteins, the loss of basement membrane proteins, and the degradation of collagen. RESULTS: Remarkably, we discovered that Ectoin, an amino acid derivative obtained from halophilic bacteria, is capable of mitigating the inhibitory impacts of cortisone on the expression of cutaneous functional proteins, including involucrin, loricrin, laminin-5, and claudin-1. Moreover, Ectoin reduces the suppressive effect of stress on collagen and hyaluronic acid synthesis by impeding GR signal transduction. Additionally, Ectoin counterbalances the UVB-induced overexpression of 11ß-HSD1, thereby diminishing the concentration of endogenous glucocorticoids. CONCLUSION: Our findings illuminate the significant potential of Ectoin as a preventative agent against stress-induced skin maladies.

Identifying Root Origin of Insulating Polymer Mediated Solar Water Oxidation.

Rational construction of high-efficiency photoelectrodes with optimized carrier migration to the ideal active sites, is crucial for enhancing solar water oxidation. However, complexity in precisely modulating interface configuration and directional charge transfer pathways retards the design of robust and stable artificial photosystems. Herein, a straightforward yet effective strategy is developed for compact encapsulation of metal oxides (MOs) with an ultrathin non-conjugated polymer layer to modulate interfacial charge migration and separation. By periodically coating highly ordered TiO2 nanoarrays with oppositely charged polyelectrolyte of poly(dimethyl diallyl ammonium chloride) (PDDA), MOs/polymer composite photoanodes are readily fabricated under ambient conditions. It is verified that electrons photogenerated from the MOs substrate can be efficiently extracted by the ultrathin solid insulating PDDA layer, significantly boosting the carrier transport kinetics and enhancing charge separation of MOs, and thus triggering a remarkable enhancement in the solar water oxidation performance. The origins of the unexpected electron-withdrawing capability of such non-conjugated insulating polymer are unambiguously uncovered, and the scenario occurring at the interface of hybrid photoelectrodes is elucidated. The work would reinforce the fundamental understanding on the origins of generic charge transport capability of insulating polymer and benefit potential wide-spread utilization of insulating polymers as co-catalysts for solar energy conversion.

Non-invasive diagnosis of liver fibrosis via MRI using targeted gadolinium-based nanoparticles.

INTRODUCTION: Accurate diagnosis of liver fibrosis is crucial for preventing cirrhosis and liver tumors. Liver fibrosis is driven by activated hepatic stellate cells (HSCs) with elevated CD44 expression. We developed hyaluronic acid (HA)-coated gadolinium-based nanoprobes to specifically target CD44 for diagnosing liver fibrosis using T1-weighted magnetic resonance imaging (MRI). MATERIALS AND METHODS: NaGdF4 nanoparticles (NPs) were synthesized via thermal decomposition and modified with polyethylene glycol (PEG) to obtain non-targeting NaGdF4@PEG NPs. These were subsequently coated with HA to target HSCs, resulting in liver fibrosis-targeting NaGdF4@PEG@HA nanoprobes. Characterization includedd transmission electron microscopy and X-ray diffraction. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8). Internalization of NaGdF4@PEG@HA nanoprobes by mouse HSCs JS1 cells via ligand-receptor interaction was observed using flow cytometry and confocal laser scanning microscopy (CLSM). Liver fibrosis was induced in C57BL/6 mice using a methionine-choline deficient (MCD) diet. MRI performance and nanoprobe distribution in fibrotic and normal livers were analyzed using a GE Discovery 3.0T MR 750 scanner. RESULTS: NaGdF4@PEG@HA nanoprobes exhibited homogeneous morphology, low toxicity, and a high T1 relaxation rate (7.645 mM⁻¹s⁻¹). CLSM and flow cytometry demonstrated effective phagocytosis of NaGdF4@PEG@HA nanoprobes by JS1 cells compared to NaGdF4@PEG. MRI scans revealed higher T1 signals in fibrotic livers compared to normal livers after injection of NaGdF4@PEG@HA. NaGdF4@PEG@HA demonstrated higher targeting ability in fibrotic mice. CONCLUSIONS: NaGdF4@PEG@HA nanoprobes effectively target HSCs with high T1 relaxation rate, facilitating efficient MRI diagnosis of liver fibrosis.

Endoscopic retrosigmoid trans-petrosal fissure approach for vestibular schwannomas: case series.

The management of vestibular schwannoma (VS) remains one of the most formidable challenges in neurosurgery owing to the eloquent nature of surrounding anatomy. Although endoscopy-assisted microsurgery has recently gained momentum in cerebellopontine angle region surgery, the feasibility of pure endoscopic technique has been rarely reported. Here we present the operative technique and preliminary outcomes of fully endoscopic retrosigmoid trans-petrosal fissure approach (ER-TPFA) for VS surgery. Clinical data of 36 consecutive cases of VS treated with the ER-TPFA from March 2021 to March 2023 were analyzed. The patients were placed in a modified lateral park-bench position, with the Dandy incision and suboccipital craniotomy performed. With the endoscopic holder, endoscopic procedures were performed using standard two-hand microsurgical techniques by one surgeon. Arachnoidal dissection of the petrosal fissure was performed for identifying the brainstem end of facial nerve and separating the tumor from the cerebellum, without brain retraction seen in traditional microsurgical technique. The tumors had an averaged size of 3.0 cm in diameter. According to the Hannover classification, nearly all the tumors were grade III-IV (97.3%). Using ER-TPFA, 33 patients (91.7%) achieved gross total resection. Anatomic preservation of the facial nerve was achieved in 35 cases, with 33 patients (91.7%) retaining a House-Brackmann score of 1-2 postoperatively. Four out of ten patients still had serviceable hearing 6 months after operation. Postoperatively, there was no post-craniotomy hematoma, cerebellar edema, and new-onset cerebellar ataxia. With a better visualization of the cerebellopontine angle region, ER-TPFA may help preserve facial nerve function and maintain high gross total resection rate while minimizing complications. We believe this retractorless technique can be a safe and effective alternative for the management of VS with satisfactory clinical results.

Clinical characteristics and surgical strategy of sporadic cerebellar hemangioblastomas.

Hemangioblastoma is a rare benign vascular tumor that occurs mostly in the cerebellum. The aim of the present study was to analyze the clinical characteristics of sporadic cerebellar hemangioblastoma and its surgical strategy. A total of 76 cases of sporadic cerebellar hemangioblastoma (42 males and 34 females; age, 46.4±13.9 years; age range, 23-72 years) admitted to the Department of Neurosurgery of the General Hospital of Northern Theater Command (Shenyang, China) from July 2012 to April 2021 were retrospectively analyzed. All patients had only one isolated tumor and underwent surgical resection. Their basic characteristics, serial radiographic examinations, surgical records and follow-up were analyzed. A total of 57 patients with cystic hemangioblastoma and eight patients with cystic solid hemangioblastoma directly underwent resection treatment. Of 11 patients with solid hemangioblastoma, 8 underwent vascular embolization prior to surgical resection. Furthermore, 3 patients with solid hemangioblastoma who were not embolized prior to surgery had intraoperative hemorrhage and poor prognosis. In addition, 3 patients underwent partial resection of the tumor and all of them suffered recurrence after the surgery. A total of 71 patients achieved good neurologic improvement. However, 5 patients had a poor prognosis after the initial surgery. In conclusion, total microsurgical resection is essential to improve the health status of patients with sporadic cerebellar cystic hemangioblastoma. In addition, preoperative embolization of arteries supplying solid hemangioblastomas can reduce intraoperative bleeding and improve prognosis.

Protocol-Stipulated Dose Modification to Manage Chemotherapy-Induced Peripheral Neuropathy in Children, Adolescents, and Young Adults With High-Risk Hodgkin Lymphoma.

PURPOSE: Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for classic Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children's Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) with bleomycin containing doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC; standard arm) in patients with high-risk cHL ages 2-21 years. METHODS: AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by the presence of dose modification. RESULTS: Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 v 19.8%, P = .91). CIPN dose modifications occurred more frequently in the BV arm (9.5% v 2.8%, P = .001); however, most patients with CIPN on the BV arm received full-dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, although older age was significantly associated with the risk of VCR dose modifications for CIPN. CONCLUSION: A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331 minimized the effect of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV arm.

Novel insights into biofilm formation and the key differentially expressed genes in Yersinia enterocolitica from meat: Implications for food safety and disease prevention.

Yersinia enterocolitica is an important foodborne pathogen that can cause a zoonotic disease known as yersiniosis, which causes symptoms such as acute diarrhea, mesenteric adenitis, terminal ileum inflammation, pseudo appendicitis, sepsis, and other complications. The mechanism of biofilm formation in Y. enterocolitica remains poorly understood, with limited research available on this topic. This study systematically examined the distribution characteristics and biofilm formation ability of Y. enterocolitica isolated from poultry and livestock related samples. Analysis of food samples collected indicated significant presence of Y. enterocolitica (207/670, 30.9 %), particularly in frozen duck meat (7/11, 63.6 %). Majority of the isolated strains did not demonstrate biofilm-forming ability (52.7 %), while a notable percentage exhibited moderate (6.8 %) to strong (11.6 %) biofilm-forming ability. Additionally, a significant percentage of strains (16/207, 7.7 %) displayed extremely high optical density/cut-off OD (OD/ODC) ratios (the average OD value of each sample divided by the average OD value of the negative controls of each 96-well plate plus 3 standard deviations) (exceeding 10). Time-course analysis of biofilm formation in 10 isolates revealed three distinct patterns: (i) rapid increase from 6 h to 12 h, with gradual peak between 48 and 72 h followed by a slight decline and stabilization; (ii) little biofilm formation at 24 h with a gradual increase up to 96 h, maintaining this level until 120 h; and (iii) complete absence of biofilm formation throughout the experiment. Subsequent examination of differentially expressed genes (DEGs) in planktonic cells and biofilms of two strains with distinct biofilm formation capabilities identified seven metabolic pathways, including ribosome, photosynthesis, fatty acid degradation, valine, leucine, and isoleucine degradation, as well as pinene, camphor, and geraniol degradation. Significantly elevated expression levels of genes associated with flagellar assembly, bacterial chemotaxis, and quorum sensing (partially) were observed exclusively in planktonic cells of the selected strain with stronger biofilm-forming ability, implying that the heightened expression of flagellar assembly and bacterial chemotaxis-related genes is an important but not sole determinant of biofilm formation. The study contributes to the elucidation of the underlying mechanisms governing biofilm formation in Y. enterocolitica and may offer valuable insights for the advancement of novel food safety strategies.

Strategic engineering of cationic systems for spatial & temporal anti-counterfeiting applications in zero-dimensional Mn(II) halides.

While spatial and time-resolved anti-counterfeiting technologies have gained increasing attention owing to their excellent tunable photoluminescence, achieving high-security-level anti-counterfeiting remains a challenge. Herein, we developed a spatial-time-dual-resolved anti-counterfeiting system using zero-dimensional (0D) organic-inorganic Mn(II) metal halides: (EMMZ)2MnBr4 (named M-1, EMMZ=1-Ethyl-3-Methylimidazolium Bromide) and (EDMMZ)2MnBr4 (named M-2, EDMMZ=1-Ethyl-2,3-Dimethylimidazolium Bromide). M-1 shows a bright green emission with a quantum yield of 78 %. It undergoes a phase transformation from the crystalline to molten state with phosphorescence quenching at 350 K. Reversible phase and luminescent conversion was observed after cooling down for 15 s. Notably, M-2 exhibits green light emission similar to M-1 but undergoes phase conversion and phosphorescence quenching at 390 K, with reversible conversion observed after cooling down for 5 s. The photoluminescence switching mode of on(green)-off-on(green) can be achieved by temperature control, demonstrating excellent performance with short response times and ultra-high cyclic reversibility. By leveraging the different quenching temperatures and reversible PL conversion times of M-1 and M-2, we propose a spatial-time-dual-resolved photoluminescence (PL) switching system that combines M-1 and M-2. This system enables multi-fold tuning of the PL switch for encryption and decryption through cationic engineering strategies by modulating temperature and cooling time. This work presents a novel and feasible design strategy for advanced-level anti-counterfeiting technology based on a spatial-time-dual-resolved system.

Predictive value of CCTA-based pericoronary adipose tissue imaging for major adverse cardiovascular events.

RATIONALE AND OBJECTIVE: To evaluate the ability of the radiomic characteristics of pericoronary adipose tissue (PCAT) as determined by coronary computed tomography angiography (CCTA) to predict the likelihood of major adverse cardiovascular events (MACEs) within the next five years. MATERIALS AND METHODS: In this retrospective casecontrol study, the case group consisted of 210 patients with coronary artery disease (CAD) who developed MACEs within five years, and the control group consisted of 210 CAD patients without MACEs who were matched with the case group patients according to baseline characteristics. Both groups were divided into training and testing cohorts at an 8:2 ratio. After data standardization and the exclusion of features with Pearson correlation coefficients of |r| ≥ 0.9, independent logistic regression models were constructed using selected radiomics features of the proximal PCAT of the left anterior descending (LAD) artery, left circumflex (LCX) artery, and right coronary artery (RCA) via least absolute shrinkage and selection operator (LASSO) techniques. An integrated PCAT radiomics model including all three coronary arteries was also developed. Five models, including individual PCAT radiomics models for the LAD artery, LCX artery, and RCA; an integrated radiomics model; and a fat attenuation index (FAI) model, were assessed for diagnostic accuracy via receiver operating characteristic (ROC) curves, calibration curves, and decision curves. RESULTS: Compared with the FAI model (AUC=0.564 in training, 0.518 in testing), the integrated radiomics model demonstrated superior diagnostic performance (area under the curve [AUC]=0.923 in training, 0.871 in testing). The AUC values of the integrated model were greater than those of the individual coronary radiomics models, with all the models showing goodness of fit (P > 0.05). The decision curves indicated greater clinical utility of the radiomics models than the FAI model. CONCLUSION: PCAT radiomics models derived from CCTA data are highly valuable for predicting future MACE risk and significantly outperform the FAI model.

A nomogram to predict the risk of death during hospitalization in Chinese neonates with respiratory failure.

Background: Neonatal respiratory failure (NRF) is a critical condition with high morbidity and mortality rates. This study aimed to develop a nomogram prediction model to early predict the risk of death in Chinese neonates with NRF. Methods: A retrospective analysis was conducted on NRF neonates from 21 tertiary neonatal intensive care units (NICUs) across 13 prefecture-level cities in Jiangsu Province, China, from March 2019 to March 2022. NRF neonates from one random NICU were selected as the external validation set, while those from the remaining 20 NICUs were divided into the training set and the internal validation set at a 7:3 ratio. Death was the primary outcome. LASSO regression and multivariate logistic regression were used to identify the predictive factors from the training set and then the nomogram was constructed. Results: A total of 5387 neonates with NRF were included in the analysis. Among them, 3444 were in the training set, 1470 were in the internal validation set, and 473 were in the external validation set. The nomogram was constructed based on the eight predictors of the 1-min Apgar score, birth weight, gestational age, the relationship between birth weight and gestational age, mode of first respiratory support, inhaled nitric oxide, antenatal corticosteroids, and vasoactive drugs. The area under the curve of the nomogram in the training set, internal validation set, and external validation set was 0.763, 0.733, and 0.891, respectively. The P-values of the Hosmer-Lemeshow goodness of fit test were 0.638, 0.273, and 0.253, respectively. Brier scores were 0.066, 0.072, and 0.037, respectively. The decision curve analysis demonstrated a significant net benefit in all cases. These data indicate the good performance of the nomogram. Conclusions: This nomogram can serve as a reference for clinicians to identify high-risk neonates early and reduce the incidence of neonatal mortality.

Fabrication of edible nanocellulose chitosan bi-component film based on a novel "swell-permeate" approach.

The fabrication of multi-component film with colloidal particles could be inconvenient. A novel "swell-permeate" (SP) strategy was proposed to form homogeneous multi-component films. The SP strategy allows colloidal particles to fit into the polymer network by stretching the polymer chains assisted by water. We demonstrated the strategy by creating films with polysaccharide substrates as ß-cyclodextrin grafted chitosan (CS) with nanocellulose. The addition of nanocellulose significantly increased the mechanical properties and the barrier performance of the films. The size of nanocellulose particles in affecting mechanical properties was investigated by applying different length of cellulose nanocrystal (CNC), the longer of which, due to denser physical entanglements, showed a better increase to the film in the elastic modulus and tensile strength to 4.54-fold and 5.71-fold, respectively. The films were also loaded with ethyl-p-coumarate (EpCA) and had an enhanced performance in anti-microbial for Altenaria alternata, Salmonella typhi, and Escherichia coli. The anti-oxidative property was increased as well, and both effects were valid both in vitro and in ready-to-eat apples. The strategy provides a practical and convenient method for fabricating colloidal particle containing films, and the novel idea of "swell-permeate" is potentially regarded as a new solution to the challenge of ready-to-eat food quality maintenance.

Customized Corneal Cross-Linking with Microneedle-Mediated Riboflavin Delivery for Keratoconus Treatment.

In this study, a novel customized corneal cross-linking (CXL) treatment is explored that utilizes microneedles (MNs) for targeted riboflavin (RF) administration prior to the CXL procedure. Unlike the conventional "one-size-fits-all" approach, this protocol offers an option for more precise and efficacious treatment. To simulate a customized corneal crosslinking technique, four distinct microneedle (MN) molds designs, including circular, semi-circular, annular and butterfly shaped, are crafted for loading an optimized RF-hyaluronic acid solution and for the subsequent fabrication of MN arrays with varying morphologies. These MNs can gently puncture the corneal epithelium while preserving the integrity of the underlying stromal layer. Following the application of these microneedles, RF solution is replenished to enhance the RF content within the stroma through the punctures created by the MNs, resulting in exceptional customized corneal cross-linking effects that are comparable to the conventional epi-off CXL protocol. Additionally, it flattened the corneal curvature within the treated zone and facilitated rapid postoperative recovery of corneal tissue. These findings suggest that the integration of customized microneedle RF delivery with corneal crosslinking technology represents a potential novel treatment modality, holding promise for the tailored treatment of corneal pathologies, and offering a more precise and efficient alternative to traditional methods.

Applying causal inference and Bayesian statistics to understanding vaccine safety signals using a simulation study.

Community perception of vaccine safety influences vaccine uptake. Our objective was to assess current vaccine safety monitoring by examining factors that may influence the availability of post-vaccination survey data, and thereby the specificity and sensitivity of existing signal detection methods. We used causal directed acyclic graphs (DAGs) and a Bayesian posterior predictive analysis (PPA) signal detection method to understand biological and behavioural factors which may influence signal detection. The DAGs informed the data simulated for scenarios in which these factors were varied. The influence of biological factors such as severity of adverse reactions and behavioural factors such as healthcare-seeking behaviour upon survey participation was found to drive signal detection. Where there was a low prevalence of moderate to severe reactions, false signals were detected when there was a strong influence of reaction severity on both survey participation and seeking medical attention. These findings provide implications for future vaccine safety monitoring.

Prediction of clear cell renal cell carcinoma prognosis based on an immunogenomic landscape analysis.

Immune cell infiltration and tumor-related immune molecules play key roles in tumorigenesis and tumor progression. The influence of immune interactions on the molecular characteristics and prognosis of clear cell renal cell carcinoma (ccRCC) remains unclear. A machine learning algorithm was applied to the transcriptome data from The Cancer Genome Atlas database to determine the immunophenotypic and immunological characteristics of ccRCC patients. These algorithms included single-sample gene set enrichment analyses and cell type identification. Using bioinformatics techniques, we examined the prognostic potential and regulatory networks of immune-related genes (IRGs) involved in ccRCC immune interactions. Fifteen IRGs (CCL7, CHGA, CMA1, CRABP2, IFNE, ISG15, NPR3, PDIA2, PGLYRP2, PLA2G2A, SAA1, TEK, TGFA, TNFSF14, and UCN2) were identified as prognostic IRGs associated with overall survival and were used to construct a prognostic model. The area under the receiver operating characteristic curve at 1 year was 0.927; 3 years, 0.822; and 5 years, 0.717, indicating good predictive accuracy. Molecular regulatory networks were found to govern immune interactions in ccRCC. Additionally, we developed a nomogram containing the model and clinical characteristics with high prognostic potential. By systematically examining the sophisticated regulatory mechanisms, molecular characteristics, and prognostic potential of ccRCC immune interactions, we provided an important framework for understanding the molecular mechanisms of ccRCC and identifying new prognostic markers and therapeutic targets for future research.

Efficacy and safety of avatrombopag in the treatment of thrombocytopenia after umbilical cord blood transplantation.

BACKGROUND: Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT), and there is no standard therapy. Avatrombopag (AVA) is a second-generation thrombopoietin (TPO) receptor agonist (TPO-RA) that has shown efficacy in immune thrombocytopenia (ITP). However, few reports have focused on its efficacy in patients diagnosed with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We conducted a retrospective study to evaluate the efficacy of AVA as a first-line TPO-RA in 65 patients after UCBT; these patients were compared with 118 historical controls. Response rates, platelet counts, megakaryocyte counts in bone marrow, bleeding events, adverse events and survival rates were evaluated in this study. Platelet reconstitution differences were compared between different medication groups. Multivariable analysis was used to explore the independent beneficial factors for platelet implantation. RESULTS: Fifty-two patients were given AVA within 30 days post-UCBT, and the treatment was continued for more than 7 days to promote platelet engraftment (AVA group); the other 13 patients were given AVA for secondary failure of platelet recovery (SFPR group). The median time to platelet engraftment was shorter in the AVA group than in the historical control group (32.5 days vs. 38.0 days, Z = 2.095, P = 0.036). Among the 52 patients in the AVA group, 46 achieved an overall response (OR) (88.5%), and the cumulative incidence of OR was 91.9%. Patients treated with AVA only had a greater 60-day cumulative incidence of platelet engraftment than patients treated with recombinant human thrombopoietin (rhTPO) only or rhTPO combined with AVA (95.2% vs. 84.5% vs. 80.6%, P <0.001). Patients suffering from SFPR had a slightly better cumulative incidence of OR (100%, P = 0.104). Patients who initiated AVA treatment within 14 days post-UCBT had a better 60-day cumulative incidence of platelet engraftment than did those who received AVA after 14 days post-UCBT (96.6% vs. 73.9%, P = 0.003). CONCLUSION: In summary, compared with those in the historical control group, our results indicate that AVA could effectively promote platelet engraftment and recovery after UCBT, especially when used in the early period (≤14 days post-UCBT).

An aberrant immune-epithelial progenitor niche drives viral lung sequelae.

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic-termed post-acute sequelae of SARS-CoV-2 (PASC)-are rapidly evolving into a major public health concern1-3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses3-6 and/or impaired organ recovery7-9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune-epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8+ T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8+ T cells stimulated local macrophages to chronically release IL-1ß, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1ß markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention10, we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.