Revolutionizing Neurocare: Biomimetic Nanodelivery Via Cell Membranes.

Brain disorders represent a significant challenge in medical science due to the formidable blood-brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell-derived nanoghosts, tumor cell membrane-coated nanoparticles, and erythrocyte membrane-based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane-encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.

Role of prostaglandin E2 and its receptors in chronic liver disease.

Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E2 (PGE2), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE2 are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE2 and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE2 and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE2-EP receptors system in treating CLD with various etiologies.

Stretchable, Transparent, and Ultra-Broadband Terahertz Shielding Thin Films Based on Wrinkled MXene Architectures.

With the increasing demand for terahertz (THz) technology in security inspection, medical imaging, and flexible electronics, there is a significant need for stretchable and transparent THz electromagnetic interference (EMI) shielding materials. Existing EMI shielding materials, like opaque metals and carbon-based films, face challenges in achieving both high transparency and high shielding efficiency (SE). Here, a wrinkled structure strategy was proposed to construct ultra-thin, stretchable, and transparent terahertz shielding MXene films, which possesses both isotropous wrinkles (height about 50 nm) and periodic wrinkles (height about 500 nm). Compared to flat film, the wrinkled MXene film (8 nm) demonstrates a remarkable 36.5% increase in SE within the THz band. The wrinkled MXene film exhibits an EMI SE of 21.1 dB at the thickness of 100 nm, and an average EMI SE/t of 700 dB µm-1 over the 0.1-10 THz. Theoretical calculations suggest that the wrinkled structure enhances the film's conductivity and surface plasmon resonances, resulting in an improved THz wave absorption. Additionally, the wrinkled structure enhances the MXene films' stretchability and stability. After bending and stretching (at 30% strain) cycles, the average THz transmittance of the wrinkled film is only 0.5% and 2.4%, respectively. The outstanding performances of the wrinkled MXene film make it a promising THz electromagnetic shielding materials for future smart windows and wearable electronics.

Motor imagery therapy improved upper limb motor function in stroke patients with hemiplegia by increasing functional connectivity of sensorimotor and cognitive networks.

Background: Motor imagery therapy (MIT) showed positive effects on upper limbs motor function. However, the mechanism by which MIT improves upper limb motor function is not fully understood. Therefore, our purpose was to investigate the changes in functional connectivity (FC) within and outside the sensorimotor network (SMN) induced by MIT associated with improvement in upper limb motor function in stroke patients. Methods: A total of 26 hemiplegic stroke patients were randomly divided into MIT (n = 13) and control (n = 13) groups. Fugl-Meyer Assessment Upper Extremity Scale (FMA-UL), Modified Barthel Index (MBI) and resting-state functional magnetic resonance imaging (rs-fMRI) were evaluated in the two groups before treatment and 4 weeks after treatment. The efficacy of MIT on motor function improvement in stroke patients with hemiplegia was evaluated by comparing the FMA-UL and MBI scores before and after treatment in the two groups. Furthermore, the FC within the SMN and between the SMN and the whole brain was measured and compared before and after different treatment methods in stroke patients. The correlation analysis between the improvement of upper limbs motor function and changes in FC within the SMN and between the SMN and the whole brain was examined. Results: The FCs between ipsilesional primary motor cortex (M1.I) and contralateral supplementary motor area (SMA.C), M1.I and ipsilesional SMA (SMA.I), and SMA.C and contralateral dorsolateral premotor cortex (DLPM.C) significantly increased in the control group but decreased in the MIT group; while the FC between SMA.C and contralateral primary somatosensory cortex (S1.C) significantly increased in the control group but showed no significant difference in the MIT group. The FCs between M1.I and the ipsilesional hippocampal gyrus and ipsilesional middle frontal gyrus significantly decreased in the control group but increased in the MIT group; while the FC in the contralateral anterior cingulate cortex significantly increased in the MIT group but there was no significant difference in the control group. The results of the correlation analysis showed that the differences in abnormal intra-FCs within the SMN negatively correlated with the differences in FMA and MBI, and the difference in abnormal inter-FCs of the SMN positively correlated with the differences in FMA and MBI. Conclusions: MIT can improve upper limb motor function and daily activities of stroke patients, and the improvement effect of conventional rehabilitation therapy (CRT) combined with MIT is significantly higher than that of CRT alone. CRT may improve the upper limb motor function of stroke patients with hemiplegia mainly through the functional reorganization between SMN, while MIT may mainly increase the interaction between SMN and other brain networks.

Research on the dynamic behavior of flexible drilling tools in ultrashort-radius radial horizontal wells.

A flexible drilling tool is a special drilling tool for ultrashort-radius radial horizontal wells. This tool is composed of many parts and has the characteristics of a multibody system. In this paper, a numerical method for the dynamic analysis of flexible drilling tools is proposed. The flexible drill tool is discretized into spatial beam elements, while the multilayer contact of the flexible drilling tool is represented by the multilayer dynamic gap element, and the dynamic model of the multibody system for the flexible drilling tool's multilayer contact is established, considering the interaction force between the drill bit and the rock. The nonlinear dynamic equation is solved using the Newmark method and Newton-Raphson method. An analysis of the dynamic behavior of a flexible drilling tool is conducted. The results indicate that the flexible drilling tool experiences vortex formation due to the interaction between the flexible drilling pipe and the guide pipe, leading to increased friction and wear. This situation hinders safe drilling operations with flexible drilling tools. The collision force of the flexible drilling tool near the bottom of the hole is more severe than that of the other tool types, which may lead to failure of the connection.

miR-99b/let-7e/miR-125a cluster suppresses pancreatic cancer through regulation of NR6A1.

This experiment investigates how the miR-99b/let-7e/miR-125a cluster regulates the mechanism of NR6A1 involved in the invasive and metastatic effects of pancreatic cancer (PCa). Bioinformatics prediction and dual luciferase reporter gene assay were applied to verify the targeted relationship between miR-99b/let-7e/miR-125a and NR6A1. ASPC1 cells underwent transfection with lentiviruses to overexpress miR-99b/let-7e/miR-125a (individual or together) to explore functions of miR-99b/let-7e/miR-125a cluster governing NR6A1 in PCa. The detection of tumorigenesis was verified by tumor formation assay in nude mice in vivo, and mouse models of liver metastasis of PCa observed cell metastasis of PCa. MiR-99b/let-7e/miR-125a cluster was screened for differential expression in PCa. NR6A1 was confirmed as a target gene of the miR-99b/let-7e/miR-125a cluster. Findings demonstrated that overexpression of the miR-99b/let-7e/miR-125a cluster inhibited cell invasion, metastasis, proliferation, and tumorigenesis in PCa. Conversely, overexpressed NR6A1, a crucial gene in the miR-99b/let-7e/miR-125a cluster, promoted cell invasion, migration, and proliferation in PCa. Moreover, the overexpression of the miR-99b/let-7e/miR-125a cluster inhibited liver metastases and tumor formation. Thus, the study concludes that the miR-99b/let-7e/miR-125a cluster impedes the invasion and metastasis of PCa cells via targeting the NR6A1 gene.

The value of CT-based radiomics in predicting hemorrhagic transformation in acute ischemic stroke patients without recanalization therapy.

Objective: The aim of this study is to investigate the clinical value of radiomics based on non-enhanced head CT in the prediction of hemorrhage transformation in acute ischemic stroke (AIS). Materials and methods: A total of 140 patients diagnosed with AIS from January 2015 to August 2022 were enrolled. Radiomic features from infarcted areas on non-enhanced CT images were extracted using ITK-SNAP. The max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select features. The radiomics signature was then constructed by multiple logistic regressions. The clinicoradiomics nomogram was constructed by combining radiomics signature and clinical characteristics. All predictive models were constructed in the training group, and these were verified in the validation group. All models were evaluated with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Of the 140 patients, 59 experienced hemorrhagic transformation, while 81 remained stable. The radiomics signature was constructed by 10 radiomics features. The clinicoradiomics nomogram was constructed by combining radiomics signature and atrial fibrillation. The area under the ROC curve (AUCs) of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the training group were 0.64, 0.86, and 0.86, respectively. The AUCs of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the validation group were 0.63, 0.90, and 0.90, respectively. The DCA curves showed that the radiomics signature performed well as well as the clinicoradiomics nomogram. The DCA curve showed that the clinical application value of the radiomics signature is similar to that of the clinicoradiomics nomogram. Conclusion: The radiomics signature, constructed without incorporating clinical characteristics, can independently and effectively predict hemorrhagic transformation in AIS patients.

Photosensitive Hydrogels Encapsulating DPSCs and AgNPs for Dental Pulp Regeneration.

OBJECTIVE: Pulp regeneration with bioactive dentin-pulp complex has been a research hotspot in recent years. Stem cell therapy provided an interest strategy to regenerate the dental-pulp complex. Hence, this study aimed to evaluate the effects of photosensitive gelatin methacrylate (GelMA) hydrogel encapsulating dental pulp stem cells (DPSCs) and silver nanoparticles (AgNPs) for dental pulp regeneration in vitro. METHODS: First, the AgNPs@GelMA hydrogels were prepared by lithium phenyl-2,4,6-trimethyl-benzoyl phosphinate (LAP) initiation via blue-light emitting diode light. The physical and chemical properties of AgNPs@GelMA hydrogels were comprehensively analysed via scanning electron microscopy (SEM), and mechanical characterisation, such as swelling ability, degradation properties, and AgNP release profile. Then, AgNPs@GelMA hydrogels encapsulated DPSCs were used to establish an AgNPs@GelMA biomimetic complex, further analysing its biocompatibility, antibacterial properties, and angiogenic capacity in vitro. RESULTS: The results indicated that GelMA hydrogels demontrated optimal characteristics with a monomer:LAP ratio of 16:1. The physico-chemical properties of AgNPs@GelMA hydrogels did not change significantly after loading with AgNPs. There was no significant difference in AgNP release rate amongst different concentrations of AgNPs@GelMA hydrogels. Fifty to 200 µg/mL AgNPs@GelMA hydrogels could disperse E faecalis biofilm and reduce its metabolic activity . Furthermore, cell proliferation was arrested in 100 and 200 µg/mL AgNPs@GelMA hydrogels. The inhibition of 50 µg/mL AgNPs@GelMA hydrogels on E faecalis biofilm was above 50%, and the cell viability of the hydrogels was higher than 90%. The angiogenesis assay indicated that AgNPs@GelMA hydrogels encapsulating DPSCs could induce the formation of capillary-like structures and express angiogenic markers CD31, vascular endothelial growth factor , and von willebrand factor (vWF) in vitro. CONCLUSIONS: Results of this study indicate that 50 µg/mL AgNPs@GelMA hydrogels encapsulating DPSCs had significant antibacterial properties and angiogenic capacity, which could provide a significant experimental basis for the regeneration of the dentin-pulp complex.

Biodegradable Zn-5Dy Alloy with Enhanced Osteo/Angio-Genic Activity and Osteointegration Effect via Regulation of SIRT4-Dependent Mitochondrial Function.

Zinc (Zn)-dysprosium (Dy) binary alloys are promising biodegradable bone fracture fixation implants owing to their attractive biodegradability and mechanical properties. However, their clinical application is a challenge for bone fracture healing, due to the lack of Zn-Dy alloys with tailored proper bio-mechanical and osteointegration properties for bone regeneration. A Zn-5Dy alloy with high strength and ductility and a degradation rate aligned with the bone remodeling cycle is developed. Here, mechanical stability is further confirmed, proving that Zn-5Dy alloy can resist aging in the degradation process, thus meeting the mechanical requirements of fracture fixation. In vitro cellular experiments reveal that the Zn-5Dy alloy enhances osteogenesis and angiogenesis by elevating SIRT4-mediated mitochondrial function. In vivo Micro-CT, SEM-EDS, and immunohistochemistry analyses further indicate good biosafety, suitable biodegradation rate, and great osteointegration of Zn-5Dy alloy during bone healing, which also depends on the upregulation of SIRT4-mediated mitochondrial events. Overall, the study is the first to report a Zn-5Dy alloy that exerts remarkable osteointegration properties and has a strong potential to promote bone healing. Furthermore, the results highlight the importance of mitochondrial modulation and shall guide the future development of mitochondria-targeting materials in enhancing bone fracture healing.

IUPHAR ECR review: The cGAS-STING pathway: Novel functions beyond innate immune and emerging therapeutic opportunities.

Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating innate immune signaling pathways to defend the host. Recent studies have revealed additional regulatory functions of STING beyond its innate immune-related activities, including the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths. These findings highlight the broader implications of STING in cellular physiology beyond its role in innate immunity. Currently, approximately 10 STING agonists have entered the clinical stage. Unlike inhibitors, which have a maximum inhibition limit, agonists have the potential for infinite amplification. STING signaling is a complex process that requires precise regulation of STING to ensure balanced immune responses and prevent detrimental autoinflammation. Recent research on the structural mechanism of STING autoinhibition and its negative regulation by adaptor protein complex 1 (AP-1) provides valuable insights into its different effects under physiological and pathological conditions, offering a new perspective for developing immune regulatory drugs. Herein, we present a comprehensive overview of the regulatory functions and molecular mechanisms of STING beyond innate immune regulation, along with updated details of its structural mechanisms. We discuss the implications of these complex regulations in various diseases, emphasizing the importance and feasibility of targeting the immunity-dependent or immunity-independent functions of STING. Moreover, we highlight the current trend in drug development and key points for clinical research, basic research, and translational research related to STING.

Flexible, Transparent and Conductive Metal Mesh Films with Ultra-High FoM for Stretchable Heating and Electromagnetic Interference Shielding.

Despite the growing demand for transparent conductive films in smart and wearable electronics for electromagnetic interference (EMI) shielding, achieving a flexible EMI shielding film, while maintaining a high transmittance remains a significant challenge. Herein, a flexible, transparent, and conductive copper (Cu) metal mesh film for EMI shielding is fabricated by self-forming crackle template method and electroplating technique. The Cu mesh film shows an ultra-low sheet resistance (0.18 Ω â–¡-1), high transmittance (85.8%@550 nm), and ultra-high figure of merit (> 13,000). It also has satisfactory stretchability and mechanical stability, with a resistance increases of only 1.3% after 1,000 bending cycles. As a stretchable heater (ε > 30%), the saturation temperature of the film can reach over 110 °C within 60 s at 1.00 V applied voltage. Moreover, the metal mesh film exhibits outstanding average EMI shielding effectiveness of 40.4 dB in the X-band at the thickness of 2.5 µm. As a demonstration, it is used as a transparent window for shielding the wireless communication electromagnetic waves. Therefore, the flexible and transparent conductive Cu mesh film proposed in this work provides a promising candidate for the next-generation EMI shielding applications.

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors.

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.

Social media unveils the hidden but high magnitude of human-mediated biological invasions in China.

Humans are responsible for the release of many non-native animals into the wild. However, these releases occur randomly and are difficult to monitor. Here, using two of the worst invasive herpetofauna as model taxa, we applied an iEcology approach and found a high magnitude of human-mediated releases in China, suggesting this approach can be used to monitor introductions and advise management bodies in a timely manner.

Well-defined in-textile photolithography towards permeable textile electronics.

Textile-based wearable electronics have attracted intensive research interest due to their excellent flexibility and breathability inherent in the unique three-dimensional porous structures. However, one of the challenges lies in achieving highly conductive patterns with high precision and robustness without sacrificing the wearing comfort. Herein, we developed a universal and robust in-textile photolithography strategy for precise and uniform metal patterning on porous textile architectures. The as-fabricated metal patterns realized a high precision of sub-100 µm with desirable mechanical stability, washability, and permeability. Moreover, such controllable coating permeated inside the textile scaffold contributes to the significant performance enhancement of miniaturized devices and electronics integration through both sides of the textiles. As a proof-of-concept, a fully integrated in-textiles system for multiplexed sweat sensing was demonstrated. The proposed method opens up new possibilities for constructing multifunctional textile-based flexible electronics with reliable performance and wearing comfort.

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot-Marie-Tooth Disease.

BACKGROUND: To identify genetic causes in 40 whole exome sequencing (WES)-negative Charcot-Marie-Tooth (CMT) families and provide a summary of the clinical and genetic features of the diagnosed patients. METHODS: The clinical information and sequencing data of 40 WES-negative families out of 131 CMT families were collected, and phenotype-driven reanalysis was conducted using the Exomiser software. RESULTS: The molecular diagnosis was regained in 4 families, increasing the overall diagnosis rate by 3.0%. One family with adolescent-onset pure CMT1 was diagnosed [POLR3B: c.2810G>A (p.R937Q)] due to the novel genotype-phenotype association. One infantile-onset, severe CMT1 family with deep sensory disturbance was diagnosed by screening the BAM file and harbored c.1174C>T (p.R392*) and 875_927delinsCTGCCCACTCTGCCCACTCTGCCCACTCTG (p.V292Afs53) of PRX. Two families were diagnosed due to characteristic phenotypes, including an infantile-onset ICMT family with renal dysfunction harboring c.213_233delinsGAGGAGCA (p.S72Rfs34) of INF2 and an adolescent-onset CMT2 family with optic atrophy harboring c.560C>T (p.P187L) and c.616A>G (p.K206E) of SLC25A46. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants of POLR3B and SLC25A46 were classified as likely pathogenic, and the variants of INF2 and PRX were pathogenic. All these variants were first reported worldwide except for p.R392* of PRX. CONCLUSIONS: We identified five novel pathogenic variants in POLR3B, PRX, INF2, and SLC25A46, which broaden their phenotypic and genotypic spectrums. Regular phenotype-driven reanalysis is a powerful strategy for increasing the diagnostic yield of WES-negative CMT patients, and long-term follow-up and screening BAM files for contiguous deletion and missense variants are both essential for reanalysis.

Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement.

BACKGROUND AND AIMS: Biallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot-Marie-Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD-related PN (SORD-PN). METHODS: A total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole-exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD-PN were collected and analyzed. RESULTS: Eleven (10.28%) of 107 patients were identified as SORD-PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > G;p.His70Gln in F-d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD-PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88-fold higher in SORD-PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138-fold higher than in healthy controls (0.07 ± 0.02 mg/L). INTERPRETATION: The novel SORD variant c.210 T > G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD-PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow-up cohort study.

Engineering core-shell chromium nanozymes with inflammation-suppressing, ROS-scavenging and antibacterial properties for pulpitis treatment.

Oral diseases are usually caused by inflammation and bacterial infection. Reactive oxygen species (ROS), which come from both autologous inflammation tissue and bacterial infection, play an important role in this process. Thus, the elimination of excessive intracellular ROS can be a promising strategy for anti-inflammatory treatment. With the rapid development of nanomedicines, nanozymes, which can maintain the intracellular redox balance and protect cells against oxidative damage, have shown great application prospects in the treatment of inflammation-related diseases. However, their performance in pulpitis and their related mechanisms have yet to be explored. Herein, we prepared dozens of metallic nanoparticles with core-shell structures, and among them, chromium nanoparticles (NanoCr) were selected for their great therapeutic potential for pulpitis disease. NanoCr showed a broad antibacterial spectrum and strong anti-inflammatory function. Antibacterial assays showed that NanoCr could effectively inhibit a variety of common pathogens of oral infection. In vitro experiments offered evidence of the multienzyme activity of NanoCr and its function in suppressing ROS-induced inflammation reactions. The experimental results show that NanoCr has optimal antibacterial and anti-inflammatory properties in in vitro cell models, showing great potential for the treatment of pulpitis. Therefore, the use of NanoCr could become a new therapeutic strategy for clinical pulpitis.

TIMELESS promotes the proliferation and migration of lung adenocarcinoma cells by activating EGFR through AMPK and SPHK1 regulation.

BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present. METHODS: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis. RESULTS: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells. CONCLUSIONS: Our study revealed that siTIM could inhibit EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and altering the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD.

Lysine Deprivation Suppresses Adipogenesis in 3T3-L1 Cells: A Transcriptome Analysis.

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes' response to amino acid level changes is crucial. It has been reported that a low concentration of lysine suppresses lipid accumulation and transcription of several adipogenic genes in 3T3-L1 preadipocytes. However, the detailed lysine-deprivation-induced cellular transcriptomic changes and the altered pathways have yet to be fully studied. Here, using 3T3-L1 cells, we performed RNA sequencing on undifferentiated and differentiated cells, and differentiated cells under a lysine-free environment, and the data were subjected to KEGG enrichment. We found that the differentiation process of 3T3-L1 cells to adipocytes required the large-scale upregulation of metabolic pathways, mainly on the mitochondrial TCA cycle, oxidative phosphorylation, and downregulation of the lysosomal pathway. Single amino acid lysine depletion suppressed differentiation dose dependently. It disrupted the metabolism of cellular amino acids, which could be partially reflected in the changes in amino acid levels in the culture medium. It inhibited the mitochondria respiratory chain and upregulated the lysosomal pathway, which are essential for adipocyte differentiation. We also noticed that cellular interleukin 6 (IL6) expression and medium IL6 level were dramatically increased, which was one of the targets for suppressing adipogenesis induced by lysine depletion. Moreover, we showed that the depletion of some essential amino acids such as methionine and cystine could induce similar phenomena. This suggests that individual amino acid deprivation may share some common pathways. This descriptive study dissects the pathways for adipogenesis and how the cellular transcriptome was altered under lysine depletion.

The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies.

With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants.