Nicotine restores olfactory function by activation of prok2R/Akt/FoxO3a axis in Parkinson's disease.

BACKGROUND: Olfactory dysfunction occurs frequently in Parkinson's disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines. RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis. CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.

Deep Brain Stimulation Modulates the Visual Pathway to Improve Freezing of Gait in Parkinson's Disease Patients.

OBJECTIVE: To investigate the involvement of the visual cortex in improving freezing of gait (FoG) after subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients using whole-brain seed-based functional connectivity. METHODS: A total of 66 PD patients with FoG who underwent bilateral STN-DBS were included in our study. Patients were divided into a FoG responder group (FoG-R) and an FoG non-responder group (FoG-nonR) according to whether FoG improved one year after DBS. We compared the differences in clinical characteristics, brain structural imaging and seed-based functional connectivity between the two groups. The locations of active contacts were further analyzed. RESULTS: All PD patients benefited from STN-DBS. No significant differences in the baseline characteristics or brain structures were found between the two groups. Seed-based functional connectivity analysis revealed that better connectivity in bilateral primary visual areas was associated with better clinical improvement in FoG (p < 0.05 familywise error [FWE] corrected). Further analysis revealed that this disparity was associated with the location of the active contacts within the rostral region of the sensorimotor subregion in the FoG-R group, in contrast to the findings in the FoG-nonR group. CONCLUSION: This study suggested that DBS in the rostral region of the STN sensorimotor subregion may alleviate FoG by strengthening functional connectivity in primary visual areas, which has significant implications for guiding surgical strategies for FoG in the future.

Manipulating Zn Metal Texture with Guided Zincophilic Sites via Electrochemical Stripping for Dendrite-Free Zn Anodes.

Constructing a three-dimensional (3D) structure along with Zn (002) texture selective exposure is a promising strategy to tackle the issues faced by Zn metal anodes. Herein, for the first time, we proposed an electrochemical stripping strategy to achieve controlled modification of the texture and microstructure of zinc foils in one step, building a hierarchical structure with (002) texture preferred exposed Zn (SZ). The SZ with favorable zincophilic properties not only can reduce the concentration polarization at the interface but also allow Zn to grow horizontally on the edge of the (002) texture by guiding the adsorption sites for Zn2+. Moreover, the honeycomb-like structure is beneficial to rearrange the distribution of the Zn2+ flux as well as alleviating stress changes during cycling. Thus, the SZ||Cu cell exhibits excellent stability with a Coulombic efficiency of 99.76% over 1800 cycles. The SZ||NaV3O8·xH2O cell with inconspicuous self-discharge effect maintains a high areal capacity of 3.67 mA h cm-2 even after 700 cycles with a low N/P ratio of 3.6. This work achieves texture architecture and structure designing on Zn foils simultaneously by metallurgical electrochemical methods and opens up a potential strategy to implement the practicality of zinc metal anodes.

Radiotherapy Resistance of 3D Bioprinted Glioma via ITGA2/p-AKT Signaling Pathway.

Due to the inherent radiation tolerance, patients who suffered from glioma frequently encounter tumor recurrence and malignant progression within the radiation target area, ultimately succumbing to treatment ineffectiveness. The precise mechanism underlying radiation tolerance remains elusive due to the dearth of in vitro models and the limitations associated with animal models. Therefore, a bioprinted glioma model is engineered, characterized the phenotypic traits in vitro, and the radiation tolerance compared to 2D ones when subjected to X-ray radiation is assessed. By comparing the differential gene expression profiles between the 2D and 3D glioma model, identify functional genes, and analyze distinctions in gene expression patterns. Results showed that 3D glioma models exhibited substantial alterations in the expression of genes associated with the stromal microenvironment, notably a significant increase in the radiation tolerance gene ITGA2 (integrin subunit A2). In 3D glioma models, the knockdown of ITGA2 via shRNA resulted in reduced radiation tolerance in glioma cells and concomitant inhibition of the p-AKT pathway. Overall, 3D bioprinted glioma model faithfully recapitulates the in vivo tumor microenvironment (TME) and exhibits enhanced resistance to radiation, mediated through the ITGA2/p-AKT pathway. This model represents a superior in vitro platform for investigating glioma radiotherapy tolerance.

Changes in decision-making function in patients with subacute mild traumatic brain injury.

Although awareness regarding patients with mild traumatic brain injury has increased, they have not received sufficient attention in clinics; hence, many patients still experience only partial recovery. Deficits in decision-making function are frequently experienced by these patients. Accurate identification of impairment in the early stages after brain injury is particularly crucial for timely intervention and the prevention of long-term cognitive consequences. Therefore, we investigated the changes in decision-making ability under tasks of ambiguity and risk in patients with mild traumatic brain injury with a rule-based neuropsychological paradigm. In this study, patients (n = 39) and matched healthy controls (n = 38) completed general neuropsychological background tests and decision-making tasks (Iowa Gambling Task and Game of Dice Task). We found that patients had extensive cognitive impairment in general attention, memory and information processing speed in the subacute phase, and confirmed that patients had different degrees of impairment in decision-making abilities under ambiguity and risk. Furthermore, the decline of memory and executive function may be related to decision-making dysfunction.

Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactory in solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy.

Research progress on the association between trimethylamine/trimethylamine-N-oxide and neurological disorders.

Trimethylamine-N-oxide (TMAO) is a common intestinal metabolite. The Choline in the nutrient forms TMA under the action of the gut microbiota, which passes through the liver and eventually forms TMAO. Initial studies of TMAO focused on cardiovascular disease, but as research progressed, TAMO's effects were found to be multisystem and closely related to the development of neurological diseases. Intestinal tract is the organ with the largest concentration of bacteria in human body, and the composition and metabolism of gut microbiota affect human health. As a two-way communication axis connecting the central nervous system and the gastrointestinal tract, the brain-gut axis provides the structural basis for TMAO to play its role. This article will review the correlation between TMA/TMAO and neurological diseases in order to find new directions and new targets for the treatment of neurological diseases.

Ferroptosis-related gene MTF-1 as a novel prognostic biomarker in low-grade glioma and its correlation with immune infiltration.

Background: Metal-responsive transcription factor-1 performs a necessary position in a range of cancers. It is unknown, though, how the prognosis of patients with low-grade gliomas is related to immune infiltration. Method: The Cancer Genome Atlas database was used in this investigation to evaluate MTF-1 transcription in low-grade glioma and healthy brain tissues, and immunohistochemistry was used to confirm MTF-1 levels. By using functional enrichment analysis and R software, the putative biological roles and signaling pathways connected to MTF-1 in LGG as well as its prognostic significance were investigated. Further research was done on the connection involving MTF-1 and tumor mutational burden in LGG. Finally, the research evaluated how MTF-1 and immune cell infiltration are related. Results: We noticed that the WHO grade, 1p/19q codeletion, and older age were all substantially linked with MTF-1 overexpression in low-grade gliomas. OS and disease-specific survival were significantly lowered as a result of MTF-1 transcription. MTF-1 was recognized as an independent OS prognostic predictor with a poor prognosis by multifactorial Cox analysis. Functional enrichment analysis revealed that the primary enrichment pathways were chemical carcinogenesis-receptor activation and the generation of miRNAs implicated in gene suppression by miRNA. Additionally, there was a negative correlation between MTF-1 overexpression and the degree of immune cell infiltration in neutrophils and DC. Conclusion: MTF-1 may be a novel prognostic biomarker.

TMED family genes and their roles in human diseases.

The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), ß (TMED 2), γ (TMED1, 3, 5, 6, 7) and δ (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases. Here we systematically review the composition, structure and function of TMED family members, and describe the progress of TMED family in human diseases, including malignancies (head and neck tumors, lung cancer, breast cancer, ovarian cancer, endometrial cancer, gastrointestinal tumors, urological tumors, osteosarcomas, etc.), immune responses, diabetes, neurodegenerative diseases, and nonalcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy (MKD), and desiccation syndrome (SS). Finally, we discuss and prospect the potential of TMED for disease prognosis prediction and therapeutic targeting, with a view to laying the foundation for therapeutic research based on TMED family causative genes.

Bioinspired immuno-radio-enhancers toward synergistic nanomedicine through radiation-induced abscopal effects and immunocheckpoint blockade therapies.

Local radio-therapy combined with immunotherapy has attracted great interest in controlling local tumors. In this study, we have developed membrane-cloaked manganese dioxide nanoparticles displaying anti-PD-L1 antibodies as targeted immuno-radio-enhancers. Mediated by anti-PD-L1 antibodies (aPD-L1) expressed on cell membranes, this kind of membrane-coated nanosystem can selectively deliver cytosine-phosphate-guanine (CpG)-loaded MnO2 nanoparticles (NPs) and induce systemic anti-tumor immunities, thereby achieving favorable immuno/radio-therapeutic outcomes. Through expressing various functional proteins onto cellular membranes, the new class of membrane-camouflaged nanovehicles can be endowed with a wide variety of artificial functionalities such as enzymatic catalytic capabilities and specific targeting. This versatile nanoplatform, in general, enables the targeted delivery of theranostics, opening a new avenue for personalized nanomedicine.

Salivary microbiome profiles for different clinical phenotypes of pituitary adenomas by single-molecular long-read sequencing.

IMPORTANCE: The gut and salivary microbiomes have been widely reported to be significantly associated with a number of neurological disorders. The stability of the microbiome in the oral cavity makes it a potentially ideal sample that can be conveniently obtained for the investigation of microbiome-based pathogenesis in diseases. In the present study, we used a single-molecule long-read sequencing technique to study the distribution of the salivary microbiota in patients with pituitary adenoma (PA) and healthy individuals, as well as among four clinical phenotypes of PA. We found that the diversity of salivary microbes was more abundant in PA patients than in healthy individuals. We also observed some unique genera in different PA phenotypes. The bioinformatics-based functional predictions identified potential links between microbes and different clinical phenotypes of PA. This study improves the existing understanding of the pathogenesis of PA and may provide diagnostic and therapeutic targets for PA.

Engineering a Ni-Al Brucite-Based Interface Layer with Regulated Zn2+ Flux for Highly Reversible Zn Metal Anodes.

Practical aqueous Zn-ion batteries are appealing for grid-scale energy storage with intrinsic safety and cost-effectiveness, yet their cycling stability and reversibility are limited by unwanted dendrite growth and water-induced erosions on Zn. Herein, a hydrophilic and Zn2+-conductive Ni-Al layered double hydroxide (NiAl-LDH) interphase layer is constructed on the surface of Zn, in which NiAl-LDH enables a more uniformly distributed Zn2+ concentration and interfacial electric field owing to its large internal Zn2+ channels and favorable charge redistribution effect. Consequently, the NiAl-LDH-integrated Zn anode achieves low voltage hysteresis and high reversibility of Zn plating/stripping with uniform underneath deposition behaviors. Remarkably, the resultant NiAl-2 LDH@Zn delivers superior cycling durability over 2800 h (∼4 months, 0.5 mA cm-2), realizes high reversibility with 99.4% average Coulombic efficiency over 1400 cycles, and confers stable operation of full Zn cells with high V2O5 mass loadings. This work offers a facile and instructive interface design approach for achieving highly stable Zn metal anodes.

Li2CO3 Nanocomposites as Cathode Lithium Replenishment Material for High-Energy-Density Li-Ion Batteries.

The irreversible capacity loss of lithium-ion batteries during initial cycling directly leads to a decrease in energy density, and promising lithium cathode replenishment can significantly alleviate this problem. In response to the problems of complex preparation, instability in air, and unfavorable residue of the conventional cathode lithium replenishment materials, a Li2CO3/carbon nanocomposite is prepared and utilized as the lithium replenishment material. With high-speed ball-milling, a nanocomposite with a tight embedment structured Li2CO3/Ketjen Black (KB) composite composed of nanosized Li2CO3 and KB is synthesized. The decomposition potential of Li2CO3 is effectively decreased to 3.8 V, and the amount of the active lithium ion being released is significantly increased, corresponding to a specific capacity of 645.2 mAh·g-1 during the initial charging cycle. It has been introduced into the full-cells composed of the NCM523 cathode and graphite anode, resulting in a capacity increase of 44 mAh·g-1 in the initial cycle and a 26.4% improvement in capacity retention over 100 cycles. The working mechanism of the Li2CO3/KB nanocomposite as the lithium replenishment agent has been discussed. The outcome of the work provides a practically feasible route to realize lithium-ion battery technology with improved energy density and cycling life.

The Effect of Alkali Metals (Li, Na, and K) on Ni/CaO Dual-Functional Materials for Integrated CO2 Capture and Hydrogenation.

Ni/CaO, a low-cost dual-functional material (DFM), has been widely studied for integrated CO2 capture and hydrogenation. The core of this dual-functional material should possess both good CO2 capture-conversion performance and structural stability. Here, we synthesized Ni/CaO DFMs modified with alkali metals (Na, K, and Li) through a combination of precipitation and combustion methods. It was found that Na-modified Ni/CaO (Na-Ni/CaO) DFM offered stable CO2 capture-conversion activity over 20 cycles, with a high CO2 capture capacity of 10.8 mmol/g and a high CO2 conversion rate of 60.5% at the same temperature of 650 °C. The enhanced CO2 capture capacity was attributed to the improved surface basicity of Na-Ni/CaO. In addition, the incorporation of Na into DFMs had a favorable effect on the formation of double salts, which shorten the CO2 capture and release process and promoted DFM stability by hindering their aggregation and the sintering of DFMs.

Building Negative-Thermal-Expansion Protective Layers on the Grain Boundary of Ni-rich Cathodes Enables Safe and Durable High Voltage Lithium-Ion Batteries.

Ni-rich layered oxide cathode materials demonstrate high energy densities for Li-ion batteries, but the electrochemically driven thermal runaway and mechanical degradation remain their long-standing challenges in practical applications. Herein, it presents a novel ZrV2 O7  (ZVO) coating with negative thermal expansion properties along the secondary particles and primary particle grain boundaries (GBs), to simultaneously enhance the structural and thermal stability of LiNi0.8 Co0.1 Mn0.1 O2 (NCM811). It unveils that, such an architecture can significantly enhance the electronic conductivity, suppress the microcracks of GBs, alleviate the layered to spinel/rock-salt phase transformation, and meanwhile relieve the lattice oxygen loss by increasing the oxygen vacancy formation energy increased (1.43 vs 1.90 eV). Consequently, the ZVO-coated NCM811 material demonstrates a remarkable cyclability with 86.5% capacity retention after 100 cycles, and an outstanding rate performance of 30 C under a high-voltage of 4.6 V, outperforming the state-of-the-art literature. More importantly, the Li+ transportation can be readily blocked at 120 °C by the negative-thermal-expansion ZVO coating, thus avoiding the high-temperature thermal runaway.

Factors Related to the Deterioration of Postoperative Lower Back Pain in Hemilaminectomy Approach for Lumbar Spinal Schwannoma Resection.

Objective: This study aimed to explore the related risk factors in patients who underwent hemilaminectomy for lumbar spinal schwannoma resection and who experienced deterioration of postoperative lower back pain in comparison to preoperative pain levels. Methods: This retrospective study recruited 61 patients from the First Affiliated Hospital of An Hui Medical University between January 2018 and June 2019. All data were collected from clinical records and analyzed at 1-month and at 1-year follow-up. The visual analog scale (VAS) was used to evaluate pain, and neurologic function was assessed using the Modified McCormick Scale. Intraoperative neurophysiological monitoring was used to assess neuronal integrity and mitigate injury. Statistical analysis of the data was performed using the SPSS version 19 software. Results: Preoperative pain improved dramatically in the 1-year follow-up (VAS: preoperative, 3.84±2.19; 1-year follow-up, 2.13±2.26; P<0.001). The pain-improved group and worsened group showed a significant difference at 1-month (VAS: 1.76±1.56; 5.54±1.26; P<0.05) and at 1-year (VAS: 0.83±1.09; 4.80±1.58; P<0.05) follow-up. The pain-improved and worsened groups had a significant difference in tumor size and hemilaminectomy removal segments at 1-month and 1-year follow-up, but A-train occurrence on electromyography could only be seen as a statistical difference in the 1-month follow-up. Logistic regression analysis revealed that tumor size was an independent risk factor for postoperative lower back pain deterioration. Conclusion: The hemilaminectomy approach is a safe and effective method that can dramatically relieve pain in spinal lumbar schwannoma resection. Tumor size is an independent risk factor for postoperative lower back pain. A-train on spontaneous electromyography has been shown to be a reliable predictive factor for the evaluation of postoperative lower back pain. However, further detailed analysis of A-train characteristics can provide a more accurate warning during surgery.

Advances in nanomedicines for lymphatic imaging and therapy.

Lymph nodes play a pivotal role in tumor progression as key components of the lymphatic system. However, the unique physiological structure of lymph nodes has traditionally constrained the drug delivery efficiency. Excitingly, nanomedicines have shown tremendous advantages in lymph node-specific delivery, enabling distinct recognition and diagnosis of lymph nodes, and hence laying the foundation for efficient tumor therapies. In this review, we comprehensively discuss the key factors affecting the specific enrichment of nanomedicines in lymph nodes, and systematically summarize nanomedicines for precise lymph node drug delivery and therapeutic application, including the lymphatic diagnosis and treatment nanodrugs and lymph node specific imaging and identification system. Notably, we delve into the critical challenges and considerations currently facing lymphatic nanomedicines, and futher propose effective strategies to address these issues. This review encapsulates recent findings, clinical applications, and future prospects for designing effective nanocarriers for lymphatic system targeting, with potential implications for improving cancer treatment strategies.

Beneficial or detrimental: Recruiting more types of benign cases for cancer diagnosis based on salivary glycopatterns.

With the advantages of convenient, painless and non-invasive collection, saliva holds great promise as a valuable biomarker source for cancer detection, pathological assessment and therapeutic monitoring. Salivary glycopatterns have shown significant potential for cancer screening in recent years. However, the understanding of benign lesions at non-cancerous sites in cancer diagnosis has been overlooked. Clarifying the influence of benign lesions on salivary glycopatterns and cancer screening is crucial for advancing the development of salivary glycopattern-based diagnostics. In this study, 2885 samples were analyzed using lectin microarrays to identify variations in salivary glycopatterns according to the number, location, and type of lesions. By utilizing our previously published data of tumor-associated salivary glycopatterns, the performance of machine learning algorithm for cancer screening was investigated to evaluate the effect of adding benign disease cases to the control group. The results demonstrated that both the location and number of lesions had discernible effects on salivary glycopatterns. And it was also revealed that incorporating a broad range of benign diseases into the controls improved the classifier's performance in distinguishing cancer cases from controls. This finding holds guiding significance for enhancing salivary glycopattern-based cancer screening and facilitates their practical implementation in clinical settings.

Patient-derived tumor models: a suitable tool for preclinical studies on esophageal cancer.

Esophageal cancer (EC) is the tenth most common cancer worldwide and has high morbidity and mortality. Its main subtypes include esophageal squamous cell carcinoma and esophageal adenocarcinoma, which are usually diagnosed during their advanced stages. The biological defects and inability of preclinical models to summarize completely the etiology of multiple factors, the complexity of the tumor microenvironment, and the genetic heterogeneity of tumors severely limit the clinical treatment of EC. Patient-derived models of EC not only retain the tissue structure, cell morphology, and differentiation characteristics of the original tumor, they also retain tumor heterogeneity. Therefore, compared with other preclinical models, they can better predict the efficacy of candidate drugs, explore novel biomarkers, combine with clinical trials, and effectively improve patient prognosis. This review discusses the methods and animals used to establish patient-derived models and genetically engineered mouse models, especially patient-derived xenograft models. It also discusses their advantages, applications, and limitations as preclinical experimental research tools to provide an important reference for the precise personalized treatment of EC and improve the prognosis of patients.

CO2 capture by Li2CaSiO4 and enhancement with alkali carbonates.

Alkali and alkali earth oxides show good CO2 capture performance for carbonation, while their regeneration occurs at high temperatures, leading to a high energy penalty. When alkali oxides and alkali earth oxides combine with SiO2 to form oxysalts, the regeneration temperatures can be reduced, and the CO2 adsorption capacity is maintained. In this study, the reaction between CO2 and Li2CaSiO4, composed of stoichiometric CaO, Li2O, and SiO2, was evaluated thermodynamically by DFT. The synthesized Li2CaSiO4 with and without alkali carbonates was used as CO2 sorbents, and their CO2 adsorption performances were examined using thermal analyses. The phase and morphology of Li2CaSiO4 before and after CO2 adsorption were characterized by XRD and SEM. According to the thermodynamic evaluation and the XRD results, Li2CaSiO4 could adsorb CO2 and form CaCO3 and Li2SiO3. The thermal analyses showed that the regeneration of Li2CaSiO4 started from 575 °C, at which it was difficult to realize the CO2 diffusion through the solid CaCO3 product layer. The mixed alkali carbonates can improve the kinetics and facilitate the CO2 adsorption of Li2CaSiO4. Alkali carbonates were effective in reducing the activation energy of the reaction and CO2 diffusion at low temperatures and improving the cyclic stability because of the dispersing carbonation products.