Assessment tools for cognitive performance in Parkinson's disease and its genetic contributors.

Background: We have shown that genetic factors associating with motor progression of Parkinson's disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better. Methods: Data were obtained from the Parkinson's Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD. Results: SDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323. Conclusion: SDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.

Prognostic Value of Coronary Microvascular Dysfunction Assessed by Coronary Angiography-Derived Index of Microcirculatory Resistance in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: CaIMR is proposed as a novel angiographic index designed to assess microcirculation without the need for pressure wires or hyperemic agents. We aimed to investigate the impact of caIMR on predicting clinical outcomes in STEMI patients. METHODS: One hundred and forty patients with STEMI who received PCI in Putuo Hospital of Shanghai from October 2021 to September 2022 were categorized into CMD and non-CMD groups according to the caIMR value. The baseline information, patient-related examinations, and the occurrence of MACE at the 12-month follow-up were collected to investigate risk factors in patients with STEMI. RESULTS: We divided 140 patients with STEMI enrolled into two groups according to caIMR results, including 61 patients diagnosed with CMD and 79 patients diagnosed with non-CMD. A total of 21 MACE occurred during the 1 year of follow-up. Compared with non-CMD group, patients with CMD showed a significantly higher risk of MACE. A multivariate Cox regression model was conducted for the patients, and it was found thatcaIMR was a significant predictor of prognosis in STEMI patients (HR: 8.921). Patients with CMD were divided into culprit vascular CMD and non-culprit vascular CMD, and the result found that culprit vascular CMD was associated with the incidence of MACE (OR: 4.75) and heart failure (OR: 7.50). CONCLUSION: CaIMR is a strong predictor of clinical outcomes and can provide an objective risk stratification for patients with STEMI. There is a strong correlation among leukocyte index, the use of furosemide, Killips classification, and clinical outcomes.

Helicobacter pylori infection alters gastric microbiota structure and biological functions in patients with gastric ulcer or duodenal ulcer.

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with gastrointestinal diseases. Our preliminary studies have indicated that H. pylori infection had a significant impact on the mucosal microbiome structure in patients with gastric ulcer (GU) or duodenal ulcer (DU). AIM: To investigate the contributions of H. pylori infection and the mucosal microbiome to the pathogenesis and progression of ulcerative diseases. METHODS: Patients with H. pylori infection and either GU or DU, and healthy individuals without H. pylori infection were included. Gastric or duodenal mucosal samples was obtained and subjected to metagenomic sequencing. The compositions of the microbial communities and their metabolic functions in the mucosal tissues were analyzed. RESULTS: Compared with that in the healthy individuals, the gastric mucosal microbiota in the H. pylori-positive patients with GU was dominated by H. pylori, with significantly reduced biodiversity. The intergroup differential functions, which were enriched in the H. pylori-positive GU patients, were all derived from H. pylori, particularly those concerning transfer RNA queuosine-modification and the synthesis of demethylmenaquinones or menaquinones. A significant enrichment of the uibE gene was detected in the synthesis pathway. There was no significant difference in microbial diversity between the H. pylori-positive DU patients and healthy controls. CONCLUSION: H. pylori infection significantly alters the gastric microbiota structure, diversity, and biological functions, which may be important contributing factors for GU.

[Applications of high performance liquid chromatography-mass spectrometry in proteomics].

Proteomics profiling plays an important role in biomedical studies. Proteomics studies are much more complicated than genome research, mainly because of the complexity and diversity of proteomic samples. High performance liquid chromatography-mass spectrometry (HPLC-MS) is a fundamental tool in proteomics research owing to its high speed, resolution, and sensitivity. Proteomics research targets from the peptides and individual proteins to larger protein complexes, the molecular weight of which gradually increases, leading to sustained increases in structural and compositional complexity and alterations in molecular properties. Therefore, the selection of various separation strategies and stationary-phase parameters is crucial when dealing with the different targets in proteomics research for in-depth proteomics analysis. This article provides an overview of commonly used chromatographic-separation strategies in the laboratory, including reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), hydrophobic interaction chromatography (HIC), ion-exchange chromatography (IEC), and size-exclusion chromatography (SEC), as well as their applications and selectivity in the context of various biomacromolecules. At present, no single chromatographic or electrophoretic technology features the peak capacity required to resolve such complex mixtures into individual components. Multidimensional liquid chromatography (MDLC), which combines different orthogonal separation modes with MS, plays an important role in proteomics research. In the MDLC strategy, IEC, together with RPLC, remains the most widely used separation mode in proteomics analysis; other chromatographic methods are also frequently used for peptide/protein fractionation. MDLC technologies and their applications in a variety of proteomics analyses have undergone great development. Two strategies in MDLC separation systems are mainly used in proteomics profiling: the "bottom-up" approach and the "top-down" approach. The "shotgun" method is a typical "bottom-up" strategy that is based on the RPLC or MDLC separation of whole-protein-sample digests coupled with MS; it is an excellent technique for identifying a large number of proteins. "Top-down" analysis is based on the separation of intact proteins and provides their detailed molecular information; thus, this technique may be advantageous for analyzing the post-translational modifications (PTMs) of proteins. In this paper, the "bottom-up" "top-down" and protein-protein interaction (PPI) analyses of proteome samples are briefly reviewed. The diverse combinations of different chromatographic modes used to set up MDLC systems are described, and compatibility issues between mobile phases and analytes, between mobile phases and MS, and between mobile phases in different separation modes in multidimensional chromatography are analyzed. Novel developments in MDLC techniques, such as high-abundance protein depletion and chromatography arrays, are further discussed. In this review, the solutions proposed by researchers when encountering compatibility issues are emphasized. Moreover, the applications of HPLC-MS combined with various sample pretreatment methods in the study of exosomal and single-cell proteomics are examined. During exosome isolation, the combined use of ultracentrifugation and SEC can yield exosomes of higher purity. The use of SEC with ultra-large-pore-size packing materials (200 nm) enables the isolation of exosomal subgroups, and proteomics studies have revealed significant differences in protein composition and function between these subgroups. In the field of single-cell proteomics, researchers have addressed challenges related to reducing sample processing volumes, preventing sample loss, and avoiding contamination during sample preparation. Innovative methods and improvements, such as the utilization of capillaries for sample processing and microchips as platforms to minimize the contact area of the droplets, have been proposed. The integration of these techniques with HPLC-MS shows some progress. In summary, this article focuses on the recent advances in HPLC-MS technology for proteomics analysis and provides a comprehensive reference for future research in the field of proteomics.

Microscopic Mechanism for Gradient Diffusion of Salt-Containing Droplets Induced by Electromagnetic Synergy: A Molecular Dynamics Study.

The electromagnetic synergy has been proven to be highly effective in separating oil-water emulsions. However, the dynamic impact mechanism of electromagnetic fields on the internal structure of salt droplets remains unclear. In this study, the molecular dynamics (MD) simulation was used to investigate the molecular diffusion of salt ions and water molecules, as well as the dynamic behavior of droplets under the combined influence of electromagnetic fields. The results indicate that ions accumulate in the electromagnetic synergistic field, causing the deformation amplitude of droplets to be smaller than that in a single electric field. The magnetic field affects the energy of the system, when the magnetic field strength is between 1 and 5T, the nonbonded energy significantly increases nonlinearly; when the magnetic field strength is greater than 5T, the total energy of the system significantly changes. In addition, the viscosity of the medium is significantly lower when the intensity of the magnetic and electric fields is controlled within a specific range, providing a new way to regulate the fluidity of fluids.

DNA nanoassembly based turn-on amplification probe for sensitive colorimetric CRISPR/Cas12a-mediated detection of pathogen DNA.

Clustered regularly interspaced short palindromic repeat (CRISPR) system has been explored as an efficient tool for nucleic acid diagnostics. However, it normally needs instrumentation or produces turn-off signals. Herein, a bulged Y-shape DNA (Y-DNA) nanoassembly was designed and synthesized as a novel turn-on probe. A CRISPR/Cas12a and Y-DNA probe mediated colorimetric assay (named as CYMCOA) strategy was developed for visual detection of pathogen DNA. Upon activating Cas12a with pathogen DNA, the Y-DNA bulge is catalytically trans-cleaved, releasing the G-quadruplex sequence embedded in the Y-DNA nanoassembly as a peroxidase-like DNAzyme. Visible signals with chromogen substrates are thus produced. The CYMCOA strategy was combined with recombinase polymerase amplification (RPA), an isothermal amplification technique, in detecting Helicobacter pylori (Hp) bacteria and SARS-CoV-2 N plasmids as two model pathogens. The bioassay has very excellent detection sensitivity and specificity, owing to the triple cascade amplification reactions and the very low mismatch tolerance. The lower limit of detection values were 0.16 cfu⋅mL-1, 1.5 copies⋅µL-1, and 0.17 copies⋅µL-1 for Hp bacteria, Hp plasmids, and SARS-CoV-2 N plasmids respectively. The detection is fast and accurate. The colorimetric bioassay strategy provides to be a simple, accurate, fast and instrumentation-free platform for nucleic acids detections in various settings, including crude and emergent situations.

Classification of psychedelic drugs based on brain-wide imaging of cellular c-Fos expression.

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for screening psychoactive drugs with psychedelic properties.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.

Silver Nanoparticles Encapped by Dihydromyricetin: Optimization of Green Synthesis, Characterization, Toxicity, and Anti-MRSA Infection Activities for Zebrafish (Danio rerio).

To achieve the environmentally friendly and rapid green synthesis of efficient and stable AgNPs for drug-resistant bacterial infection, this study optimized the green synthesis process of silver nanoparticles (AgNPs) using Dihydromyricetin (DMY). Then, we assessed the impact of AgNPs on zebrafish embryo development, as well as their therapeutic efficacy on zebrafish infected with Methicillin-resistant Staphylococcus aureus (MRSA). Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) analyses revealed that AgNPs possessed an average size of 23.6 nm, a polymer dispersity index (PDI) of 0.197 ± 0.0196, and a zeta potential of -18.1 ± 1.18 mV. Compared to other published green synthesis products, the optimized DMY-AgNPs exhibited smaller sizes, narrower size distributions, and enhanced stability. Furthermore, the minimum concentration of DMY-AgNPs required to affect zebrafish hatching and survival was determined to be 25.0 µg/mL, indicating the low toxicity of DMY-AgNPs. Following a 5-day feeding regimen with DMY-AgNP-containing food, significant improvements were observed in the recovery of the gills, intestines, and livers in MRSA-infected zebrafish. These results suggested that optimized DMY-AgNPs hold promise for application in aquacultures and offer potential for further clinical use against drug-resistant bacteria.

Radiomic biomarkers of locoregional recurrence: prognostic insights from oral cavity squamous cell carcinoma preoperative CT scans.

Introduction: This study aimed to identify CT-based imaging biomarkers for locoregional recurrence (LR) in Oral Cavity Squamous Cell Carcinoma (OSCC) patients. Methods: Computed tomography scans were collected from 78 patients with OSCC who underwent surgical treatment at a single medical center. We extracted 1,092 radiomic features from gross tumor volume in each patient's pre-treatment CT. Clinical characteristics were also obtained, including race, sex, age, tobacco and alcohol use, tumor staging, and treatment modality. A feature selection algorithm was used to eliminate the most redundant features, followed by a selection of the best subset of the Logistic regression model (LRM). The best LRM model was determined based on the best prediction accuracy in terms of the area under Receiver operating characteristic curve. Finally, significant radiomic features in the final LRM model were identified as imaging biomarkers. Results and discussion: Two radiomics biomarkers, Large Dependence Emphasis (LDE) of the Gray Level Dependence Matrix (GLDM) and Long Run Emphasis (LRE) of the Gray Level Run Length Matrix (GLRLM) of the 3D Laplacian of Gaussian (LoG σ=3), have demonstrated the capability to preoperatively distinguish patients with and without LR, exhibiting exceptional testing specificity (1.00) and sensitivity (0.82). The group with LRE > 2.99 showed a 3-year recurrence-free survival rate of 0.81, in contrast to 0.49 for the group with LRE ≤ 2.99. Similarly, the group with LDE > 120 showed a rate of 0.82, compared to 0.49 for the group with LDE ≤ 120. These biomarkers broaden our understanding of using radiomics to predict OSCC progression, enabling personalized treatment plans to enhance patient survival.

Applications of magnetic solid-phase extraction in the sample preparation of natural product analysis (2020-2023).

Sample preparation, including extraction, separation, and purification, is a vital process for natural product analysis. As an attractive sample pretreatment method, magnetic solid-phase extraction (MSPE) has gained plenty of attention, mainly due to its simpler operation, less consumption of organic solvents, and shorter processing time than traditional SPE. This updated review is devoted to summarizing the applications of MSPE based on different magnetic nanomaterials in the analysis of various natural products in complex matrixes, such as biological samples, plants, and Chinese herbal preparations in the past four years (2020-2023). The preparation and fabrication of different materials are briefly introduced. Furthermore, the extraction mechanism and interaction forces between adsorbent and analytes are elaborated, and the advantages and disadvantages of different adsorbents coupled with various analytical methods for MSPE of different natural products are summarized. Moreover, the future trends and opportunities for MSPE in the natural product analysis are discussed. It is expected that this work can provide updated information for future research on the applications of MSPE in such fields.

Gas chromatography-ion mobility spectrometry (GC-IMS) technique and its recent applications in grain research.

Grains are the primary source of food for most people worldwide and constitute a major source of carbohydrates. Many novel technologies are being employed to ensure the safety and reliability of grain supply and production. Gas chromatography-ion mobility spectrometry (GC-IMS) can effectively separate and sensitively detect volatile organic compounds. It possesses advantages such as speed, convenience, high sensitivity, no pretreatment, and wide applicability. In recent years, many studies have shown that the application of GC-IMS technology for grain flavor analysis can play a crucial role in grains. This article elucidates the working principle of GC-IMS technology, reviews the application of GC-IMS in grains in the past 5 years. GC-IMS technology is mainly applied in four aspects in grains. In grain classification, it distinguishes varieties, quality, origin, production year, and processing methods based on the trace differences in volatile organic compounds, thereby fulfilling various grain classification requirements such as origin tracing, geographical indication product recognition, variety identification, production year identification, and detection of counterfeit and inferior grain samples. In optimizing the processing technology of grains and their products, it can improve food flavor, reduce undesirable flavors, and identify better processing parameters. In grain storage, it can determine the storage time, detect spoilage phenomena such as mold and discoloration during storage, eliminate pests affecting storage, and predict the vitality of seeds after storage. In aroma evaluation of grains and their processed products, it can assess the impact of new raw materials, new technologies, fermentation processes, and even oral processing on the quality of grain products. This article also summarizes the characteristics of GC-IMS technology, compiles typical grain flavor compounds, and provides prospects for the future application of GC-IMS. © 2024 Society of Chemical Industry.

Ghrelin inhibits autophagy mediated by AKT/mTOR pathway to ameliorate retinal angiogenesis induced by high glucose stress.

AIM: To observe the effect of ghrelin, a growth hormone-releasing peptide, on retinal angiogenesis in vitro under high glucose (HG) stress and to explore the possible mechanism of autophagy. METHODS: Human retinal microvascular endothelial cells (HRMECs) were treated with high concentration of glucose alone or in combination with ghrelin. The cell migration, tube formation and the expression of the autophagy-related proteins LC3-II/I, Beclin-1, p62, phosphorylated AKT (p-AKT)/AKT and phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR were detected. Then, to clarify the correlation between ghrelin effect and autophagy, AKT inhibitor VIII was adopted to treat HRMECs, and cell migration, tube formation as well as the protein expressions of LC3-II/I, Beclin-1 and p62 were observed. RESULTS: Under HG stress, ghrelin inhibited migration and tube formation of HRMECs. Ghrelin inhibited the increases in the protein levels of LC3-II/I, Beclin-1 and the decreases in the protein levels of p62, p-AKT/AKT and p-mTOR/mTOR induced by HG stress. Moreover, under the action of AKT/mTOR pathway inhibitors, the effects of ghrelin on migration and tube formation were both reduced. In addition, the expression of LC3-II/I and Beclin-1 were significantly up-regulated and the expression of p62 was down-regulated. CONCLUSION: Retinal angiogenesis under in vitro HG stress can be inhibited by ghrelin through activating AKT/mTOR pathway to inhibit autophagy.

Passive immunotherapy for Alzheimer's disease: challenges & future directions.

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.

Rutaecarpine Alleviates Early Brain Injury-Induced Inflammatory Response Following Subarachnoid Hemorrhage via SIRT6/NF-[Formula: see text]B Pathway.

Subarachnoid hemorrhage (SAH), a specific subtype of cerebrovascular accident, is characterized by the extravasation of blood into the interstice between the brain and its enveloping delicate tissues. This pathophysiological phenomenon can precipitate an early brain injury (EBI), which is characterized by inflammation and neuronal death. Rutaecarpine (Rut), a flavonoid compound discovered in various plants, has been shown to have protective effects against SAH-induced cerebral insult in rodent models. In our study, we used a rodent SAH model to evaluate the effect of Rut on EBI and investigated the effect of Rut on the inflammatory response and its regulation of SIRT6 expression in vitro. We found that Rut exerts a protective effect on EBI in SAH rats, which is partly due to its ability to inhibit the inflammatory response. Notably, Rut up-regulated Sirtuin 6 (SIRT6) expression, leading to an increase in H3K9 deacetylation and inhibition of nuclear factor-kappa B (NF-[Formula: see text]B) transcriptional activation, thereby mediating the inflammatory response. In addition, further data showed that SIRT6 was proven to mediate the regulation of Rut on the microglial inflammatory response. These findings highlight the importance of SIRT6 in the regulation of inflammation and suggest a potential mechanism for the protective effect of Rut on EBI. In summary, Rut may have the potential to prevent and treat SAH-induced brain injury by interacting with SIRT6. Our findings may provide a new therapeutic strategy for the treatment of SAH-induced EBI.

The Role of JAK-STAT-SOCS1 Axis in Tumorigenesis, Malignant Progression and Lymphatic Metastasis of Penile Cancer.

Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.

Reelin links Apolipoprotein E4, Tau, and Amyloid-ß in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the cerebral cortex and hippocampus, and is characterised by progressive cognitive decline and memory loss. A recent report of a patient carrying a novel gain-of-function variant of RELN (H3447R, termed RELN-COLBOS) who developed resilience against presenilin-linked autosomal-dominant AD (ADAD) has generated enormous interest. The RELN-COLBOS variant enhances interactions with the apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which are associated with delayed AD onset and progression. These findings were validated in a transgenic mouse model. Reelin is involved in neurodevelopment, neurogenesis, and neuronal plasticity. The evidence accumulated thus far has demonstrated that the Reelin pathway links apolipoprotein E4 (ApoE4), amyloid-ß (Aß), and tubulin-associated unit (Tau), which are key proteins that have been implicated in AD pathogenesis. Reelin and key components of the Reelin pathway have been highlighted as potential therapeutic targets and biomarkers for AD.

Molybdate-Templated Luminescent Silver Alkynyl Nanoclusters: Total Structure Determination and Optical Property Analysis.

Two novel MoO42--templated luminescent silver alkynyl nanoclusters with 20-nuclearity ([(MoO42-)@Ag20(C≡CtBu)8(Ph2PO2)7(tfa)2]·(tfa-) (1)) and 18-nuclearity ([(MoO42-)@Ag18(C≡CtBu)8(Ph2PO2)7]·(OH) (2)) (tfa = trifluoroacetate) were synthesized with the green light maximum emissions at 507 and 516 nm, respectively. The nanoclusters were investigated and characterized by single-crystal X-ray crystallography, electrospray ionization mass spectrum (ESI-MS), X-ray photoelectron spectroscopy, thermogravimetry (TG), photoluminescence (PL), ultraviolet-visible (UV-vis) spectroscopy, and density functional theory calculations (DFT). The two nanoclusters differ in their structure by a supplementary [Ag2(tfa)2] organometallic surface motif, which significantly participates in the frontier molecular orbitals of 1, resulting in similar bonding patterns but different optical properties between the two clusters. Indeed, both nanoclusters show strong temperature-dependent photoluminescence properties, which make them potential candidates in the fields of optical devices for further applications.

Three-stage niobium mineralization at Bayan Obo, China.

The Chinese Bayan Obo deposit is a world-class rare earth element (REE) deposit with considerable niobium (Nb) and iron (Fe) resources. A complete genetic understanding on all metals is fundamental for establishing genetic models at Bayan Obo. With extensive research being focused on REE enrichment, the timing and controls of Nb enrichment remain unresolved at Bayan Obo, which is mainly due to the challenges in dating, i.e. multistage thermal events, fine-grained minerals with complex textures and the rare occurrence of uranium-enriched minerals with mature dating methods. Based on robust geological and petrographic frameworks, here we conducted ion probe uranium-lead (U-Pb) dating of ferrocolumbite to unravel the timing, hence the genesis of Nb mineralization. Three types of hydrothermal ferrocolumbites-key Nb-bearing minerals-are identified based on their textures and mineral assemblages. They yield U-Pb ages of 1312 ± 47 Ma (n = 99), 438 ± 7 Ma (n = 93), and 268 ± 5 Ma (n = 19), respectively. In line with deposit geology, we tentatively link the first, second and third stage Nb mineralization to Mesoproterozoic carbonatite magmatism, ubiquitous early Paleozoic hydrothermal activity, and Permian granitic magmatism, respectively. While quantifying the contribution of metal endowment from each stage requires further investigation, our new dates highlight that multi-stage mineralization is critical for Nb enrichment at Bayan Obo, which may also have implications for the enrichment mechanism of Nb in REE deposits in general.