Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy.

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory, resistant to antiepileptic drugs, and has a high recurrence rate. The pathogenesis of temporal lobe epilepsy is complex and is not fully understood. Intracellular calcium dynamics have been implicated in temporal lobe epilepsy. However, the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown, and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice. In this study, we used a multi-channel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process. We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes. In particular, cortical spreading depression, which has recently been frequently used to represent the continuously and substantially increased calcium signals, was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from grade II to grade V. However, vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures. Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to grade I episodes. In addition, the latency of cortical spreading depression was prolonged, and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced. Intriguingly, it was possible to rescue the altered intracellular calcium dynamics. Via simultaneous analysis of calcium signals and epileptic behaviors, we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced, and that the end-point behaviors of temporal lobe epilepsy were improved. Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades. Furthermore, the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy, thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

Spatiotemporal insight into early pregnancy governed by immune-featured stromal cells.

Endometrial decidualization connecting embryo implantation and placentation is transient but essential for successful pregnancy, which, however, is not systematically investigated. Here, we use a scStereo-seq technology to spatially visualize and define the dynamic functional decidual hubs assembled by distinct immune, endothelial, trophoblast, and decidual stromal cells (DSCs) in early pregnant mice. We unravel the DSC transdifferentiation trajectory and surprisingly discover a dual-featured type of immune-featured DSCs (iDSCs). We find that immature DSCs attract immune cells and induce decidual angiogenesis at the mesenchymal-epithelial transition hub during decidualization initiation. iDSCs enable immune cell recruitment and suppression, govern vascularization, and promote cytolysis at immune cell assembling and vascular hubs, respectively, to establish decidual homeostasis at a later stage. Interestingly, dysfunctional and spatially disordered iDSCs cause abnormal accumulation of immune cells in the vascular hub, which disrupts decidual hub specification and eventually leads to pregnancy complications in DBA/2-mated CBA/J mice.

High NA and polarization-insensitive ultra-broadband achromatic metalens from 500 to 1050†nm for multicolor two-photon endomicroscopy imaging.

Multicolor two-photon endomicroscopy has become a highly competitive tool for functional imaging in biomedical researches. However, to make the imaging system miniature and applicable for freely behaving animal brain activity, metalenses have received much attention in compact imaging systems. For high resolution multicolor imaging and maximizing fluorescence collection, there is a challenge metalenses faced to achieve large numerical aperture (NA) and focus the NIR excitation and VIS emission lights of multiple fluorophores to the same distance simultaneously because of the limitation of the group delay range of the meta-units. In this paper, we proposed a high NA and polarization-insensitive ultra-broadband achromatic metalens specifically for achromatically focusing the excitation and emission light of multiple fluorophores commonly used in neuroscience studies. TiO2 and Si meta-unit libraries composed of heights, widths and the corresponding phase and group delay were constructed, and the optimal meta-units were selected by particle swarm optimization algorithm to engineer the dispersion of metalens in the VIS band and NIR band, respectively. Combining dispersion engineering with spatial multiplexing, the proposed metalens achieved the maximal effective NA up to 0.8 and large achromatic bandwidth ranging from 500 nm to 1050 nm, which exhibited the coefficient of variation of focal lengths was only 3.41%. The proposed achromatic metalens could successfully achromatically focus different fluorescence with any polarization, which was suitable for most fluorophores. Our results firmly establish that the proposed metalens can open the door to high resolution and minimally invasive multicolor two-photon functional imaging in intravital deep brain.

Design strategy and research progress of multifunctional nanoparticles in lung cancer therapy.

INTRODUCTION: Lung cancer is one of the cancer types with the highest mortality rate, exploring a more effective treatment modality that improves therapeutic efficacy while mitigating side effects is now an urgent requirement. Designing multifunctional nanoparticles can be used to overcome the limitations of drugs and conventional drug delivery systems. Nanotechnology has been widely researched, and through different needs, suitable nanocarriers can be selected to load anti-cancer drugs to improve the therapeutic effect. It is foreseeable that with the rapid development of nanotechnology, more and more lung cancer patients will benefit from nanotechnology. This paper reviews the merits of various multifunctional nanoparticles in the treatment of lung cancer to provide novel ideas for lung cancer treatment. AREAS COVERED: This review focuses on summarizing various nanoparticles for targeted lung cancer therapy and their advantages and disadvantages, using nanoparticles loaded with anti-cancer drugs, delivered to lung cancer sites, enhancing drug half-life, improving anti-cancer drug efficacy and reducing side effects. EXPERT OPINION: The delivery mode of nanoparticles with superior pharmacokinetic properties in the in vivo circulation enhances the half-life of the drug, and provides tissue-targeted selectivity and the ability to overcome biological barriers, bringing a revolution in the field of oncology.

PtAg18 superatoms costabilized by phosphines and halides: synthesis, structure, and catalysis.

Reported herein is the facial synthesis, molecular structure, and catalysis of a Pt/Ag nanocluster costabilized by organic ligands of phosphines and inorganic ligands of chlorides. The nanocluster with molecular formula of [PtAg18(dppp)6Cl8](SbF6)2 has been obtained facilely by the one pot method. The structure of the cluster could be anatomized as the stabilizaiton of PtAg12-centered icosahedral core by the metalloligand of dppp-Ag-Cl, in which Cl- not only caps the surface Ag atoms but also binds the core and surface motifs. Featuring eight free electrons in its structure, the cluster exhibits high stability. More interestingly, the exposure of surface metal sites endows the cluster with counterintutively  high catalytic activity in hydrogenation reactions.

Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue.

N6-methyladenosine (m6A) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of m6A in a self-renewing somatic tissue, we deleted Mettl3 in epidermal progenitors in vivo. Mice lacking Mettl3 demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the m6A-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of m6A on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m6A in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed m6A in proper epithelial development and self-renewal.

SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation.

BACKGROUND: Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. METHODS: Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. RESULTS: We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. CONCLUSION: Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy.

Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin.

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.

Ssa1-targeted antibody prevents host invasion by Candida albicans.

Introduction: Candida albicans is a commensal fungus that colonizes most healthy individuals' skin and mucosal surfaces but can also cause life-threatening invasive infections, particularly in immunocompromised patients. Despite antifungal treatment availability, drug resistance is increasing, and mortality rates remain unacceptably high. Heat shock protein Ssa1, a conserved member of the Hsp70 family in yeast, is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and enables C. albicans to cause maximal damage to host cells and induces disseminated and oropharyngeal disease. Result: Here we discovered a mouse monoclonal antibody (mAb 13F4) that targeting C. albicans Ssa1 with high affinity (EC50 = 39.78 ng/mL). mAb 13F4 prevented C. albicans from adhering to and invading human epithelial cells, displayed antifungal activity, and synergized with fluconazole in proof of concept in vivo studies. mAb 13F4 significantly prolonged the survival rate of the hematogenous disseminated candidiasis mice to 75%. We constructed a mAb 13F4 three-dimensional structure using homology modeling methods and found that the antigen-binding fragment (Fab) interacts with the Ssa1 N-terminus. Discussion: These results suggest that blocking Ssa1 cell surface function may effectively control invasive C. albicans infections and provide a potential new treatment strategy for invasive fungal infections.

Extraction and characterisation of pigment from Yanzhiguo [Prunus napaulensis (Ser.) Steud.].

Yanzhiguo [Prunus napaulensis (Ser.) Steud] belongs to Rosaceae family and is consumed as wild fruit, pulp and juice. However, its potential for extracting natural pigment has not yet been explored. Herein, the components in the fresh Yanzhiguo pulp were preliminarily analyzed by liquid chromatography coupled to mass spectrometry. And, the optimal pre-treatment conditions were established for further extraction of Yanzhiguo pigment based on the a* value. Then, by combining the data from single-factor experiments and response surface methodology, the optimal extraction process was established as: 35% EtOH, a liquid-solid ratio of 200:1 mL g-1, an extraction time of 65 min, and an extraction temperature of 100 °C. Moreover, it was found that the a* value and yield had high fitness except when extracted into ethanol (EtOH) with different concentrations. Meanwhile, our result demonstrated Yanzhiguo pigment had high stability in general environments with carmine (a synthetic pigment) as control, except for extreme environments such as direct (hot) sunlight, high temperature (75 °C) and strong alkaline (pH ≥ 11). Also, Yanzhiguo pigment exhibited good antioxidant activity. Our results contribute to more information on Yanzhiguo pigment and promote its application by providing efficient extraction technology.

Treatment outcomes after radiofrequency ablation in patients with non-B non-C hepatocellular carcinoma within Milan criteria: comparison with HBV-related hepatocellular carcinoma.

PURPOSE: This study aims to evaluate the treatment outcomes of radiofrequency ablation (RFA) for patients with non-B non-C hepatocellular carcinoma (HCC) (NBNC-HCC) within Milan criteria, as well as to compare them with those of patients with hepatitis B virus (HBV)-related HCC (HBV-HCC). METHODS: From January 2007 to February 2020, 303 patients with primary HCC who underwent RFA were retrospectively reviewed, including 259 patients with HBV-HCC (HBV-HCC group) and 44 patients with NBNC-HCC (NBNC-HCC group). The clinical characteristics and treatment survivals were evaluated and compared. Moreover, the propensity score matching was used to reduce selection bias. RESULTS: A significantly lower proportion of cirrhosis was observed in the NBNC-HCC group (p = .048). Before propensity score matching, local tumor progression, disease-free survival, and overall survival after RFA showed no significant differences between the two groups (all p > .05). After matching, the overall survival rates in the NBNC-HCC group were significantly better than those in the HBV-HCC group (p = .042). Moreover, for patients with NBNC-HCC, tumor size (hazard ratio = 8.749, 95% confidence interval, 1.599-47.849; p = .012) was the only independent predictor of local tumor progression. CONCLUSIONS: Patients with NBNC-HCC within the Milan criteria after RFA had better long-term survival than patients with HBV-HCC, although larger, prospective and multicenter trials are required to validate these results.

Somatomotor-Visual Resting State Functional Connectivity Increases After Two Years in the UK Biobank Longitudinal Cohort.

PURPOSE: Functional magnetic resonance imaging (fMRI) and functional connectivity (FC) have been used to follow aging in both children and older adults. Robust changes have been observed in children, where high connectivity among all brain regions changes to a more modular structure with maturation. In this work, we examine changes in FC in older adults after two years of aging in the UK Biobank longitudinal cohort. APPROACH: We process data using the Power264 atlas, then test whether FC changes in the 2,722-subject longitudinal cohort are statistically significant using a Bonferroni-corrected t-test. We also compare the ability of Power264 and UKB-provided, ICA-based FC to determine which of a longitudinal scan pair is older. RESULTS: We find a 6.8\% average increase in SMT-VIS connectivity from younger to older scan (from $\rho=0.39$ to $\rho=0.42$) that occurs in male, female, older subject ($>65$ years old), and younger subject ($<55$ years old) groups. Among all inter-network connections, this average SMT-VIS connectivity is the best predictor of relative scan age, accurately predicting which scan is older 57\% of the time. Using the full FC and a training set of 2,000 subjects, one is able to predict which scan is older 82.5\% of the time using either the full Power264 FC or the UKB-provided ICA-based FC. CONCLUSIONS: We conclude that SMT-VIS connectivity increases in the longitudinal cohort, while resting state FC increases generally with age in the cross-sectional cohort. However, we consider the possibility of a change in resting state scanner task between UKB longitudinal data acquisitions.

The key constituents underlying the combined toxicity of eight cosmetic contaminants towards Vibrio qinghaiensis.

Cosmetic additives (ADDs) and packaging plasticizers (PLAs) probably present potential risks and dangers to the environment and human body as emerging pollutants. To investigate their potential risks and dangers, five ADDs including methyl paraben (MET), ethyl paraben (ETH), propyl paraben (PRO), butyl-hydroxy anisole (BHA), and salicylic acid (SAL), as well as three PLAs including bisphenol A (BPA), bisphenol S (BPS) and tris(2-butoxyethyl) phosphate (TBEP) were selected as research objects, and ten mixture rays (R1-R10) composed of the eight components were designed by the uniform design ray (UD-Ray) method. The toxicities of the eight cosmetic pollutants and their eight-component mixture system towards Vibrio qinghaiensis sp.-Q67 (Q67) were systematically determined by the time-dependent microplate toxicity analysis (t-MTA) method. The three-dimensional (3D) surface of deviation from the concentration addition model (dCA) was utilized to qualitatively and quantitatively analyse the toxicity interaction of the mixtures and the correlation between toxicity interaction and the components' concentration ratios. Finally, eight individual pollutants and representative rays with significant inhibitory and interactive effects were selected to analyse DNA and soluble proteolysis as well as the microstructure and morphology of Q67 after treatment with single chemicals and their mixtures. The results showed that the eight cosmetic pollutants had conspicuous concentration-dependent toxicity and acute toxicity, and none of them, except BPS, BPA and ETH, had time-dependent toxicity. All rays had time/concentration-dependent toxicity and acute toxicity. At the same time, the toxicity interaction of these mixture rays was predominantly antagonism and the strongest antagonism appeared at high concentrations at 12 h. Nevertheless, the components' concentration ratio (pi) was the decisive factor for the type of mixture interaction. The correlation analysis revealed a significant positive linear correlation between mixture toxicity and pETH and pBPA, which indicated that ETH and BPA were the key components of the toxic effects. However, there was a significant negative linear correlation between the antagonism intensity and pBPA and pTBEP, which demonstrated that BPA and TBEP were the key components of the antagonism intensity. Pollutants and their mixtures can also damage cellular structures, and mixtures can exacerbate the dissolution of DNA and soluble proteins.

Identifiability in Functional Connectivity May Unintentionally Inflate Prediction Results.

Functional magnetic resonance (fMRI) is an invaluable tool in studying cognitive processes in vivo. Many recent studies use functional connectivity (FC), partial correlation connectivity (PC), or fMRI-derived brain networks to predict phenotypes with results that sometimes cannot be replicated. At the same time, FC can be used to identify the same subject from different scans with great accuracy. In this paper, we show a method by which one can unknowingly inflate classification results from 61% accuracy to 86% accuracy by treating longitudinal or contemporaneous scans of the same subject as independent data points. Using the UK Biobank dataset, we find one can achieve the same level of variance explained with 50 training subjects by exploiting identifiability as with 10,000 training subjects without double-dipping. We replicate this effect in four different datasets: the UK Biobank (UKB), the Philadelphia Neurodevelopmental Cohort (PNC), the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP), and an OpenNeuro Fibromyalgia dataset (Fibro). The unintentional improvement ranges between 7% and 25% in the four datasets. Additionally, we find that by using dynamic functional connectivity (dFC), one can apply this method even when one is limited to a single scan per subject. One major problem is that features such as ROIs or connectivities that are reported alongside inflated results may confuse future work. This article hopes to shed light on how even minor pipeline anomalies may lead to unexpectedly superb results.

Reduced nitrite accumulation at the primary nitrite maximum in the cyclonic eddies in the western North Pacific subtropical gyre.

Nitrite, an intermediate product of the oxidation of ammonia to nitrate (nitrification), accumulates in upper oceans, forming the primary nitrite maximum (PNM). Nitrite concentrations in the PNM are relatively low in the western North Pacific subtropical gyre (wNPSG), where eddies are frequent and intense. To explain these low nitrite concentrations, we investigated nitrification in cyclonic eddies in the wNPSG. We detected relatively low half-saturation constants (i.e., high substrate affinities) for ammonia and nitrite oxidation at 150 to 200 meter water depth. Eddy-induced displacement of high-affinity nitrifiers and increased substrate supply enhanced ammonia and nitrite oxidation, depleting ambient substrate concentrations in the euphotic zone. Nitrite oxidation is more strongly enhanced by the cyclonic eddies than ammonia oxidation, reducing concentrations and accelerating the turnover of nitrite in the PNM. These findings demonstrate a spatial decoupling of the two steps of nitrification in response to mesoscale processes and provide insights into physical-ecological controls on the PNM.

Ginsenosides in endometrium-related diseases: Emerging roles and mechanisms.

Ginsenosides, agents extracted from an important herb (ginseng), are expected to provide new therapies for endometrium-related diseases. Based on the molecular types of ginsenosides, we reviewed the main pharmacological effects of ginsenosides against endometrium-related diseases (e.g., endometrial cancers, endometriosis, and endometritis). The mechanism of action of ginsenosides involves inducing apoptosis of endometrium-related cells, promoting autophagy of endometrium-related cells, regulating epithelial-mesenchymal transition (EMT) in endometrium-related cells, and activating the immune system to kill cells associated with endometrial diseases. We hope to provide a theoretical foundation for the treatment of endometrium-related diseases by ginsenosides.

Association of select psychiatric disorders with incident brain aneurysm and subarachnoid hemorrhage among veterans.

Background: Brain aneurysms represent a significant cause of hemorrhagic stroke. Prior research has demonstrated links between stress and stroke, including brain aneurysms. We aimed to determine relationships between select psychiatric disorders and aneurysms and aneurysmal SAH. Methods: We performed retrospective, case-control study of a National Veterans Affairs population with two experimental groups (aneurysm-only and aneurysmal SAH) and 10-fold controls per group matched by age, date, and clinical data source. The studied the presence of 4 psychiatric disorders: Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), generalized anxiety disorder (GAD), and other mood disorders. Our main outcomes Unadjusted and multivariable adjusted ORs of PTSD, MDD, GAD, and mood disorders within aneurysm-only and aSAH groups. Results: In 6,320,789 US Veterans who were enrolled for at least 5 years in Medicare and/or the Veterans Health Administration, we identified 35,094 cases of aneurysm without SAH and 5,749 cases of aneurysm with SAH between 1/2005 and 12/2019. In analyses adjusted for sex, hypertension, and tobacco use, patients with aneurysm were more likely than matched controls to have a history of PTSD (OR 1.48), MDD (OR 1.33), GAD (OR 1.26), and other mood disorders (OR 1.34) (all p-values < 0.0001). Similarly, patients with aSAH were more likely than controls to have a history of PTSD (OR 1.35), MDD (OR 1.38), GAD (OR 1.18), and other mood disorders (OR 1.30) (all p-values < 0.0001). Conclusion: The study, the largest of its kind, further suggests links between psychiatric disorders and stroke. This is important as patients with aneurysms are not routinely screened for such psychiatric risk factors. Additional research on this topic could lead to novel strategies to improve stroke prevention.

LHPP-mediated inorganic pyrophosphate hydrolysis-driven lysosomal acidification in astrocytes regulates adult neurogenesis.

In bacteria, archaea, protists, and plants, the hydrolysis of pyrophosphate (PPi) by inorganic pyrophosphatase (PPase) can, under stress conditions, substitute for ATP-driven proton flux to generate a proton gradient and induce luminal acidification. However, this strategy is considered to be lost in eukaryotes. Here, we report that LHPP, a poorly understood PPase that exhibits activity at acidic pH, is primarily expressed in astrocytes and partly localized on lysosomal membranes. Under stress conditions, LHPP is recruited to vacuolar ATPase (V-ATPase) and facilitates V-ATPase-dependent proton transport and lysosomal acidification by hydrolyzing PPi. LHPP knockout (KO) mice have no discernable phenotype but are resilient to chronic-stress-induced depression-like behaviors. Mechanistically, LHPP deficiency prevents lysosome-dependent degradation of C/EBPß and induces the expression of a group of chemokines that promote adult neurogenesis. Together, these findings suggest that LHPP is likely to be a therapeutic target for stress-related brain disease.