Fast and sensitive GCaMP calcium indicators for imaging neural populations.

Calcium imaging with protein-based indicators1,2 is widely used to follow neural activity in intact nervous systems, but current protein sensors report neural activity at timescales much slower than electrical signalling and are limited by trade-offs between sensitivity and kinetics. Here we used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators3-8. The resulting 'jGCaMP8' sensors, based on the calcium-binding protein calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (half-rise times of 2 ms) and the highest sensitivity for neural activity reported for a protein-based calcium sensor. jGCaMP8 sensors will allow tracking of large populations of neurons on timescales relevant to neural computation.

Programmed cell death-1 receptor-mediated regulation of Tbet+NK1.1- innate lymphoid cells within the tumor microenvironment.

Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1- ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1- ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet+NK1.1- ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet+NK1.1- ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet+NK1.1- ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet+NK1.1- ILCs within the TME.

New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis.

PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

Palladium-Catalyzed Sequential Cross-Coupling/Annulation of ortho-Vinyl Bromobenzene with Aryl Bromide: Bimetallic Pathway versus Pd(II)-Pd(IV) Pathway: A DFT Investigation.

The palladium-catalyzed sequential cross-coupling/annulation of ortho-vinyl bromobenzenes with aryl bromides generating phenanthrenes was characterized by density functional theory (DFT). The Pd(II)-Pd(IV) pathway (Path V) is shown to be less probable than the bimetallic pathway (Path I), the latter proceeding via the following six steps: oxidative addition, vinyl-C(sp2)-H activation, Pd(II)-Pd(II) transmetalation, C-C coupling, aryl-C(sp2)-H activation, and reductive elimination. The aryl-C(sp2)-H activation process acts as the rate-determining step (RDS) of the entire chemical transformation, with an activation free energy barrier of ca. 27.4-28.8 kcal·mol-1, in good agreement with the corresponding experimental data (phenanthrenes' yields of ca. 65-90% at 130 °C after 5 h of reaction). The K2CO3 additive effectively reduces the activation free energy barrier of the RDS through direct participation in the reaction while preferentially modulating the charge distributions and increasing the stability of corresponding intermediates and complexes along the reaction path. Furthermore, bonding and electronic structure analyses of the key structures indicate that the chemo- and regioselectivities of the reaction are strongly influenced by both electronic effects and steric hindrance.

Metal-Centered Boron-Wheel Cluster of Y©B112- with Rare D11h Symmetry.

Molecules with high point-group symmetry are interesting prototype species in the textbook. As transition metal-centered boron clusters tend to have highly symmetric structures to fulfill multicenter bonding and high stability, new boron clusters with rare point-group symmetry may be viable. Through in-depth scrutiny over the structures of experimentally already observed transition metal-centered boron-wheel complexes, geometric and electronic design principles are summarized, based on which we studied M©B11k- (M = Y, La; Zr, Hf; k = 1, 2) clusters and found that a Y©B112- boron-wheel complex has an unprecedented D11h point-group symmetry. The remarkable stability of the planar Y©B112- complex is illustrated via extensive global-minimum structural search as well as comprehensive chemical bonding analyses. Similar to other boron-wheel complexes, the Y©B112- complex is shown to possess σ and π double aromaticity, indeed following the electronic design principle previously summarized. This new compound is expected to be experimentally identified, which will extend the currently known largest possible planar molecular symmetry and enrich the metal-centered boron-wheel class.

Ultrafast Vibrational Wave Packet Dynamics of the Aqueous Guanine Radical Anion Induced by Photodetachment.

Studying the ultrafast dynamics of ionized aqueous biomolecules is important for gaining an understanding of the interaction of ionizing radiation with biological matter. Guanine plays an essential role in biological systems as one of the four nucleobases that form the building blocks of deoxyribonucleic acid (DNA). Guanine radicals can induce oxidative damage to DNA, particularly due to the lower ionization potential of guanine compared to the other nucleobases, sugars, and phosphate groups that are constituents of DNA. This study utilizes femtosecond optical pump-probe spectroscopy to observe the ultrafast vibrational wave packet dynamics of the guanine radical anion launched by photodetachment of the aqueous guanine dianion. The vibrational wave packet motion is resolved into 11 vibrational modes along which structural reorganization occurs upon photodetachment. These vibrational modes are assigned with the aid of density functional theory (DFT) calculations. Our work sheds light on the ultrafast vibrational dynamics following the ionization of nucleobases in an aqueous medium.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

[Non-targeted metabolomics of spleen and liver metabolism in mice treated with Pruni Semen processed with different methods].

Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to investigate the impacts of Pruni Semen processed with different methods(raw and fried) on the liver and spleen metabolism in mice. A total of 24 male mice were randomly assigned to three groups: raw Pruni Semen group, fried Pruni Semen group, and control(deionized water) group. Mice in the three groups were orally administrated with 0.01 g·mL~(-1) Pruni Semen decoction or deionized water for one week. After that, the liver and spleen tissues were collected, and liquid chromatography-mass spectrometry(LC-MS)-based metabolomic analysis was carried out to investigate the impact of Pruni Semen on the liver and spleen metabolism in mice. Compared with thte control group, the raw Pruni Semen group showed up-regulation of 11 metabolites and down-regulation of 57 metabolites in the spleen(P<0.05), as well as up-regulation of 15 metabolites and down-regulation of 58 metabolites in the liver(P<0.05). The fried Pruni Semen group showed up-regulation of 31 metabolites and down-regulation of 10 metabolites in the spleen(P<0.05), along with up-regulation of 26 metabolites and down-regulation of 61 metabolites in the liver(P<0.05). The differential metabolites identified in the raw Pruni Semen group were primarily associated with alanine, aspartate, and glutamate metabolism, purine metabolism, amino sugar and nucleotide sugar metabolism, and D-glutamine and D-glutamate metabolism. The differential metabolites identified in the fried Pruni Semen group predominantly involved riboflavin metabolism, amino sugar and nucleotide sugar metabolism, purine metabolism, alanine, aspartate, and glutamate metabolism, D-glutamine and D-glutamate metabolism, and glutathione metabolism. The findings suggest that both raw and fried Pruni Semen have the potential to modulate the metabolism of the liver and spleen in mice by influencing the glutamine and glutamate metabolism.

Integration of Metal Catalysis and Organocatalysis in a Metal Nanocluster with Anchored Proline.

Chiral metal nanoclusters have recently been attracting great attention. It is challenging to realize asymmetric catalysis via atomically precise metal nanoclusters. Herein, we report the synthesis and total structure determination of chiral clusters [Au7Ag8(dppf)3(l-/d-proline)6](BF4)2 (l-/d-Au7Ag8). Superatomic clusters l-/d-Au7Ag8 display intense and mirror-image Cotton effects in their CD spectra. Density functional theory (DFT) calculations were carried out to understand the correlation between electronic structures and the optical activity of the enantiomeric pair. Surprisingly, the incorporation of proline in a metal nanocluster can significantly promote the catalytic efficiency in asymmetric Aldol reactions. The increase of catalytic activity of Au7Ag8 in comparison with organocatalysis by proline is attributed to the cooperative effect of the metal core and prolines, showing the advantages of the integration of metal catalysis and organocatalysis in a metal nanocluster.

Unraveling intratumoral complexity in metastatic dermatofibrosarcoma protuberans through single-cell RNA sequencing analysis.

Dermatofibrosarcoma protuberans (DFSP) stands as a rare and locally aggressive soft tissue tumor, characterized by intricated molecular alterations. The imperative to unravel the complexities of intratumor heterogeneity underscores effective clinical management. Herein, we harnessed single-cell RNA sequencing (scRNA-seq) to conduct a comprehensive analysis encompassing samples from primary sites, satellite foci, and lymph node metastases. Rigorous preprocessing of raw scRNA-seq data ensued, and employing t-distributed stochastic neighbor embedding (tSNE) analysis, we unveiled seven major cell populations and fifteen distinct subpopulations. Malignant cell subpopulations were delineated using infercnv for copy number variation calculations. Functional and metabolic variations of diverse malignant cell populations across samples were deciphered utilizing GSVA and the scMetabolism R packages. Additionally, the exploration of differentiation trajectories within diverse fibroblast subpopulations was orchestrated through pseudotime trajectory analyses employing CytoTRACE and Monocle2, and further bolstered by GO analyses to elucidate the functional disparities across distinct differentiation states. In parallel, we segmented the cellular components of the immune microenvironment and verified the presence of SPP1+ macrophage, which constituted the major constituent in lymph node metastases. Remarkably, the CellChat facilitated a comprehensive intercellular communication analysis. This study culminates in an all-encompassing single-cell transcriptome atlas, propounding novel insights into the multifaceted nature of intratumor heterogeneity and fundamental molecular mechanisms propelling metastatic DFSP.

Plastome evolution and phylogenomics of Impatiens (Balsaminaceae).

MAIN CONCLUSION: This study reported seven new plastomes from Impatiens and observed three highly variable regions for phylogeny and DNA barcoding, which resolved the relationships among sections of subgenus Impatiens. Impatiens L. (Balsaminaceae, Ericales) is one of the largest and most diverse genera of angiosperms, widely known for its taxonomic difficulty. In this study, we reevaluated the infrageneric relationships within the genus Impatiens, using complete plastome sequence data. Seven complete plastomes of Impatiens (representing 6 species) were newly sequenced and characterized along with 20 previously published plastomes of other Impatiens species, plus 2 plastomes of outgroups (Hydrocera triflora, Balsaminaceae; Marcgravia coriacea, Marcgraviaceae). The total size of these 29 plastomes ranged from 151,538 bp to 152,917 bp, except 2 samples of Impatiens morsei, which exhibited a shorter length and lost some genes encoding NADH dehydrogenase subunits. Moreover, the number of simple sequence repeats (SSRs) ranged from 51 to 113, and the number of long repeats from 17 to 26. In addition, three highly variable regions were identified (trnG-GCC (The previous one), ndhF-rpl32-trnL-UGA-ccsA, and ycf1). Our phylogenomic analysis based on 80 plastome-derived protein-coding genes strongly supported the monophyly of Impatiens and its two subgenera (Clavicarpa and Impatiens), and fully resolved relationships among the six (out of seven) sampled sections of subgenus Impatiens. Overall, the plastome DNA markers and phylogenetic results reported in this study will facilitate future identification, taxonomic and DNA barcoding studies in Impatiens as well as evolutionary studies in Balsaminaceae.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization.

BACKGROUND: Postoperative transarterial chemoembolization (PA-TACE) is an effective adjuvant therapy for preventing early postoperative recurrence of hepatocellular carcinoma (HCC); however, many patients are insensitive to it. Therefore, the present study aimed to explore the in-depth reasons for PA-TACE resistance and provide a reliable basis for selecting patients who will benefit the most from PA-TACE. METHODS: The unique gene expression profiles of primary tumors from PA-TACE-sensitive or -insensitive patients were analyzed using microarray data. Combined differential expression analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were used to screen for potential drivers of PA-TACE insensitivity. The expression of ALDOB was silenced or overexpressed in hepatoma cell lines, and changes in glycolytic activity, cycle, apoptosis, and malignant biological phenotypes were observed under normoxia and hypoxia. Finally, an animal model was constructed to verify the effects of ALDOB dysregulation on the tumorigenic ability of HCC cells in vivo. RESULTS: The inhibition of ALDOB promoted the up-regulation of Ki67 expression, and glycolytic activity was significantly enhanced. Moreover, the proliferation, invasion, and migration capabilities were increased in HCC cells and even worse in hypoxia. This advantage of malignant behavior was also validated using in vivo models. CONCLUSION: Down-regulation of ALDOB may underlie the metabolic reprogramming observed in HCC by promoting the malignant behavior of HCC cells. Hypoxia and ALDOB down-regulation acted additively, which was closely related to PA-TACE insensitivity. The use of ALDOB and Ki67 as a combined marker has the potential to identify the 'PA-TACE beneficiary population'.

SGLT2 inhibitor empagliflozin promotes revascularization in diabetic mouse hindlimb ischemia by inhibiting ferroptosis.

Gliflozins are known as SGLT2 inhibitors, which are used to treat diabetic patients by inhibiting glucose reabsorption in kidney proximal tubules. Recent studies show that gliflozins may exert other effects independent of SGLT2 pathways. In this study we investigated their effects on skeletal muscle cell viability and paracrine function, which were crucial for promoting revascularization in diabetic hindlimb ischemia (HLI). We showed that treatment with empagliflozin (0.1-40 µM) dose-dependently increased high glucose (25 mM)-impaired viability of skeletal muscle C2C12 cells. Canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin and tofogliflozin exerted similar protective effects on skeletal muscle cells cultured under the hyperglycemic condition. Transcriptomic analysis revealed an enrichment of pathways related to ferroptosis in empagliflozin-treated C2C12 cells. We further demonstrated that empagliflozin and other gliflozins (10 µM) restored GPX4 expression in high glucose-treated C2C12 cells, thereby suppressing ferroptosis and promoting cell viability. Empagliflozin (10 µM) also markedly enhanced the proliferation and migration of blood vessel-forming cells by promoting paracrine function of skeletal muscle C2C12 cells. In diabetic HLI mice, injection of empagliflozin into the gastrocnemius muscle of the left hindlimb (10 mg/kg, every 3 days for 21 days) significantly enhanced revascularization and blood perfusion recovery. Collectively, these results reveal a novel effect of empagliflozin, a clinical hypoglycemic gliflozin drug, in inhibiting ferroptosis and enhancing skeletal muscle cell survival and paracrine function under hyperglycemic condition via restoring the expression of GPX4. This study highlights the potential of intramuscular injection of empagliflozin for treating diabetic HLI.

Exosome-based engineering strategies for the diagnosis and treatment of oral and maxillofacial diseases.

Oral and maxillofacial diseases are one of the most prevalent diseases in the world, which not only seriously affect the health of patients' oral and maxillofacial tissues, but also bring serious economic and psychological burdens to patients. Therefore, oral and maxillofacial diseases require effective treatment. Traditional treatments have limited effects. In recent years, nature exosomes have attracted increasing attention due to their ability to diagnose and treat diseases. However, the application of nature exosomes is limited due to low yield, high impurities, lack of targeting, and high cost. Engineered exosomes can be endowed with better comprehensive therapeutic properties by modifying exosomes of parent cells or directly modifying exosomes, and biomaterial loading exosomes. Compared with natural exosomes, these engineered exosomes can achieve more effective diagnosis and treatment of oral and maxillary system diseases, and provide reference and guidance for clinical application. This paper reviews the engineering modification methods of exosomes and the application of engineered exosomes in oral and maxillofacial diseases and looks forward to future research directions.

Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.

BACKGROUND: Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. CASE PRESENTATION: We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. CONCLUSION: Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.

Molecular Mechanisms of AMPA Receptor Trafficking in the Nervous System.

Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.

[The Role and Significance of Hepatic Environmental Cells in Tumor Metastatic Colonization to Liver].

Metastasis, a main cause of death in tumor patients, is a complicated process that involves multiple steps, presenting a major clinical challenge. Tumor cells break the physical boundaries of a primary tumor, intravasate into the lumina of blood vessels, travel around through blood circulation, extravasate into distant organs, colonize the host organs, and eventually develop into the foci of metastatic cancer. The metastasis of tumor cells exhibits organ-tropism, i.e., tumor cells preferentially spread to specific organs. Liver is a common site for metastasis. The pattern of metastasis in uveal melanoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma shows organ-tropism for liver. The anatomical structure of liver determines its hemodynamic characteristics, e.g., low pressure and slow blood flow, which tend to facilitate the stasis and colonization of tumor cells in the liver. Besides the hemodynamic features, the metastatic colonization of liver depends largely on the interaction between tumor cells and the hepatic microenvironment (especially liver-resident cellular components). Resident cells of the hepatic microenvironment include hepatocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KCs), etc. Herein, we discussed the role and significance of liver-resident cells in the metastatic colonization of tumor in the liver.

Symmetry-Driven Assembly of a Penta-Shell Keplerate Cuprofullerene for Metallofullerene Frameworks.

Two metallofullerene frameworks (MFFs) constructed from a penta-shell Keplerate cuprofullerene chloride, C60 @Cu24 @Cl44 @Cu12 @Cl12 , have been successfully prepared via a C60 -templated symmetry-driven strategy. The icosahedral cuprofullerene chloride is assembled on a C60 molecule through [η2 -(C=C)]-CuI and CuI -Cl coordination bonds, resulting in the penta-shell Keplerate with the C60 core canopied by 24 Cu, 44 Cl, 12 Cu and 12 Cl atoms that fulfill the tic@rco@oae@ico@ico penta-shell polyhedral configuration. By sharing the outmost-shell Cl atoms, the cuprofullerene chlorides are connected into 2D or 3D (snf net) frameworks. TD-DFT calculations reveal that the charge transfer from the outmost CuI and Cl to C60 core is responsible for their light absorption expansion to near-infrared region, implying anionic halogenation may be an effective strategy to tune the light absorption properties of metallofullerene materials.

Mimicking DNA Periodic Docking Grooves for Adaptive Identification of l-/d-Tryptophan in a Biological Metal-Organic Framework.

Bioinspired metal-organic frameworks (MOFs) serve as suitable crystalline models for recognition and sensing of biomolecules mimicking natural processes, providing new ideas and concepts for cutting-edge biomedical applications. Here, we have successfully prepared a robust biological metal-organic framework with periodic docking grooves resembling the major and minor grooves in the DNA double helix structure, which can be used as unique recognition sites for selectively identifying l-/d-tryptophan (l-/d-Trp). Notably, successful encapsulation of Trp could be observed by single-crystal X-ray diffraction for the first time. Trp has matched size and shape to fit snugly into the major groove. Combined with isothermal titration calorimetry, it was found that ZnBTCHx could spontaneously capture l-/d-Trp through two different thermodynamic pathways: enthalpy-driven for encapsulating l-Trp and entropy-driven for uptaking d-Trp. Furthermore, molecular dynamics and density functional theory verified the role of hydrogen bonding and π-π/C-H···π interactions in the host-guest interface. This work provides unique insight for the construction of bionic models to mimic the natural binding properties, which is of great significance for the fields of pharmaceutical chemistry and biomedical science.