Menin Deficiency Induces Autism-Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1-Related Encephalopathy.

FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism-like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over-expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1-related encephalopathy.

PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy.

The programmed cell death 1 (PD-1) immune checkpoint of co-inhibitory signaling plays crucial roles in controlling the magnitude and duration of T cell activation to limit tissue damage and maintain self-tolerance. Cancer cells hijack the co-inhibitory pathway and escape immune surveillance by overexpressing the PD-1 ligand PD-L1. Immune checkpoint inhibitors, such as PD-1 blocking antibody have been approved for tumor immunotherapy. However, not all patients can benefit from PD-1 monotherapy. Combination immunotherapy based on PD-1 axis blockade substantially improves clinical anti-tumor efficacy. In this review, we briefly summarize the current progress on the mechanisms of PD-1-mediated inhibition of T cell activation and strategies for cancer combination immunotherapy.

Anti-vibriosis bioactive molecules from marine-derived variant Streptomyces sp. ZZ741A.

The infection of vibrio is an important cause of huge economic losses in aquaculture industry. At present, antibiotics are mainly used to prevent and reduce the infection of the vibrio, which has accelerated the emergence of multi-drug-resistant strains. New generation alternative anti-vibrio drugs were in urgent to solve this problem. In this study, six compounds (1-6) were isolated from the Streptomyces sp. ZZ741A, a marine-derived Streptomyces variant, including one new compound, 2-carbamoylphenyl isobutyrate (1), five known ones, nocardamine (2), dehydroxynocardamine (3), phenylacetic acid (4), thiophenol (5) and 2,3-dihydroxybenzoic acid (6). The anti-vibriosis assay showed that compounds 2 and 3 had specific inhibition activity against Vibrio vulnificus, Vibrio alginolyticus, and Vibrio parahaemolyticus with the MIC values ranging from 8 to 128 µg/mL. The molecular docking study of their possible mechanism of anti-vibriosis activity showed that the activity might come from the inhibition of Outer membrane protein U (OmpU).

Cationic Nanoemulsion-Encapsulated Retinoic Acid as an Adjuvant to Promote OVA-Specific Systemic and Mucosal Responses.

Cationic nanostructures have emerged as an adjuvant and antigen delivery system that enhances dendritic cell maturation, ROS generation, and antigen uptake and then promotes antigen-specific immune responses. In recent years, retinoic acid (RA) has received increasing attention due to its effect in activating the mucosal immune response; however, in order to use RA as a mucosal adjuvant, it is necessary to solve the problem of its dissolution, loading, and delivery. Here, we describe a cationic nanoemulsion-encapsulated retinoic acid (CNE-RA) delivery system composed of the cationic lipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOTAP), retinoic acid, squalene as the oil phase, polysorbate 80 as surfactant, and sorbitan trioleate 85 as co-surfactant. Its physical and chemical properties were characterized using dynamic light scattering and a spectrophotometer. Immunization of mice with the mixture of antigen (ovalbumin, OVA) and CNE-RA significantly elevated the levels of anti-OVA secretory immunoglobulin A (sIgA) in vaginal lavage fluid and the small intestinal lavage fluid of mice compared with OVA alone. This protocol describes a detailed method for the preparation, characterization, and evaluation of the adjuvant effect of CNE-RA.

Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Methods: Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Results: Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. Conclusion: FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

CRISPR/CasΦ2-mediated gene editing in wheat and rye.

The compact CRISPR/CasΦ2 system provides a complementary genome engineering tool for efficient gene editing including cytosine and adenosine base editing in wheat and rye with high specificity, efficient use of the protospacer-adjacent motif TTN, and an alternative base-editing window.

A new chromosome-scale duck genome shows a major histocompatibility complex with several expanded multigene families.

BACKGROUND: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC). RESULTS: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIß, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model. CONCLUSIONS: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control.

Anti-Ferroptotic Effect of Cannabidiol in Human Skin Keratinocytes Characterized by Data-Independent Acquisition-Based Proteomics.

Skin cells are susceptible to oxidative stress and various types of cell death, including an iron-dependent form known as ferroptosis. Cannabidiol (CBD) can protect skin cells against oxidative stress, but whether this is attributed to the inhibition of ferroptosis is unknown. Herein, we evaluated the anti-ferroptotic effect of CBD in human keratinocytes using biochemical assays (radical scavenging and iron chelating) and cell-based models (for lipid peroxidation and intracellular iron). CBD's anti-ferroptotic effect was further characterized by proteomic analysis. This study identifies anti-ferroptosis as a mechanism of CBD's skin protective effects.

Aromatic and magnetic properties in a series of heavy rare earth-doped Ge6 cluster anions.

A series of pentagonal bipyramidal anionic germanium clusters doped with heavy rare earth elements, REGe 6 - (RE = Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), have been identified at the PBE0/def2-TZVP level using density functional theory (DFT). Our findings reveal that the centrally doped pentagonal ring structure demonstrates enhanced stability and heightened aromaticity due to its uniform bonding characteristics and a larger charge transfer region. Through natural population analysis and spin density diagrams, we observed a monotonic decrease in the magnetic moment from Gd to Yb. This is attributed to the decreasing number of unpaired electrons in the 4f orbitals of the heavy rare earth atoms. Interestingly, the system doped with Er atoms showed lower stability and anti-aromaticity, likely due to the involvement of the 4f orbitals in bonding. Conversely, the systems doped with Gd and Tb atoms stood out for their high magnetism and stability, making them potential building blocks for rare earth-doped semiconductor materials.

Learning to Aggregate Multi-Scale Context for Instance Segmentation in Remote Sensing Images.

The task of instance segmentation in remote sensing images, aiming at performing per-pixel labeling of objects at the instance level, is of great importance for various civil applications. Despite previous successes, most existing instance segmentation methods designed for natural images encounter sharp performance degradations when they are directly applied to top-view remote sensing images. Through careful analysis, we observe that the challenges mainly come from the lack of discriminative object features due to severe scale variations, low contrasts, and clustered distributions. In order to address these problems, a novel context aggregation network (CATNet) is proposed to improve the feature extraction process. The proposed model exploits three lightweight plug-and-play modules, namely, dense feature pyramid network (DenseFPN), spatial context pyramid (SCP), and hierarchical region of interest extractor (HRoIE), to aggregate global visual context at feature, spatial, and instance domains, respectively. DenseFPN is a multi-scale feature propagation module that establishes more flexible information flows by adopting interlevel residual connections, cross-level dense connections, and feature reweighting strategy. Leveraging the attention mechanism, SCP further augments the features by aggregating global spatial context into local regions. For each instance, HRoIE adaptively generates RoI features for different downstream tasks. Extensive evaluations of the proposed scheme on iSAID, DIOR, NWPU VHR-10, and HRSID datasets demonstrate that the proposed approach outperforms state-of-the-arts under similar computational costs. Source code and pretrained models are available at https://github.com/yeliudev/CATNet.

Exploring the stability and aromaticity of rare earth doped tin cluster MSn16- (M = Sc, Y, La).

Rare earth elements have high chemical reactivity, and doping them into semiconductor clusters can induce novel physicochemical properties. The study of the physicochemical mechanisms of interactions between rare earth and tin atoms will enhance our understanding of rare earth functional materials from a microscopic perspective. Hence, the structure, electronic characteristics, stability, and aromaticity of endohedral cages MSn16- (M = Sc, Y, La) have been investigated using a combination of the hybrid PBE0 functional, stochastic kicking, and artificial bee colony global search technology. By comparing the simulated results with experimental photoelectron spectra, it is determined that the most stable structure of these clusters is the Frank-Kasper polyhedron. The doping of atoms has a minimal influence on density of states of the pure tin system, except for causing a widening of the energy gap. Various methods such as ab initio molecular dynamics simulations, the spherical jellium model, adaptive natural density partitioning, localized orbital locator, and electron density difference are employed to analyze the stability of these clusters. The aromaticity of the clusters is examined using iso-chemical shielding surfaces and the gauge-including magnetically induced currents. This study demonstrates that the stability and aromaticity of a tin cage can be systematically adjusted through doping.

The structure and assembly mechanisms of T4-like cyanophages community in the South China Sea.

Marine ecosystems contain an immense diversity of phages, many of which infect cyanobacteria (cyanophage) that are largely responsible for primary productivity. To characterize the genetic diversity and biogeographic distribution of the marine T4-like cyanophage community in the northern South China Sea, the T4-like cyanophage portal protein gene (g20) was amplified. Phylogenetic analysis revealed that marine T4-like cyanophages were highly diverse, with g20 operational taxonomic units being affiliated with five defined clades (Clusters I-V). Cluster II had a wide geographic distribution, Cluster IV was the most abundant in the open sea, and Cluster I was dominant in coastal shelf environments. Our results showed T4-like cyanophages (based on g20) community was generally shaped via heterogeneous selection. Highly variable environmental factors (such as salinity and temperature) can heterogeneously select different cyanophage communities. Nevertheless, the dominant drivers of the T4-like cyanophage community based on the g20 and g23 (T4-like phage major capsid protein gene) were different, probably due to different coverages by the primer sets. Furthermore, the community assembly processes of T4-like cyanophages were affected by host traits (abundance and distribution), viral traits (latent period, burst size, and host range), and environmental properties (temperature and salinity).IMPORTANCECyanophages are abundant and ubiquitous in the oceans, altering population structures and evolution of cyanobacteria, which account for a large portion of global carbon fixation, through host mortality, horizontal gene transfer, and the modulation of host metabolism. However, little is known about the biogeography and ecological drivers that shape the cyanophage community. Here, we use g20 and g23 genes to examine the biogeographic patterns and the assembly mechanisms of T4-like cyanophage community in the northern part of the South China Sea. The different coverages of primer sets might lead to the different dominant drivers of T4-like cyanophage community based on g20 and g23 genes. Our results showed that characteristics of viral traits (latent period, burst size, and host range) and host traits (abundance and distribution) were found to either limit or enhance the biogeographic distribution of T4-like cyanophages. Overall, both virus and host properties are critical to consider when determining rules of community assembly for viruses.

Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

High-Index Faceted Cu2 O@CuO Mesocrystals Act as Efficient Catalyst for Si Hydrochlorination to Trichlorosilane.

Mesocrystals (MCs) with high-index facets may have superior catalytic properties to those with low-index facets and their nanocrystal counterparts. However, synthesizing such mesocrystal materials is still very challenging because of the metastability of MCs and energetic high-index crystal facets. This work reports a successful solvothermal method followed by calcination for synthesizing copper oxide-based MCs possessing a core-shell structure (denoted as Cu2 O@CuO HIMCs). Furthermore, these MCs are predominantly bounded by the high-index facets such as {311} or {312} with a high-density of stepped atoms. When used as catalysts in Si hydrochlorination to produce trichlorosilane (TCS, the primary feedstock of high-purity crystalline Si), Cu2 O@CuO HIMCs exhibit significantly enhanced Si conversion and TCS selectivity compared to those with flat surfaces and their nanostructured counterparts. Theoretical calculations reveal that both the core-shell structure and the high-index surface contribute to the increased electron density of Cu sites in Cu2 O@CuO HIMCs, promoting the adsorption and dissociation of HCl and stabilizing the dissociated Cl* intermediate. This work provides a simple method for synthesizing high-index faceted MCs and offers a feasible strategy to enhance the catalytic performance of MCs.

LncRNA BCRT1 depletion suppresses cervical cancer cell growth via sponging miR-432-5p/CCR7 axis.

Breast cancer-related transcript 1 (BCRT1), a lncRNA that is overexpressed in several human cancers, facilitates the progression of breast cancer and osteosarcoma. Nevertheless, the function of BCRT1 in cervical cancer (CC) still remains unknown. In this study, BCRT1 was significantly overexpressed in CC tissues and correlated with the advanced stage of CC patients. BCRT1 depletion dampened CC cell proliferation, and drives cell apoptosis and cell cycle inhibition. Mechanistically, BCRT1 bound miR-432-5p and negatively modulated miR-432-5p's expression in CC cells. Reduced miR-452-3p expression was observed in CC tissues and exerted tumor suppressive function in CC cell growth. Further mechanism study revealed that CCR7 was clarified as a target of miR-432-5p and was inhibited following BCRT1 depletion. CCR7 transfection could recover CC cell growth that was suppressed with BCRT1 down-regulation. These results revealed the novel function of BCRT1/miR-432-5p/CCR7 pathway in CC, suggesting BCRT1 might be a potential biomarker and target for CC treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03863-x.

Mapping and Functional Dissection of the Rumpless Trait in Piao Chicken Identifies a Causal Loss of Function Mutation in the Novel Gene Rum.

Rumpless chickens exhibit an abnormality in their tail development. The genetics and biology of this trait has been studied for decades to illustrate a broad variation in both the types of inheritance and the severity in the developmental defects of the tail. In this study, we created a backcross pedigree by intercrossing Piao (rumpless) with Xianju (normal) to investigate the genetic mechanisms and molecular basis of the rumpless trait in Piao chicken. Through genome-wide association and linkage analyses, the candidate region was fine-mapped to 798.5 kb (chromosome 2: 86.9 to 87.7 Mb). Whole-genome sequencing analyses identified a single variant, a 4.2 kb deletion, which was completely associated with the rumpless phenotype. Explorations of the expression data identified a novel causative gene, Rum, that produced a long, intronless transcript across the deletion. The expression of Rum is embryo-specific, and it regulates the expression of MSGN1, a key factor in regulating T-box transcription factors required for mesoderm formation and differentiation. These results provide genetic and molecular experimental evidence for a novel mechanism regulating tail development in chicken and report the likely causal mutation for the tail abnormity in the Piao chicken. The novel regulatory gene, Rum, will, due to its role in fundamental embryo development, be of interest for further explorations of a potential role in tail and skeletal development also in other vertebrates.

Recombinant Salmonella gallinarum (S. gallinarum) Vaccine Candidate Expressing Avian Pathogenic Escherichia coli Type I Fimbriae Provides Protections against APEC O78 and O161 Serogroups and S. gallinarum Infection.

Avian pathogenic Escherichia coli (APEC) is one of the leading pathogens that cause devastating economic losses to the poultry industry. Type I fimbriae are essential adhesion factors of APEC, which can be targeted and developed as a vaccine candidate against multiple APEC serogroups due to their excellent immunogenicity and high homology. In this study, the recombinant strain SG102 was developed by expressing the APEC type I fimbriae gene cluster (fim) on the cell surface of an avirulent Salmonella gallinarum (S. gallinarum) vector strain using a chromosome-plasmid-balanced lethal system. The expression of APEC type I fimbriae was verified by erythrocyte hemagglutination assays and antigen-antibody agglutination tests. In vitro, the level of the SG102 strain adhering to leghorn male hepatoma (LMH) cells was significantly higher than that of the empty plasmid control strain, SG101. At two weeks after oral immunization, the SG102 strain remained detectable in the livers, spleens, and ceca of SG102-immunized chickens, while the SG101 strain was eliminated in SG101-immunized chickens. At 14 days after the secondary immunization with 5 × 109 CFU of the SG102 strain orally, highly antigen-specific humoral and mucosal immune responses against APEC type I fimbriae protein were detected in SG102-immunized chickens, with IgG and secretory IgA (sIgA) concentrations of 221.50 µg/mL and 1.68 µg/mL, respectively. The survival rates of SG102-immunized chickens were 65% (13/20) and 60% (12/20) after challenge with 50 LD50 doses of APEC virulent strains O78 and O161 serogroups, respectively. By contrast, 95% (19/20) and 100% (20/20) of SG101-immunized chickens died in challenge studies involving APEC O78 and O161 infections, respectively. In addition, the SG102 strain effectively provided protection against lethal challenges from the virulent S. gallinarum strain. These results demonstrate that the SG102 strain, which expresses APEC type I fimbriae, is a promising vaccine candidate against APEC O78 and O161 serogroups as well as S. gallinarum infections.

Erratum: Correction Notice: Establishment of Human PD-1/PD-L1 Blockade Assay Based on Surface Plasmon Resonance (SPR) Biosensor.

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Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species.

Precursors of advanced glycation endproducts, namely, reactive carbonyl species (RCSs), are aging biomarkers that contribute to cell death. However, the impact of RCSs on ferroptosis-an iron-dependent form of cell death-in skin cells remains unknown. Herein, we constructed a cellular model (with human keratinocyte; HaCaT cells) to evaluate the cytotoxicity of the combinations of RCSs (including glyoxal; GO and methyglyoxal; MGO) and erastin (a ferroptosis inducer) using bioassays (measuring cellular lipid peroxidation and iron content) and proteomics with sequential window acquisition of all theoretical mass spectra. Additionally, a data-independent acquisition approach was used to characterize RCSs' and erastin's molecular network including genes, canonical pathways, and upstream regulators. Using this model, we evaluated the cytoprotective effects of two dietary flavonoids including cannflavins A and B against RCSs and erastin-induced cytotoxicity in HaCaT cells. Cannflavins A and B (at 0.625 to 20 µM) inhibited ferroptosis by restoring the cell viability (by 56.6-78.6% and 63.8-81.1%) and suppressing cellular lipid peroxidation (by 42.3-70.2% and 28.8-63.6%), respectively. They also alleviated GO + erastin- or MGO + erastin-induced cytotoxicity by 62.2-67.6% and 56.1-69.3%, and 35.6-54.5% and 33.8-62.0%, respectively. Mechanistic studies supported that the cytoprotective effects of cannflavins A and B are associated with their antioxidant activities including free radical scavenging capacity and an inhibitory effect on glycation. This is the first study showing that cannflavins A and B protect human keratinocytes from RCSs + erastin-induced cytotoxicity, which supports their potential applications as dietary interventions for aging-related skin conditions.