Role of autonomic nervous system in BDE-209 maternal exposure induced immunotoxicity in female offspring.

Decabrominated diphenyl ether (BDE-209) is a typical persistent organic pollutant that can cross the placental barrier, increasing the exposure risk for offspring. Norepinephrine (NE) from nerve terminals and acetylcholine (Ach) can bind to specific receptors on immune cells, inhibit the immune function of the body then cause immunotoxicity. However, whether maternal exposure to BDE-209 could lead to immunotoxicity in the offspring by acting on the sympathetic and parasympathetic nervous systems remains unclear. In view of this, the pregnancy and lactation rat BDE-209 exposure model was established and the results demonstrated that pregnancy and lactation BDE-209 exposure could induce immunotoxicity to female offspring via affecting immunopathology (hematological and biochemical parameters, organ indices, and spleen histopathological), decreasing humoral immunity (serum hemolysin, immunoglobulins, and cytokine productions), damaging cellular immunity (splenic lymphocytes and spleen cytokine productions), and restraining nonspecific immunity. Moreover, a dramatically significant correlation was observed between spleen nerve indices and immunity indices. Additionally, the mechanism revealed that maternal BDE-209 exposure caused offspring immunotoxicity through (1) activating MHC/PKCθ/NF-κB pathway; (2) promoting sympathetic nervous pathway, by upregulating the expression of ß2AR protein, which in turn elevating cAMP, following activate PKA and phosphorylate CREB, ultimately leading to immunotoxicity;(3) activating parasympathetic nerve pathway by reducing the binding with Ach and α7nAchR, upregulating the expression of JAK2 and phosphorylating STAT3, induced immunotoxicity of female offspring.

Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression.

BACKGROUND: Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. METHODS: The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. RESULTS: Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. CONCLUSIONS: This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.

Differential effects of high-definition transcranial direct current stimulation (HD-tDCS) on attentional guidance by working memory in males with substance use disorder according to memory modality.

Information stored in working memory can guide perception selection, and this process is modulated by cognitive control. Although previous studies have demonstrated that neurostimulation over the left dorsolateral prefrontal cortex (lDLPFC) contributes to restore cognitive control among individuals with substance use disorder (SUD), there remains an open question about the potential stimulation effects on memory-driven attention. To address this issue, the present study adopted a combined working memory/attention paradigm while employing high-definition transcranial direct current stimulation (HD-tDCS) to stimulate the lDLPFC. Observers were asked to maintain visual or audiovisual information in memory while executing a search task, while the validity of the memory contents for the subsequent search task could be either invalid or neutral. The results showed a faint memory-driven attentional suppression effect in sham stimulation only under the audiovisual condition. Moreover, anodal HD-tDCS facilitated attentional suppression effect in both the strength and temporal dynamics under the visual-only condition, whereas the effect was impaired or unchanged under the audiovisual condition. Surprisingly, cathodal HD-tDCS selectively improved temporal dynamics of the attentional suppression effect under the audiovisual condition. The present study revealed the differential enhancement of HD-tDCS on cognitive control over visual and audiovisual memory-driven attention among individuals with SUD.

Bulk Photovoltaic Effect in Polar 3D Perovskitoid Enables Self-Powered Polarization-Sensitive Photodetection.

The family of polar hybrid perovskites, in which bulk photovoltaic effects (BPVEs) drive steady photocurrent without bias voltage, have shown promising potentials in self-powered polarization-sensitive photodetection. However, reports of BPVEs in 3D perovskites remain scare, being mainly hindered by the limited dipole moment or lack of symmetry breaking. Herein, a polar 3D perovskitoid, (BDA)Pb2 Br6 (BDA = NH3 C4 H8 NH3 ), where the spontaneous polarization (Ps )-induced BPVE drives self-powered photodetection of polarized-light is reported. Emphatically, the edge-sharing Pb2 Br10 dimer building unit allows the optical anisotropy and polarity in 3D (BDA)Pb2 Br6 , which triggers distinct optical absorption dichroism ratio of ≈2.80 and BPVE dictated photocurrent of 3.5 µA cm-2 . Strikingly, these merits contribute to a polarization-sensitive photodetection with a high polarization ratio (≈4) under self-powered mode, beyond those of 2D hybrid perovskites and inorganic materials. This study highlights the potential of polar 3D perovskitoids toward intelligent optoelectronic applications.

Single-cell transcriptomics enable the characterization of local extension in retinoblastoma.

Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

A whale optimization algorithm based on atom-like structure differential evolution for solving engineering design problems.

The whale optimization algorithm has received much attention since its introduction due to its outstanding performance. However, like other algorithms, the whale optimization algorithm still suffers from some classical problems. To address the issues of slow convergence, low optimization precision, and susceptibility to local convergence in the whale optimization algorithm (WOA). Defining the optimization behavior of whale individuals as quantum mechanical behavior, a whale optimization algorithm based on atom-like structure differential evolution (WOAAD) is proposed. Enhancing the spiral update mechanism by introducing a sine strategy guided by the electron orbital center. Improving the random-walk foraging mechanism by applying mutation operations to both the electron orbital center and random individuals. Performing crossover operations between the newly generated individuals from the improved mechanisms and random dimensions, followed by a selection process to retain superior individuals. This accelerates algorithm convergence, enhances optimization precision, and prevents the algorithm from falling into local convergence. Finally, implementing a scouting bee strategy, where whale individuals progressively increase the number of optimization failures within a limited parameter L. When a threshold is reached, random initialization is carried out to enhance population diversity. Conducting simulation experiments to compare the improved algorithm with the whale optimization algorithm, other optimization algorithms, and other enhanced whale optimization algorithms. The experimental results indicate that the improved algorithm significantly accelerates convergence, enhances optimization precision, and prevents the algorithm from falling into local convergence. Applying the improved algorithm to five engineering design problems, the experimental results demonstrate that the improved algorithm exhibits good applicability.

Heterogeneous Expression Patterns of the Minichromosome Maintenance Complex Members in Retinoblastoma Unveil Its Clinical Significance.

Purpose: To explore the expression patterns and clinical significance of minichromosome maintenance (MCM) complex members in retinoblastoma (RB). Methods: Single-cell RNA sequencing datasets from five normal retina, six intraocular, and five extraocular RB samples were integrated to characterize the expression patterns of MCM complex members at the single-cell level. Western blot and quantitative PCR were used to detect the expression of MCM complex members in RB cell lines. Immunohistochemistry was conducted to validate the expression of MCM complex members in RB patient samples and a RB mouse model. Results: The expression of MCM2-7 is increased in RB tissue, with MCM2/3/7 showing particularly higher levels in extraocular RB. MCM3/7 are abundantly detected in cell types associated with oncogenesis. Both mRNA and protein levels of MCM3/4/6/7 are increased in RB cell lines. Immunohistochemistry further confirmed the elevated expression of MCM3 in extraocular RB, with MCM6 being the most abundantly expressed MCM in RB. Conclusions: The distinct MCM expression patterns across various RB cell types suggest diverse functional roles, offering valuable insights for targeted therapeutic strategies. The upregulation of MCM3, MCM4, MCM6, and MCM7 in RB, with a specific emphasis on MCM6 as a notable marker, highlights their potential significance.

Halide Ordering Enables Superior Charge Transport in 3D (NMPDA)Pb2 I4 Br2 Perovskitoid Single Crystal.

Halide composition engineering has been demonstrated as an effective strategy for optical and electronic properties modulation in 3D perovskites. While the impact of halide mixing on the structural and charge transport properties of 3D perovskitoids remains largely unexplored. Herein, it is demonstrated that bromine (Br) mixing in 3D (NMPDA)Pb2 I6 (NMPDA = N-methyl-1,3-propane diammonium) perovskitoid yields stabilized (NMPDA)Pb2 I4 Br2 with specific ordered halide sites, where Br ions locate at the edge-sharing sites. The halide ordered structure enables stronger H-bonds, shorter interlayer distance, and lower octahedra distortion in (NMPDA)Pb2 I4 Br2 with respect to the pristine (NMPDA)Pb2 I6 . These attributes further result in high ion migration activation energy, low defect states density, and enhanced carrier mobility-lifetime product (µτ), as underpinned by the electrical properties investigation and DFT calculations. Remarkably, the parallel configured photodetector based on (NMPDA)Pb2 I4 Br2 single crystal delivers a high on/off current ratio of 3.92 × 103 , a satisfying photoresponsivity and detectivity of 0.28 A W-1 and 3.05 × 1012 Jones under 10.94 µW cm-2 irradiation, superior to that of (NMPDA)Pb2 I6 and the reported 3D perovskitoids. This work sheds novel insight on exploring 3D mixed halide perovskitoids toward advanced and stable optoelectronic devices.

Sine Cosine Algorithm for Elite Individual Collaborative Search and Its Application in Mechanical Optimization Designs.

To address the shortcomings of the sine cosine algorithm such as the low search accuracy, slow convergence speed, and easily falling into local optimality, a sine cosine algorithm for elite individual collaborative search was proposed. Firstly, tent chaotic mapping was used to initialize the population and the hyperbolic tangent function was applied non-linearly to adjust the parameters of the sine cosine algorithm, which enhanced the uniformity of population distribution and balanced the global exploration and local exploitation ability. Secondly, the search method of the sine cosine algorithm was improved by combining the search strategy of the sine cosine algorithm, the m-neighborhood locally optimal individual-guided search strategy, and the global optimal individual-guided search strategy, and, then, the three search strategies were executed alternately, which achieved collaboration, improved the convergence accuracy, and prevented the algorithm from falling into local optima. Finally, a greedy selection strategy was employed to select the best individuals for the population, which accelerated the convergence speed of the sine cosine algorithm. The simulation results illustrated that the sine cosine algorithm for elite individual collaborative search demonstrated a better optimization performance than the sine cosine algorithm, the other improved sine cosine algorithms, the other chaos-based algorithms, and other intelligent optimization algorithms. In addition, the feasibility and applicability of the sine cosine algorithm for elite individual collaborative search were further demonstrated by two mechanical optimization design experiments.

Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins.

This study aimed to explore the important role of the rhizosphere microbiome in the quality of Atractylodes lancea (Thunb.) DC. (A. lancea). The rhizosphere microbial community of A. lancea at two sampling sites was studied using metagenomic technology. The results of α-diversity analysis showed that the rhizosphere microbial richness and diversity were higher in the Maoshan area. The higher abundance of core microorganisms of the rhizosphere, especially Penicillium and Streptomyces, in the Maoshan area compared with those in the Yingshan area might be an important factor affecting the yield of A. lancea. Redundancy analysis illustrated that the available phosphorus had a significant effect on the rhizosphere microbial community structure of A. lancea. We also showed that the plant-microbe and microbe-microbe interactions were closer in the Maoshan area than in the Yingshan area, and Streptomyces were the main contributors to the potential functional difference between the two regions. A. lancea in the Maoshan area had a high content of atractylodin and atractylon, which might be related to the enhanced abundance of Streptomyces, Candidatus-Solibacter, and Frankia. Taken together, this study provided theoretical insights into the interaction between medicinal plants and the rhizosphere microbiome and provides a valuable reference for studying beneficial microbes of A. lancea.

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

The integrated single-cell analysis developed an immunogenic cell death signature to predict lung adenocarcinoma prognosis and immunotherapy.

BACKGROUND: Research on immunogenic cell death (ICD) in lung adenocarcinoma (LUAD) has been relatively limited. This study aims to create ICD-related signatures for accurate survival prognosis prediction in LUAD patients, addressing the challenge of lacking reliable early prognostic indicators for this type of cancer. METHODS: Using single-cell RNA sequencing (scRNA-seq) analysis, ICD activity in cells was calculated by AUCell algorithm, divided into high- and low-ICD groups according to median values, and key ICD regulatory genes were identified through differential analysis, and these genes were integrated into TCGA data to construct prognostic signatures using LASSO and COX regression analysis, and multi-dimensional analysis of ICD-related signatures in terms of prognosis, immunotherapy, tumor microenvironment (TME), and mutational landscape. RESULTS: The constructed signature reveals a pronounced disparity in prognosis between the high- and low-risk groups of LUAD patients. The statistical discrepancies in survival times among LUAD patients from both the TCGA and GEO databases further corroborate this observation. Additionally, heightened levels of immune cell infiltration expression are evidenced in the low-risk group, suggesting a potential benefit from immunotherapeutic interventions for these patients. The expression levels of pivotal risk-associated genes in tissue samples were assessed utilizing qRT-PCR, thereby unveiling PITX3 as a plausible therapeutic target in the context of LUAD. CONCLUSIONS: Our constructed ICD-related signatures provide help in predicting the prognosis and immunotherapy of LUAD patients, and to some extent guide the clinical treatment of LUAD patients.

Broadband red emission from one-dimensional hexamethonium lead bromide perovskitoid.

Broadband emissions from low-dimensional hybrid perovskites have aroused intense interest. However, the achievement of broadband red emission in lead halide perovskites remains challenging. Herein, we report a one-dimensional (1D) hybrid lead bromide perovskitoid, (HM)Pb2Br6 (HM = hexamethonium), featuring a corrugated "3 × 3" [Pb2Br6]2- chain. The unique structure results in intriguingly red emission peaking at 692 nm, with a PLQY of around 6.24%. Our spectroscopic and computational studies reveal that the red emission derives from self-localized Pb23+, Pb3+ and Br2- species confined within the inorganic lead bromide lattice that function as radiative centres. This finding will benefit the design of perovskite systems for efficient red emission.

Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway.

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO2). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.

Fluorinated hydrogel nanoparticles with regulable fluorine contents and T2 relaxation times as 19F MRI contrast agents.

Medical imaging contrast agents that are able to provide detailed biological information have attracted increasing attention. Among the new emerging imaging contrast agents, 19F magnetic resonance imaging contrast agents (19F MRI CAs) are extremely promising for their weak background disturbing signal from the body. However, to prepare 19F MRI CAs with a long T2 relaxation time and excellent biocompatibility in a simple and highly effective strategy is still a challenge. Herein, we report a new type of 19F MRI hydrogel nanocontrast agents (19F MRI HNCAs) synthesized by a surfactant-free emulsion polymerization with commercial fluorinated monomers. The T2 relaxation time of 19F MRI HNCA-1 was found to be 25-40 ms, guaranteeing its good imaging ability in vitro. In addition, according to an investigation into the relationship between the fluorine content and 19F MRI signal intensity, the 19F MRI signal intensity was not only determined by the fluorine content in 19F MRI HNCAs but also by the hydration microenvironment around the fluorine atoms. Moreover, 19F MRI HNCAs demonstrated excellent biocompatibility and imaging capability inside cells. The primary exploration demonstrated that 19F MRI HNCAs as a new type of 19F MRI contrast agent hold potential for imaging lesion sites and tracking cells in vivo by 19F MRI technology.

Extraction, structural characterization, and biological activities of a new glucan from Codonopsis pilosula.

In this study, a powerful and rapid aqueous two-phase system (ATPS) method was used to extract polysaccharides from Codonopsis pilosula. The ATPS process was investigated with response surface methodology (RSM). At an ammonium sulfate concentration of 17%, ethanol concentration of 30%, and extraction temperature of 40 °C at pH 6, the total extraction yield of polysaccharides reached (31.57 ± 1.28)%. After separation and purification, a homogenized polysaccharide CPP 2-4 with molecular weight of 3.9 × 104 kDa was obtained from the bottom phase. The physicochemical properties and structural features confirmed that CPP 2-4 was an α-1,6-glucan. Activity studies showed that the IC50 of CPP 2-4 for DPPH radical scavenging was 0.105 mg/mL. The FRAP and ABTS assays showed that CPP 2-4 had strong antioxidant activity in a dose-dependent manner. Furthermore, CPP 2-4 inhibited NO release in RAW264.7 cells induced by lipopolysaccharide, which indicated a certain anti-inflammatory effect. This study improved the extraction rate of polysaccharides from C. pilosula and identified a glucan for the first time, that can contribute to a better understanding of the composition and structure of polysaccharides from C. pilosula and provide data support for the medicine and food homology of C. pilosula.

Anticancer Activity of Diosgenin and Its Molecular Mechanism.

Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of various cancers such as oral squamous cell carcinoma, laryngeal cancer, esophageal cancer, liver cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, glioma, and leukemia. This article aims to provide an overview of the in vivo, in vitro, and clinical studies reporting the diosgenin's anticancer effects. Preclinical studies have shown promising effects of diosgenin on inhibiting tumor cell proliferation and growth, promoting apoptosis, inducing differentiation and autophagy, inhibiting tumor cell metastasis and invasion, blocking cell cycle, regulating immunity and improving gut microbiome. Clinical investigations have revealed clinical dosage and safety property of diosgenin. Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.

A high-fidelity RNA-targeting Cas13 restores paternal Ube3a expression and improves motor functions in Angelman syndrome mice.

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of antisense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expression of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.