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ObjectiveTo provide scientific support for the compilation of high-quality anti-nuclear, biological, and chemical (NBC) medical textbooks in China by retrieving books in the field of biological weapons defense in China, summarizing the publication time and distribution of publishing institutions, and categorizing content and key points of related books.MethodsRelevant subject terms in the field of biological weapons defense were searched through the official website of China National Digital Library and other websites, up until December 31, 2023, and were limited to books. Topic analysis was conducted on the introductions and contents of the books using the latent Dirichlet allocation (LDA) model. The number of topics was determined based on perplexity, and topics were identified according to the intertopic distance map, followed by a qualitative description of the core content of each topic.ResultsA total of 104 books were included in this study, among which four were identified as higher educational textbooks. The volume of publications increased during the periods 2002‒2004 and 2020‒2023. Research institutions accounted for the highest percentage of publishers (37.78%), and 56.67% of the publishers were military institutions. The study identified six topics: "distribution, defense, and response to biological weapons", "category, diagnosis, and treatment of biological warfare agents", "response to biological public health emergencies", "status of nuclear, biological, and chemical weapons internationally", "biosafety risk management and prevention and control", and "technologies and equipment related to biological hazard identification".ConclusionThere are few books in the field of biological weapons defense in China and the content is relatively outdated. In the future, the preparation of teaching materials should be aimed at practical emergency handling techniques for biological weapons, enhance the emphasis on biological weapons detection and biological warfare early warning, improve the fundamental theories at different training levels, and timely update the current research status in the field.

Objective To explore the impact of knocking down Sec31A on the malignant phenotype of head and neck squamous cell carcinoma(HNSCC) and its possible mechanisms. Methods Transcriptome sequencing data of HNSCC tissues and adjacent tissues were obtained from the TCGA database, and the expression levels of Sec31A were compared. Immunohistochemical staining was used to analyze the expression of Sec31A in HNSCC tissues. Kaplan-Meier survival analysis was used to compare the relationship between Sec31A and the prognosis of HNSCC patients. Small interfering plasmids si-Sec31A and si-NC were transfected into HNSCC cell lines HN6 and HN4, and the impact of knocking down Sec31A on the biological behavior of HNSCC cells was detected through CCK-8 experiments, plate cloning experiments, scratch healing experiments, and Transwell experiments. Changes in the expression levels of PI3K/AKT/mTOR pathway related proteins in cells were detected after knocking down Sec31A with HN6 and HN4 through Western Blot(WB)experiments. Stable transfected cell lines of HN6 siSec31A and HN6 siNC were constructed and inoculated subcutaneously in nude mice to further verify the tumorigenic effect of Sec31A in vivo. Results TCGA data showed that Sec31A was higher in HNSCC tissues than in adjacent normal tissues(P

Abstract Objective This study aims to comprehensively analyze the clinical characteristics and identify the differentially expressed genes associated with drug‐resistant epilepsy (DRE) in patients with focal cortical dysplasia (FCD). Methods A retrospective investigation was conducted from July 2019 to June 2022, involving 40 pediatric cases of DRE linked to FCD. Subsequent follow‐ups were done to assess post‐surgical outcomes. Transcriptomic sequencing and quantitative reverse transcription polymerase chain reaction (qRT‐PCR) were used to examine differential gene expression between the FCD and control groups. Results Among the 40 patients included in the study, focal to bilateral tonic–clonic seizures (13/40, 32.50%) and epileptic spasms (9/40, 22.50%) were the predominant seizure types. Magnetic resonance imaging (MRI) showed frequent involvement of the frontal (22/40, 55%) and temporal lobes (12/40, 30%). In cases with negative MRI results (13/13, 100%), positron emission tomography/computed tomography (PET‐CT) scans revealed hypometabolic lesions. Fused MRI/PET‐CT images demonstrated lesion reduction in 40.74% (11/27) of cases compared with PET‐CT alone, while 59.26% (16/27) yielded results consistent with PET‐CT findings. FCD type II was identified in 26 cases, and FCD type I in 13 cases. At the last follow‐up, 38 patients were prescribed an average of 1.27 ± 1.05 anti‐seizure medications (ASMs), with two patients discontinuing treatment. After a postoperative follow‐up period of 23.50 months, 75% (30/40) of patients achieved Engel class I outcome. Transcriptomic sequencing and qRT‐PCR analysis identified several genes primarily associated with cilia, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1. Significance This study highlights focal to bilateral tonic–clonic seizures as the most common seizure type in patients with DRE due to FCD. Surgical intervention primarily targeted lesions in the frontal and temporal lobes. Patients with FCD‐related DRE showed a promising prognosis for seizure control post‐surgery. The identified genes, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1, could serve as potential biomarkers for FCD. Plain Language Summary This study aimed to comprehensively evaluate the clinical data of individuals affected by focal cortical dysplasia and analyze transcriptomic data from brain tissues. We found that focal to bilateral tonic–clonic seizures were the most prevalent seizure type in patients with drug‐resistant epilepsy. In cases treated surgically, the frontal and temporal lobes were the primary sites of the lesions. Moreover, patients with focal cortical dysplasia‐induced drug‐resistant epilepsy exhibited a favorable prognosis for seizure control after surgery. CFAP47, CFAP126, JHY, RSPH4A, and SPAG1 have emerged as potential pathogenic genes for the development of focal cortical dysplasia.

La-related protein 7 (LARP7) are a family of RNA chaperones that protect the 3'-end of RNA and are components of specific ribonucleoprotein complexes (RNP). In Tetrahymena thermophila telomerase, LARP7 protein p65 together with telomerase reverse transcriptase (TERT) and telomerase RNA (TER) form the core RNP. p65 has four known domains-N-terminal domain (NTD), La motif (LaM), RNA recognition motif 1 (RRM1), and C-terminal xRRM2. To date, only the xRRM2 and LaM and their interactions with TER have been structurally characterized. Conformational dynamics leading to low resolution in cryo-EM density maps have limited our understanding of how full-length p65 specifically recognizes and remodels TER for telomerase assembly. Here, we combined focused classification of Tetrahymena telomerase cryo-EM maps with NMR spectroscopy to determine the structure of p65-TER. Three previously unknown helices are identified, one in the otherwise intrinsically disordered NTD that binds the La module, one that extends RRM1, and another preceding xRRM2, that stabilize p65-TER interactions. The extended La module (αN, LaM and RRM1) interacts with the four 3' terminal U nucleotides, while LaM and αN additionally interact with TER pseudoknot, and LaM with stem 1 and 5' end. Our results reveal the extensive p65-TER interactions that promote TER 3'-end protection, TER folding, and core RNP assembly and stabilization. The structure of full-length p65 with TER also sheds light on the biological roles of genuine La and LARP7 proteins as RNA chaperones and core RNP components.

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring’s PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection.

Telomerase is an RNA-protein complex comprising telomerase reverse transcriptase, a non-coding telomerase RNA, and proteins involved in biogenesis, assembly, localization, or recruitment. Telomerase synthesizes the telomeric DNA at the 3-ends of linear chromosomes. During the past decade, structural studies have defined the architecture of Tetrahymena and human telomerase as well as protein and RNA domain structures, but high-resolution details of interactions remained largely elusive. In the past two years, several sub-4 Å cryo-electron microscopy structures of telomerase were published, including Tetrahymena telomerase at different steps of telomere repeat addition and human telomerase with telomere shelterin proteins that recruit telomerase to telomeres. These and other recent structural studies have expanded our understanding of telomerase assembly, mechanism, recruitment, and mutations leading to disease.

Telomeres are the physical ends of linear chromosomes. They are composed of short repeating sequences (such as TTGGGG in the G-strand for Tetrahymena thermophila) of double-stranded DNA with a single-strand 3' overhang of the G-strand and, in humans, the six shelterin proteins: TPP1, POT1, TRF1, TRF2, RAP1 and TIN21,2. TPP1 and POT1 associate with the 3' overhang, with POT1 binding the G-strand3 and TPP1 (in complex with TIN24) recruiting telomerase via interaction with telomerase reverse transcriptase5 (TERT). The telomere DNA ends are replicated and maintained by telomerase6, for the G-strand, and subsequently DNA polymerase α-primase7,8 (PolαPrim), for the C-strand9. PolαPrim activity is stimulated by the heterotrimeric complex CTC1-STN1-TEN110-12 (CST), but the structural basis of the recruitment of PolαPrim and CST to telomere ends remains unknown. Here we report cryo-electron microscopy (cryo-EM) structures of Tetrahymena CST in the context of the telomerase holoenzyme, in both the absence and the presence of PolαPrim, and of PolαPrim alone. Tetrahymena Ctc1 binds telomerase subunit p50, a TPP1 orthologue, on a flexible Ctc1 binding motif revealed by cryo-EM and NMR spectroscopy. The PolαPrim polymerase subunit POLA1 binds Ctc1 and Stn1, and its interface with Ctc1 forms an entry port for G-strand DNA to the POLA1 active site. We thus provide a snapshot of four key components that are required for telomeric DNA synthesis in a single active complex-telomerase-core ribonucleoprotein, p50, CST and PolαPrim-that provides insights into the recruitment of CST and PolαPrim and the handoff between G-strand and C-strand synthesis.

Abstract Background Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. Non-small cell lung cancer (NSCLC) is one of the most common malignant cancers. Information on the functions and mechanism of circRNAs in lung cancer is limited; thus, the topic needs more exploration. The purpose of this study was to identify aberrantly expressed circRNAs in lung cancer, unravel their roles in NSCLC progression, and provide new targets for lung cancer diagnosis and therapy. Methods High-throughput sequencing was used to analyze differential circRNA expression in patients with lung cancer. qRT‒PCR was used to determine the level of circHERC1 in lung cancer tissues and plasma samples. Gain- and loss-of-function experiments were implemented to observe the impacts of circHERC1 on the growth, invasion, and metastasis of lung cancer cells in vitro and in vivo. Mechanistically, dual luciferase reporter assays, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circHERC1. Nucleocytoplasmic localization of FOXO1 was determined by nucleocytoplasmic isolation and immunofluorescence. The interaction of circHERC1 with FOXO1 was verified by RNA pull-down, RNA immunoprecipitation (RIP) and western blot assays. The proliferation and migration of circHERC1 in vivo were verified by subcutaneous and tail vein injection in nude mice. Results CircHERC1 was significantly upregulated in lung cancer tissues and cells, ectopic expression of circHERC1 strikingly facilitated the proliferation, invasion and metastasis, and inhibited the apoptosis of lung cancer cells in vitro and in vivo. However, knockdown of circHERC1 exerted the opposite effects. CircHERC1 was mainly distributed in the cytoplasm. Further mechanistic research indicated that circHERC1 acted as a competing endogenous RNA of miR-142-3p to relieve the repressive effect of miR-142-3p on its target HMGB1, activating the MAPK/ERK and NF-κB pathways and promoting cell migration and invasion. More importantly, we found that circHERC1 could bind FOXO1 and sequester it in the cytoplasm, adjusting the feedback AKT pathway. The accumulation of FOXO1 in the cytosol and nuclear exclusion promoted cell proliferation and inhibited apoptosis. CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential prognostic biomarker and therapeutic target for NSCLC. Conclusions CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential diagnosis biomarker and therapeutic target for NSCLC. Our findings indicate that circHERC1 facilitates the invasion and metastasis of NSCLC cells by regulating the miR-142-3p/HMGB1 axis and activating the MAPK/ERK and NF-κB pathways. In addition, circHERC1 can promote cell proliferation and inhibit apoptosis by sequestering FOXO1 in the cytoplasm to regulate AKT activity and BIM transcription.

A physics-based low frequency noise (LFN) model for AlxGa1−xN/GaN high electron mobility transistors (HEMTs) is proposed in this article. By treating the distributed low-density surface donor states as the responsible mechanism and exhibiting charge neutrality in combination with the electric field across the barrier layer, a compact expression for Schottky barrier height (SBH) capturing the physics behind the variations of AlxGa1−xN layer thickness is profiled, which incorporates the effect of strain relaxation caused by high Al fraction. Furthermore, the SBH is applied to develop VTH and IDS. The LFN model, dominated by the fluctuations of carriers and drain current in the channel caused by the trapping/detrapping process, is subsequently obtained. It is indicated that the larger threshold voltage, higher drain current, and normalized noise are observed by our model with respect to the traditional SBH expressed only by an interpolated linear function of x. The drain current noise behavior showing the 1/f spectrum down to very low frequencies is seriously subjected to the barrier thickness-dependent SBH of AlxGa1−xN/GaN HEMTs. The accuracy of the proposed model is also verified by comparison with the experimental results from different devices.

Abstract Background To evaluate the glycemic control effects of vhiglitazar (carfloglitazar), a novel peroxisome proliferator‐activated receptor pan‐agonist, in patients with type 2 diabetes mellitus (T2DM) with metabolic syndrome (MetS) or insulin resistance (IR) using pooled data analysis of two phase III clinical trials. Methods Data were collected from two randomized phase III clinical trials in China, comparing chiglitazar to placebo or sitagliptin in T2DM patients. The MetS was defined by the Adult Treatment Panel III MetS criteria, and IR was defined by homeostatic model assessment for insulin resistance (HOMA‐IR) ≥4.31 (male) or 4.51 (female). The main end point of this analysis was glycemic control in the different arms within each subgroup. Results In the MetS subgroup, changes in glycated hemoglobin (HbA1c) from baseline at week 24 in the chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg arms were −1.44%, −1.68%, and −1.37%, respectively; p

Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG1. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging2-5. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP16,7. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein8,9. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase10, and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR153211,12 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies13,14 are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.

M2 macrophages in the tumor microenvironment are important drivers of cancer metastasis. Exosomes play a critical role in the crosstalk between different cells by delivering microRNAs or other cargos. Whether exosomes derived from pro-tumorigenic M2 macrophages (M2-Exos) could modulate the metastatic behavior of renal cell carcinoma (RCC) is unclear. This study found that M2-Exos promotes migration and invasion in RCC cells. Inhibiting miR-21-5p in M2-Exos significantly reversed their pro-metastatic effects on RCC cells in vitro and in the avian embryo chorioallantoic membrane in vivo tumor model. We further found that the pro-metastatic mechanism of miR-21-5p in M2-Exos is by targeting PTEN-3'UTR to regulate PTEN/Akt signaling. Taken together, our results demonstrate that M2-Exos carries miR-21-5p promote metastatic features of RCC cells through PTEN/Akt signaling. Reversing this could serve as a novel approach to control RCC metastasis.