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Abstract Background Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer. Methods A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays. Results H. pylori can colonize the host’s stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression. Conclusions H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process. Graphical abstract

Abstract Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.

Abstract The mechanism of nuclear size determination and alteration during normal lineage development and cancer pathologies which is not fully understood. As recently reported, chromatin modification can change nuclear morphology. Therefore, we screened a range of pharmacological chemical compounds that impact the activity of chromatin-modifying enzymes, in order to get a clue of the specific types of chromatin-modifying enzymes that remarkably effect nuclear size and shape. We found that interrupted activity of chromatin-modifying enzymes is associated with nuclear shape abnormalities. Furthermore, the activity of chromatin-modifying enzymes perturbs cell fate determination in cellular maintenance and lineage commitment. Our results indicated that chromatin-modifying enzyme regulates cell fate decision during lineage differentiation and is associate with nuclear size alteration.

Abstract Background Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. Methods BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. Results BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P

Abstract Proper organization of intracellular assemblies is fundamental for efficient promotion of biochemical processes and optimal assembly functionality. Although advances in imaging technologies have shed light on how the centrosome is organized, how its constituent proteins are coherently architected to elicit downstream events remains poorly understood. Using multidisciplinary approaches, we showed that two long coiled-coil proteins, Cep63 and Cep152, form a heterotetrameric building block that undergoes a stepwise formation into higher molecular weight complexes, ultimately generating a cylindrical architecture around a centriole. Mutants defective in Cep63•Cep152 heterotetramer formation displayed crippled pericentriolar Cep152 organization, polo-like kinase 4 (Plk4) relocalization to the procentriole assembly site, and Plk4-mediated centriole duplication. Given that the organization of pericentriolar materials (PCM) is evolutionarily conserved, this work could serve as a model for investigating the structure and function of PCM in other species, while offering a new direction in probing the organizational defects of PCM-related human diseases.

Abstract Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.

Spatial irregular sampling and random noise are two important factors that restrict the accuracy of seismic imaging. Seismic wavefield reconstruction and denoising based on sparse representation are two popular antidotes to these two inevitable issues, respectively. This article presents a non-parametric simultaneous reconstruction and denoising via sparse and low-rank regularization that dealt with the prestack gathers efficiently and automatically. The proposed method makes no additional prior assumptions on original data other than that the seismic signal is compressible. The key parameters estimation adopts a data-driven framework without person-dependent intervention. The basic idea of the approach is to combine the two related algorithms. Thus, the sparse decomposition needs to be performed only once. We first extract the solution matrix via Fourier dictionary and then perform the reconstruction and denoising successively in the sparse domain. Obtaining a perfect interpolation result requires that the seismic data satisfy the Shannon–Nyquist sampling theorem. However, data with steep-dip events or gaps, which cannot be adequate for the procedure, are a challenge that must be faced. This work proposes to deal with the common-offset gathers, which is characterized by flat, even approximate horizontal events, to handle the under-sampling obstacle. Another excellent property of the common-offset gathers is the simple and periodic repetitive texture structure, which can be represented sparsely and accurately by the Fourier dictionary. Thus, the computational complexity of the sparse representation is reduced. Both synthetic and practical applications indicate that our algorithm is efficient and effective.

BackgroundLugol chromoendoscopy (LCE) is a technique that is inexpensive and convenient for screening esophageal neoplastic lesions. However, the specificity of LCE is limited. The purpose of this study was to determine the risk characteristics of lesions related to false-positive results for LCE.MethodsIn this retrospective study, 871 lesions in 773 patients scheduled for LCE in Wuhan Union Hospital and First Affiliated Hospital of Shihezi University between April 2013 and October 2018 were enrolled. The 871 lesions were used to determine the diagnostic performance of LCE for detecting esophageal neoplastic lesions and were divided into an LCE-positive group (627 lesions) and an LCE-negative group (244 lesions). Six hundred and twenty-seven unstained/understained lesions from 563 patients were used to determine the significant risk factors for misdiagnosis of neoplasms by LCE. Among them, 358 lesions and 269 lesions were classified into the misdiagnosed group and correctly diagnosed group, respectively. A multivariate logistic regression analysis was conducted for suspected esophageal neoplastic lesions during the LCE examination.ResultsThe sensitivity, specificity, and overall accuracy for LCE were 100%, 40.5%, and 58.9%, respectively. Among 13 characteristics of lesions, lesions with branching vascular network (OR 4.53, 95% CI 2.23–9.21, p < 0.001), smooth lesions (OR 2.40, 95% CI 1.38–4.18, p = 0.002) under white light endoscopy (WLE), lesions with a size < 5 mm (OR 3.06, 95% CI 1.38–6.78, p = 0.006), ill-demarcated lesions (OR 7.83, 95% CI 4.59–13.37, p < 0.001), and pink color sign (PCS)-negative (OR 4.04, 95% CI 2.38–6.84, p < 0.001) lesions after reaction with iodine solution were independent risk factors for misdiagnosis as neoplastic lesions by LCE.ConclusionLCE has a high sensitivity but limited specificity for screening esophageal neoplastic lesions. For unstained or understained lesions, branching vascular network or smooth appearance under WLE, a size < 5 mm in diameter, ill-demarcated, or PCS-negative lesions after staining are related to the misdiagnosis of esophageal neoplastic lesions by LCE based on logistic regression. The multivariate logistic model may be used to predict the possibility of misdiagnosis and help improve the specificity of LCE in diagnosing esophageal neoplastic lesions.

Based on Hertz contact theory, two parabolic cylinder normal contact models are established. The effect of contact angle on normal approach, actual contact area, and normal contact stiffness are investigated, and the effect of the distance from the focus to the directrix (focus distance) on the mechanical characteristics of the models is further analyzed. The parabolic cylinder contact model was verified by simulation analysis and comparison with cylinder contact model. The results demonstrated that the contact angle, focal distance, and load have significant effects on the mechanical properties of the model. The simulation data are basically consistent with the contact model data, and the parabolic cylinder contact model and cylinder contact model have the same change trend. The results verify the correctness of the parabolic cylinder contact model and reveal the variation of the mechanical properties of the contact model.

Abstract Background Although pancreaticoduodenectomy with vein resection (PDVR) is widely performed in selected patients with indications, its benefits remain controversial. In this meta-analysis, we evaluate the safety and efficacy of PDVR in comparison to standard pancreaticoduodenectomy (PD). Methods We searched PubMed, Embase, and Cochrane as well as the Chinese National Knowledge Infrastructure, Weipu, and Wanfang databases for studies that evaluate the value of PVDR. The data of the patients who underwent PD or PDVR were analyzed using Review Manager and STATA software. Results In comparison with the PD group, the PDVR group had a lower R0 resection rate and higher rates of complications such as biliary fistula, reoperation rate, delayed gastric emptying, cardiopulmonary abnormalities, hemorrhage, in-hospital mortality, 30-day mortality. The blood loss, duration of operation, total hospital stay is higher in PDVR group. Conclusions Compared to standard PD, PDVR was associated with a greater risk of some specific complications and increase the mortality rate, total hospital stay time, combine with vein resection have a lower R0 resection rate. Therefore, combine with vascular resection for pancreatic cancer needs to be carefully selected by the surgeon.

The centrosome is a membraneless organelle composed of two centrioles and an amorphous pericentriolar material but the overall centrosome organizations remains unknown. Here authors show that two scaffold proteins, Cep63 and Cep152, self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4.

Fano-like lineshapes in whispering-gallery modes (WGMs) microresonators are of critical for many actual applications, such as high-sensitivity sensors, slow light, and optical switches. In this paper, we theoretically and experimentally demonstrate dynamic transmission lineshapes, including Lorentzian lineshapes, Fano-like lineshapes and gain-like lineshapes, with a simple system, where a surface nanoscale axial photonic (SNAP) microbottle is coupled to the transition of a tapered fiber by carefully choosing tapered fiber diameters. Controlled and robust coupling with a clean and almost equidistant spectrum for different axial modes is achieved while maintaining contact between the resonator and the taper. Our device offers five similar dynamic transmission lineshapes arranged in order simultaneously, demonstrating stable tuning and a high number of potential degrees of freedom in contrast to other coupling systems for single- or double-coupled microresonators. By using coupled-mode theory, these transmission lineshapes are fitted to explain these experiment observations. We also explore a tunable transmission spectra obtained by increasing the powers of the input laser. Our approach hold unique potential in sensitivity-enhanced sensing, quantum information processing, and all-optical switching.

The weak part of the stiffness of machine tool combined structure is the key to improve the stiffness of machine tool. To overcome the static deformation with difficulty acquisition, the paper chooses machine tool combined structure which can be equivalent to one-dimensional bar structure, and a weakness index (WI) is proposed to identify the weak part of the stiffness by means of the dynamic hammer test method. Based on the bar structure as a numerical example, the weak parts are modeled as EA reduction in stiffness while the mass is maintained at a constant value. Thorough finite element (FE) method simulations are performed to assess the robustness and limitations of the method in several scenarios with single and multiple weakness. On the crossbeam of gantry type machine tool, the sensors are used to collect vibration data, the structural modal parameters are obtained by singular value decomposition (SVD) technique, and the dynamic characteristics are systematically reconstructed by using modal state space method to obtain stiffness data at zero-frequency. Then, the weak part of the structural stiffness is identified by the weakness index. Finally, the comparison of FE simulations and experiment results are provided to illustrate the working of the method.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematodermic malignancy derived from plasmacytoid dendritic cell precursors. Despite advances in our understanding of tumor cell surface markers, the pathogenesis of BPDCN remains largely unknown. No standard or optimal treatments are available for BPDCN, and the prognosis is usually poor. We report herein a case of BPDCN that harbored multiple genetic mutations in epigenetic modifiers such as TET2 and ZRSR2 . Genetic studies in patients with BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.

Background: Neuroendocrine carcinomas (NECs) and mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal (GI) tract are both rare and malignant; however, it is unclear whether their prognosis is the same. Methods: In this cross-sectional study, a total of 12,878 patients with NEC or MiNEN in the GI tract were reviewed retrospectively by searching the Surveillance, Epidemiology, and End Results ( SEER ) program database. Next, we compared the characteristics and survival between patients with NEC or MiNEN and further analyzed the prognostic factors for the patients. Results: The data showed that patients with MiNEN had a worse prognosis as compared with patients with pure NEC in the small intestine (SI) and appendix, whereas there was no significant survival difference between NEC and MiNEN in the other parts of the GI system. On the whole, age ⩾55 years ( p

F-box genes play an important role in the growth and development of plants, but there are few studies on its role in a plant’s response to abiotic stresses. In order to further study the functions of F-box genes in tomato (Solanum lycopersicum, Sl), a total of 139 F-box genes were identified in the whole genome of tomato using bioinformatics methods, and the basic information, transcript structure, conserved motif, cis-elements, chromosomal location, gene evolution, phylogenetic relationship, expression patterns and the expression under cold stress, drought stress, jasmonic acid (JA) treatment and salicylic acid (SA) treatment were analyzed. The results showed that SlFBX genes were distributed on 12 chromosomes of tomato and were prone to TD (tandem duplication) at the ends of chromosomes. WGD (whole genome duplication), TD, PD (proximal duplication) and TRD (transposed duplication) modes seem play an important role in the expansion and evolution of tomato SlFBX genes. The most recent divergence occurred 1.3042 million years ago, between SlFBX89 and SlFBX103. The cis-elements in SlFBX genes’ promoter regions were mainly responded to phytohormone and abiotic stress. Expression analysis based on transcriptome data and qRT-PCR (Real-time quantitative PCR) analysis of SlFBX genes showed that most SlFBX genes were differentially expressed under abiotic stress. SlFBX24 was significantly up-regulated at 12 h under cold stress. This study reported the SlFBX gene family of tomato for the first time, providing a theoretical basis for the detailed study of SlFBX genes in the future, especially the function of SlFBX genes under abiotic stress.

A pair of kinases, RIPK1 and RIPK3, as well as the RIPK3 substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both Ripk3- and Mlkl-knockout mice retain ‘youthful’ morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The RIPK3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice. When the testes of young wild-type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.

Background. Prostate cancer (PC) prevention is effectively achieved through its inhibition. Oridonin (ORD), an active diterpenoid isolated from Rabdosia rubescens, has been shown to have an inhibitory effect on PC cells, although its impact on PC is unknown. Objectives. The present work investigated the actions and probable mechanisms of ORD on cellular proliferation, apoptosis, PC, and the wingless-type MMTV integration site family member 2 (Wnt)/β-catenin signaling pathway using the androgen-independent PC-3 cell line. Materials and methods. In this study, cell viability was analyzed with MTT assay method, apoptotic morphology determined using DAPI dye method, while protein (CD1333, OCT-4, Nanog, SOX-2 & Aldh1A1) and mRNA expressions were analyzed with western blotting and real time polymerase chain reaction (PCR). Results. We demonstrated a concentration-dependent ORD inhibition of PC-3 cell proliferation and inhibition of induction apoptosis. Furthermore, ORD decreased PC-3 Wnt-2, phosphorylated glycogen synthase kinase-3 (p-GSK3), and β-catenin protein levels and downregulated cyclin-D1 and c-myc messenger ribonucleic acid (mRNA). Conclusions. Oridonin inhibited proliferation and induced apoptosis in PC-3 cells, with the findings suggesting that it acted via the Wnt/β-catenin pathway to exert its effects. This study demonstrates that ORD may impact PC. [ABSTRACT FROM AUTHOR]