Search

Abstract The Janis–Newman–Winicour (JNW) spacetime can describe a naked singularity with a photon sphere that smoothly transforms into a Schwarzschild black hole. Our analysis reveals that photons, upon entering the photon sphere, converge to the singularity in a finite coordinate time. Furthermore, if the singularity is subjected to some regularization, these photons can traverse the regularized singularity. Subsequently, we investigate the gravitational lensing of distant sources and show that new images emerge within the critical curve formed by light rays escaping from the photon sphere. These newfound images offer a powerful tool for the detection and study of JNW naked singularities.

Abstract Currently, the biological understanding of Crohn’s disease (CD) remains limited. PANoptosis is a revolutionary form of cell death reported to participate in numerous diseases, including CD. In our study, we aimed to uncover the roles of PANoptosis in CD. Differentially expressed PANoptosis-related genes (DE-PRGs) were identified by overlapping PANoptosis-related genes and differentially expressed genes between CD and normal samples in a combined microarray dataset. Three machine learning algorithms were adopted to detect hub DE-PRGs. To stratify the heterogeneity within CD patients, nonnegative matrix factorization clustering was conducted. In terms of immune landscape analysis, the “ssGSEA” method was applied. qRT-PCR was performed to examine the expression levels of the hub DE-PRGs in CD patients and colitis model mice. Ten hub DE-PRGs with satisfactory diagnostic performance were identified and validated: CD44, CIDEC, NDRG1, NUMA1, PEA15, RAG1, S100A8, S100A9, TIMP1 and XBP1. These genes displayed significant associations with certain immune cell types and CD-related genes. We also constructed gene‒microRNA, gene‒transcription factor and drug‒gene interaction networks. CD samples were classified into two PANoptosis patterns according to the expression levels of the hub DE-PRGs. Our results suggest that PANoptosis plays a nonnegligible role in CD by modulating the immune system and interacting with CD-related genes.

Abstract This paper investigates the observational signatures of hot spots orbiting scalarized Reissner–Nordström black holes, which have been reported to possess multiple photon spheres. In contrast to the single-photon sphere case, hot spots orbiting black holes with two photon spheres produce additional image tracks in time integrated images capturing a complete orbit of hot spots. Notably, these newly observed patterns manifest as a distinct second-highest peak in temporal magnitudes when observed at low inclination angles. These findings offer promising observational probes for distinguishing black holes with multiple photon spheres from their single-photon sphere counterparts.

Abstract Background Centromeres are critical for maintaining genomic stability in eukaryotes, and their turnover shapes genome architectures and drives karyotype evolution. However, the co-evolution of centromeres from different species in allopolyploids over millions of years remains largely unknown. Results Here, we generate three near-complete genome assemblies, a tetraploid Brachypodium hybridum and its two diploid ancestors, Brachypodium distachyon and Brachypodium stacei. We detect high degrees of sequence, structural, and epigenetic variations of centromeres at base-pair resolution between closely related Brachypodium genomes, indicating the appearance and accumulation of species-specific centromere repeats from a common origin during evolution. We also find that centromere homogenization is accompanied by local satellite repeats bursting and retrotransposon purging, and the frequency of retrotransposon invasions drives the degree of interspecies centromere diversification. We further investigate the dynamics of centromeres during alloploidization process, and find that dramatic genetics and epigenetics architecture variations are associated with the turnover of centromeres between homologous chromosomal pairs from diploid to tetraploid. Additionally, our pangenomes analysis reveals the ongoing variations of satellite repeats and stable evolutionary homeostasis within centromeres among individuals of each Brachypodium genome with different polyploidy levels. Conclusions Our results provide unprecedented information on the genomic, epigenomic, and functional diversity of highly repetitive DNA between closely related species and their allopolyploid genomes at both coarse and fine scale.

Abstract Background Expanding new nurse training and education is a priority for nursing educators as well as a critical initiative to stabilize the nursing workforce. Given that there is currently no standardized program for the training of new nurses in China, we investigated the effectiveness of the bridge-in, objective, pre-assessment, participatory learning, post-assessment, and summary model combined with case-based learning ((BOPPPS-CBL) for the standardized training of new nurses. Methods The mixed method approach with explanatory sequential (quantitative-qualitative) method was used. A questionnaire was used to compare the impact of the BOPPPS-CBL model and the Traditional Learning Model (TLM) on the core competencies of 185 new nurses for two years of standardized training. Quantitative data were analyzed using SPSS 22.0. Focus group interviews were used with four groups of new nurses and perceptions of BOPPPS-CBL training were recorded. Qualitative data were analyzed thematically. Results According to the quantitative data, more new nurses agreed that the BOPPPS-CBL model stimulated their learning and improved their core nursing competencies than the TLM. The BOPPPS-CBL group outperformed the TLM group on theoretical knowledge tests. Qualitative data revealed that 87.5% of new nurses agreed on the value of BOPPPS-CBL training, and three themes were extracted: (1) role promotion; (2) formation of new thinking to solve clinical problems; and (3) suggestions for improvement. Conclusion BOPPPS-CBL training had a significant impact on improving new nurses’ core competencies and promoting the transition of new nurses to clinical practice nurses in China. The study recommends BOPPPS-CBL training as an effective teaching model for the standardized training and education of new nurses.

Abstract Background Renal transplant recipients (RTRs) have a 3- to 5-fold higher risk of developing malignant tumors than the general population, with new malignant tumors after transplantation considered to be the leading cause of death in RTRs. In pathological practice, it is rare for neoplasms with different histology to be located in the same organ. We report the first case of a synchronous papillary renal neoplasm with reverse polarity (PRNRP) and urothelial carcinoma (UC) in the ipsilateral kidney in an RTR. Molecular detection was conducted by next-generation sequencing. Case presentation A 68-year-old female suffered from uremia 19 years ago and underwent renal transplantation (RT) after receiving dialysis for 6 months. Hematuria occurred one month ago and an enhanced CT showed that there were two abnormal density foci in the middle and lower parts of the autologous left kidney. A laparoscopic left nephrectomy and ureterectomy were performed. Gross examination revealed a mass (I) in the left renal parenchyma, 2*1.8*1.5 cm in size, that protruded from the renal capsule, and a cauliflower-like mass (II), 5*2.5*2 cm in size, adjacent to the mass (I). Microscopic findings revealed these lesions were PRNRP and UC, respectively. PCR analysis revealed a KRAS gene mutation (G12D in exon 2) in the PRNRP, while NGS analysis revealed FGFR3 (S249C in exon 7) and KDM6A (Q271Ter in exon 10 and A782Lfs in exon 17) mutations in the UC. Conclusions We report here for the first time an extraordinarily rare case of synchronous renal tumors of a PRNRP and UC in the ipsilateral kidney of an RTR. We identified simultaneous KRAS, FGFR3, and KDM6A mutations in two different renal masses in the ipsilateral kidney. Pathologic assessment with comparative molecular analysis of mutational profiles facilitates tumor studies after RT and may be of great value in clinical management strategies.

Abstract Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for osteoporosis currently. However, further evidence is needed to learn more regarding other common anti-osteoporosis drugs and the risk for AFF. In this study, reports of AFF were identified from Food and Drug Administration Adverse Event Reporting System database. Disproportionality analyses were performed to examine the reporting odds ratio (ROR), information component (IC) and adjusted ROR (adj. ROR) signals for AFF for common anti-osteoporosis drugs. A total of 1692 unique AFF reports were identified. The disproportionality signals (the lower bound of 95% confidence interval > 1 for ROR and adjusted ROR, and > 0 for IC) were detected for alendronate, denosumab, pamidronate, risedronate, zoledronate, ibandronate, and teriparatide while no signal was detected for raloxifene, abaloparatide, and romosozumab. When restricted in patients with osteoporosis, the disproportionality signals were still detected for alendronate, pamidronate, risedronate, denosumab, and ibandronate. Our results suggest that alendronate has the largest risk signal, while the risks varied among different bisphosphonates. In addition, denosumab was found statistically associated with AFF in both the entire database and patients with osteoporosis.

Objective: The EKAN is a reliable and validated tool for objectively measuring the evidence-based practice (EBP) knowledge of nurses. Thus, we set out to translate and culturally modify the Evidence-Based Practice Knowledge Assessment in Nursing (EKAN), and then evaluate its validity and reliability among Chinese practicing nurses. Methods: This cross-sectional study consisted of two phases. The first phase involved translating the EKAN into Chinese (EKAN-Chinese), using a process of forward translation, back translation, review, cultural adjustment as well as a pilot study. The second phase aimed to assess the psychometric properties of the EKAN-Chinese and establish a baseline measure of EBP knowledge among 120 nurses from a large general hospital in Beijing, China. Data were collected from August to November 2022 and analyzed with Rasch software. This study was reported using the cross-sectional STROBE checklist. Results: The newly translated, EKAN-Chinese was pilot-tested after slight modification of four items without altering the intended meaning. The outfit unweighted mean square was 1.03 (SD = −0.13), the infit weighted mean square was 1.00 (−0.17), and the mean difficulty index ranged from −3.43 to 2.85 according to validity indices. The results of the reliability indices revealed low person reliability (0.49), high item reliability (0.96), moderate person separation index (0.99), and sufficient item separation index (4.71). The mean EKAN-Chinese sum score was 9.8 (max score = 20, SD = 2.9). Conclusion: The newly translated EKAN-Chinese showed sufficient psychometric evidence to support use in practicing Chinese nurses. The EKAN-Chinese can be used by nurse leaders in China as a potential screening tool to 1) objectively identify nurses who need educational training in evidence-based nursing practice, and 2) gauge the effectiveness of education and training programs to improve EBP knowledge and ultimately, evidence-based care.

Crack detection is a crucial task for the structural health diagnosis of buildings. The current widely used manual inspection methods have inherent limitations and safety hazards, while traditional digital image processing methods require manual feature extraction and also have substantial limitations. In this paper, we propose a crack recognition method based on pyramid features and memory mechanisms that leverages a U-shaped network, long short-term memory mechanisms, and a pyramid feature design to address the recognition accuracy, robustness, and universality issues with deep learning-based crack detection methods in recent years. Experiments were conducted on four publicly available datasets and one private dataset. Compared with the commonly used FCN8s, SegNet, UNet, and DeepLabv3+ models and other related studies using the same evaluation criteria and datasets, our proposed model shows better overall performance in terms of all metrics evaluated.

Abstract It has been recently reported that, at late times, the total luminosity of a star freely falling in black holes decays exponentially with time, and one or two series of flashes with decreasing intensity are seen by a specific observer, depending on the number of photon spheres. In this paper, we examine observational appearances of an infalling star in a reflection-asymmetric wormhole, which has two photon spheres, one on each side of the wormhole. We find that the late-time total luminosity measured by distant observers gradually decays with time or remains roughly constant due to the absence of the event horizon. Moreover, a specific observer would detect a couple of light flashes in a bright background at late times. These observations would offer a new tool to distinguish wormholes from black holes, even those with multiple photon spheres.

Abstract Aim To explore factors associated with decision regret after cystectomy among Chinese bladder cancer patients. Methods This cross‐sectional study involved 112 patients, who had received radical bladder cancer resection. Participants were recruited from August 2021 until January 2022. The decision regret scale (DRS), decision conflict scale (DCS), and the Functional Assessment of Cancer Therapy–Bladder cancer (FACT‐BL) form were used to measure decision regret, decision conflict, and quality of life. Investigator‐designed items further explored perceptions involved in decision‐making participation and outcomes. Results The average score for decision regret was 26.21 (SD 15.886), while decision conflict was 20.27 (SD 13.375) and quality of life was 94.74 (SD 20.873). 57.1% of our participants had a little knowledge about the quality of life of patients who chose an alternate urinary diversion method; however, only 13.4% reported having a clear understanding. In addition, 8.9%, 26.8%, and 36.6% thought that quality of life related to alternate decisions was poor, average, or good, respectively. Multiple regression analysis suggested that decision regret is associated with decision conflict, quality of life, and the perceptions that others (who took alternate urinary diversion decisions) had a better quality of life. Conclusion Decision regret is common among Chinese bladder cancer patients, after cystectomy. The prevalence of regret appears to be much higher in Chinese bladder cancer patients compared to similar studies from other regions. Decisions in mainland China are often made by the treating physician or by family members which may cause more profound regret. However, education and economic status are positively related to higher levels of regret which creates questions around knowing, participation, and expectations, which must be explored.

Abstract Background Mucosa-associated lymphoid tissue (MALT) lymphoma is a common, low-grade, malignant B-cell lymphoma. However, simultaneous MALT lymphoma in the thymus and lung is extremely rare, and concomitant adenocarcinoma of the lung is even rarer. Herein, we report a rare case of a collision tumor in which MALT lymphoma was found in both the thymus and lung with Sjögren’s syndrome (SS) and adenocarcinoma in the lung. Case presentation A physical examination of a 32-year-old woman revealed an anterior superior mediastinal space-occupying lesion, and chest computed tomography (CT) indicated a nodular ground-glass opacity and irregular mixed-density focus in the right lung. All lung cancer-related tumor biomarkers were within normal ranges. The thymus and part of the lung tissue were surgically resected. The histopathology and molecular examinations confirmed MALT lymphoma of the thymus and lung with lung adenocarcinoma. SS was also diagnosed. No special postoperative treatment was performed for the MALT lymphoma, and the patient underwent immunosuppressive therapy for SS after 4 months of follow-up observation. Conclusions MALT lymphoma of the thymus and lung tissues has no specific presentation on imaging and is difficult to differentiate from common malignant tumors, and the definite diagnoses of these tumors are highly dependent on histopathological examination in combination with molecular testing and cytogenetics. SS may be an important potential condition for the occurrence of MALT lymphoma in the thymus and lung. Additional similar cases are needed to clarify the biological pathways and potential molecular mechanisms of rare lymphomas and collision tumors.

Objective: To study the factors associated with premenstrual syndrome (PMS) in emergency department (ED) nurses. Methods: A multicenter cross-sectional study was conducted in female ED nurses in China. Data gathering questionnaires included the Daily Record of Severity of Problems, Chinese Nurses Stressor Scale, Social Support Rating Scale, and Self-Rating Anxiety Scale. All questionnaires were used to assess the symptoms prospectively over 2 months. Results: A total of 289 ED nurses were recruited. The incidence of PMS was 67.47%. The most common symptoms were tiredness (76.90%), anger (76.90%), restlessness (75.40%), snoring (69.20%). Univariate analysis showed that the BMI and occupational stress score was significantly higher, and the age was significantly younger in the PMS group compared with the non-PMS group. According to the multiple linear regression, the symptoms of PMS were positively associated with the occupational stress score and anxiety score, and negatively with the level of education received. Conclusions: occupational stress, anxiety, and education level may associated with the occurrence of PMS in ED nurses.

Background: Urinary catheterization after vaginal prolapse surgery can cause inconvenience for patients, elevate the risk of urinary tract infections, and potentially prolong the hospitalization. In China, there is no consensus on the optimal time to remove the urinary catheter after vaginal prolapse surgery. Thus, it will be valuable to gain insight into the nationwide catheterization management after the vaginal prolapse surgery. Methods: From March to May 2020, an online questionnaire was shared and purposive non-probabilistic sampling was used to recruit the participants. The urogynecologists currently performing vaginal prolapse surgery and involved nurses were included in this study. Results: 1363 urogynecologists and 436 nurses responded and 99.5% of them reported using transurethral indwelling catheters (TIC) for post-operative bladder drainage in their practices. The duration of initial catheterization after vaginal prolapse surgery was generally 1–7 days, with a median duration of 3 days for anterior colporrhaphy (AC) and anterior & posterior colporrhaphy (APC), and 2 days for other procedures. For the same type of surgery, the median duration of catheterization varied by region. For AC, it was shorter by 1 day in West China and South China (P ​

Abstract Background Non-small cell lung cancer (NSCLC) is still one of the diseases with the highest mortality and morbidity, and lung adenocarcinoma (LUAD) accounts for more than half of all NSCLC cases in most countries. miRNA can be used as a potential biological marker and treatment for lung adenocarcinoma. However, the effect of miR-937-3p to the invasion and metastasis of LUAD cells is not clear. Methods miRNA microarray is used to analyze the expression of miRNA in lung adenocarcinoma tissue. Transwell migration, Wound-healing assay and Western blot analysis are used to analyze cell migration, invasion and epithelial-mesenchymal transition (EMT) capabilities. Tube formation is used to assess angiogenesis ability. In addition, dual luciferase reporter gene detection is used to identify the potential binding between miRNA and target mRNA. In vivo experiments were performed on male NOD/SCID nude mice by tail vein injection to establish a transplanted tumor model. The CHIP experiment is used to verify the transcription factors of miRNA. Result In our study, miR-937-3p was high-regulated in LUAD cell lines and tissues, and its expression level was related to tumor progression. We found that miR-937-3p high-expression has an effect on cell invasion and metastasis. In molecular mechanism, miR-937-3p causes SOX11 reduction by directly binding to the 3′-UTR of SOX11.In addition, MYC affects miR-937-3p transcription by binding to its promoter region. Conclusions Our research shows that miR-937-3p is mediated by MYC and can control the angiogenesis, invasion and metastasis of LUAD by regulating SOX11, thereby promoting the progress of LUAD. We speculate that miR-937-3p can be used as a therapeutic target and potential biomarker for LUAD.

Objective: To provide a general description of women with postpartum urinary incontinence (PPUI), and investigate the effect of different types of PPUI with varied severity on affected women's quality of life. Methods: We performed a cross-sectional study in China that included 130 women with reported symptoms of PPUI. At the sixth to eighth week postpartum, we analyzed sociodemographic and clinical characteristics and compared women's quality of life (measured using the I-QOL and IIQ-7) by severity of PPUI (measured using the ICI-Q-SF), types of PPUI, stages of prolapse, and age. Results: 81 of the (62.3%) participating women were classified as mild PPUI, 43 as (33.1%) moderate, and 6 as (4.6%) severe, with 80 of these (61.5%) were grouped into stress urinary incontinence (SUI). With the symptoms of PPUI becoming more severer the total I-QOL score decreased significantly, and the total IIQ-7 score increased. Women with MUI reported lower scores for I-QOL and behavioral impacts, and higher scores of IIQ-7 than those with SUI. Conclusions: We found that more severe symptoms of UI and prolapse more negatively affected the quality of life of postpartum women, and women with MUI experienced a lower QOL.

Background: There has been growing evidence that the aberrantly expressed Homeobox-C 4 (HOXC4) plays crucial roles in the development of some cancer types. However, it remains unclear as far as its expression patterns and prognostic significance are concerned, as is tumor immunity.Methods: To investigate the expression levels and prognostic implications of HOXC4, multiple data sources were used in conjunction with quantitative real-time polymerase chain reaction (qRT-PCR) verification. Afterward, diverse immunological-related analyses, along with anti-cancer drug sensitivity, were performed in a number of cancer types. A further exploration of the underlying mechanisms of HOXC4 in tumorigenesis and immunity was carried out using the Gene Set Enrichment Analysis (GSEA) and the Gene Set Variation Analysis (GSVA).Results: Based on extensive database mining, HOXC4 was ubiquitously expressed across 21 tumor cell lines and significantly higher than that of normal tissues in 21 tumor types. The outcome of survival analysis including overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS) and progression-free interval (PFI) revealed that upregulation of HOXC4 expression in several cancers was associated with worse prognosis. Additionally, HOXC4 was observed to correlate closely with colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), rectum adenocarcinoma (READ), and thyroid carcinoma (THCA) in terms of tumor immune cells infiltration. As a result of our comprehensive pan-cancer study, we have identified a significant link between the expression of HOXC4 and the efficacy of immunotherapy-related treatments, together with anti-cancer drug sensitivity. As a final note, HOXC4 was found to modulate multiple signaling pathways involved in tumorigenesis and immunity.Conclusion: HOXC4 has been implicated in our study for the first time as an oncogene in cancers with a poor prognosis, potentially laying the groundwork for promising clinical biomarkers and immunotherapy approaches.

To study the strength degradation mechanism of compacted loess during dry-wet cycles, 0–5 dry-wet cycles tests and many triaxial compression tests were carried out on loess with an optimal moisture content. During the dry-wet cycles, the loess samples were analyzed by nuclear magnetic resonance and scanning electron microscopy. Studies have shown that at the macro level, with increasing numbers of wet and dry cycles and increasing cycle amplitude, the cohesive force and internal friction angle of the loess decrease, and the shear strength of the loess deteriorates significantly. At the micro level, with the number of wet and dry cycles increasing, the connection between particles changes from surface-to-surface contacts to point-to-point or point-to-surface contacts. The edges and corners of the particles decrease, the roundness increases, the large pores gradually decrease, the small pores gradually increase, and the fractal dimension gradually increases. In terms of microscopic view, the NMR test shows that with increasing numbers of dry-wet cycles, the T2 peak curve increases, the curve width increases slightly, the peak area gradually increases, and the porosity increases. From the macroscopic, mesoscopic, and microscopic multiscale analysis, the structure of loess is degraded under the action of dry and wet cycles; the strength of the loess is degraded significantly after 0 to 3 cycles and then gradually stabilizes. These research results can provide a certain reference value for the management of loess collapse geological disasters in semiarid climates.

To investigate the microstructure of paleosol and its expansion characteristics, the paleosol of the Zaosheng #3 tunnel of the Yinxi high-speed railway was studied. Based on X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), nuclear magnetic resonance (NMR), and scanning electron microscopy techniques (SEM), the microstructure of the paleosol was analyzed in terms of the mineral composition, formation elements, pore structure, and particle morphology. Five groups of undisturbed and remolded soils with different moisture contents were tested for the unloaded expansion rate and loaded expansion rate. The results show that the mineral components of the paleosol are mainly quartz, potash feldspar, calcite, and hematite, with the highest-content-component quartz accounting for 45.4% of the total content; the clay mineral composition of the paleosol has the highest content of montmorillonite at 12.3%. The elemental composition of the paleosol is dominated by Al, Si, Ca, and Fe, which form expansive mineral components such as quartz and montmorillonite, creating inherent conditions for expansibility of the paleosol. The T2 distribution curves of the undisturbed and remolded paleosol are composed of three peaks. The pore distribution of paleosol mainly includes medium pores, followed by large pores, and the contents of small pores and superlarge pores are very small. In terms of particle contact, the undisturbed soil is mostly in the form of “surface-surface” and “surface-edge” contact, and the remolded soil is mainly in the form of “point-surface” and “point-point” contact. The unloaded expansion rate of remolded soil is approximately twice that of undisturbed soil. The rate of loaded expansion of both soils decreases with increasing moisture content.

Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is a pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles in steatosis, insulin resistance, cancers and inflammatory and fibrotic diseases. In addition, DPP4 binds to the spike protein of the MERS virus, causing it to be the human cell surface receptor for that virus. DPP4 has been identified as a potential binding target of SARS-CoV-2 spike protein, so this question requires experimental investigation. Understanding protein structure and function requires reliable protocols for production and purification. We developed such strategies for baculovirus generated soluble recombinant human DPP4 (residues 29–766) produced in insect cells. Purification used differential ammonium sulphate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in series with immobilised metal affinity chromatography, and ion-exchange chromatography. The binding affinities of DPP4 to the SARS-CoV-2 full-length spike protein and its receptor-binding domain (RBD) were measured using surface plasmon resonance and ELISA. This optimised DPP4 purification procedure yielded 1 to 1.8 mg of pure fully active soluble DPP4 protein per litre of insect cell culture with specific activity >30 U/mg, indicative of high purity. No specific binding between DPP4 and CoV-2 spike protein was detected by surface plasmon resonance or ELISA. In summary, a procedure for high purity high yield soluble human DPP4 was achieved and used to show that, unlike MERS, SARS-CoV-2 does not bind human DPP4.

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.

Dipeptidyl Peptidase (DPP) 4 and related dipeptidyl peptidases are emerging as current and potential therapeutic targets. DPP9 is an intracellular protease that is regulated by redox status and by SUMO1. DPP9 can influence antigen processing, epidermal growth factor (EGF)-mediated signaling and tumor biology. We made the first gene knock-in (gki) mouse with a serine to alanine point mutation at the DPP9 active site (S729A). Weaned heterozygote DPP9 (wt/S729A) pups from 110 intercrosses were indistinguishable from wild-type littermates. No homozygote DPP9 (S729A/S729A) weaned mice were detected. DPP9 (S729A/S729A) homozygote embryos, which were morphologically indistinguishable from their wild-type littermate embryos at embryonic day (ED) 12.5 to ED 17.5, were born live but these neonates died within 8 to 24 hours of birth. All neonates suckled and contained milk spots and were of similar body weight. No gender differences were seen. No histological or DPP9 immunostaining pattern differences were seen between genotypes in embryos and neonates. Mouse embryonic fibroblasts (MEFs) from DPP9 (S729A/S729A) ED13.5 embryos and neonate DPP9 (S729A/S729A) mouse livers collected within 6 hours after birth had levels of DPP9 protein and DPP9-related proteases that were similar to wild-type but had less DPP9/DPP8-derived activity. These data confirmed the absence of DPP9 enzymatic activity due to the presence of the serine to alanine mutation and no compensation from related proteases. These novel findings suggest that DPP9 enzymatic activity is essential for early neonatal survival in mice.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention. [ABSTRACT FROM AUTHOR]

Extended engineering structures such as bridges, tunnels, and pipelines are vulnerable to surface fault ruptures, and thus large-scale tests using multi-shaking tables are necessary to investigate the structural performance in this special scenario. Because of the properties of the conventional displacement-controlled shaking table system with proportional-integral-derivative controllers, acceleration and displacement input strategies have respective drawbacks when used to reproduce across-fault ground motions. This study presents a new hybrid input strategy to reproduce across-fault ground motions on multi-shaking tables, which overcomes the limitations of traditional acceleration or displacement input. In particular, the new input strategy aims to match both low-frequency displacements and high-frequency accelerations. The proposed hybrid input strategy was validated by the previously performed shaking table tests of a steel-concrete composite rigid-frame bridge under the across-fault ground motions. For comparison, conventional acceleration and displacement input strategies were also used in the tests to excite the bridge model. Test results including the reproduced ground motions and the structural responses obtained by the three input strategies are presented and compared. The test results indicate that the proposed hybrid input strategy can reproduce across-fault ground motions with improved fidelity on conventional multi-shaking tables. This study can provide useful references for the shaking table tests of bridge, tunnel and pipeline structures with the consideration of crossing fault-rupture zones. [ABSTRACT FROM AUTHOR]