POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status.

Human tumors with exonuclease domain mutations in the gene encoding DNA polymerase ε (POLE) have incredibly high mutation burdens. These errors arise in four unique mutation signatures occurring in different relative amounts, the etiologies of which remain poorly understood. We used CRISPR-Cas9 to engineer human cell lines expressing POLE tumor variants, with and without mismatch repair (MMR). Whole-exome sequencing of these cells after defined numbers of population doublings permitted analysis of nascent mutation accumulation. Unlike an exonuclease active site mutant that we previously characterized, POLE cancer mutants readily drive signature mutagenesis in the presence of functional MMR. Comparison of cell line and human patient data suggests that the relative abundance of mutation signatures partitions POLE tumors into distinct subgroups dependent on the nature of the POLE allele, its expression level, and MMR status. These results suggest that different POLE mutants have previously unappreciated differences in replication fidelity and mutagenesis.

RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5.

RNA-binding motif protein 10 (RBM10) is a frequently mutated tumor suppressor in lung adenocarcinoma (LUAD). Yet, it remains unknown whether cancer-derived mutant RBM10 compromises its tumor suppression function and, if so, the molecular insight of the underlying mechanisms. Here, we show that wild-type RBM10 suppresses lung cancer cell growth and proliferation by inactivating c-Myc that is essential for cancer cell survival. RBM10 directly binds to c-Myc and promotes c-Myc's ubiquitin-dependent degradation, while RBM10 knockdown leads to the induction of c-Myc level and activity. This negative action on c-Myc is further boosted by ribosomal proteins (RPs) uL18 (RPL5) and uL5 (RPL11) via their direct binding to RBM10. Cancer-derived mutant RBM10-I316F fails to bind to uL18 and uL5 and to inactivate c-Myc, thus incapable of suppressing tumorigenesis. Our findings uncover RBM10 as a pivotal c-Myc repressor by cooperating with uL18 and uL5 in lung cancer cells, as its failure to do so upon mutation favors tumorigenesis.

A Programmable Microfluidic Paper-Based Analytical Device for Simultaneous Colorimetric and Photothermal Visual Sensing of Multiple Enzyme Activities.

New strategies for the simultaneous and portable detection of multiple enzyme activities are highly desirable for clinical diagnosis and home care. However, the methods developed thus far generally suffer from high costs, cumbersome procedures, and heavy reliance on large-scale instruments. To satisfy the actual requirements of rapid, accurate, and on-site detection of multiple enzyme activities, we report herein a smartphone-assisted programmable microfluidic paper-based analytical device (µPAD) that utilizes colorimetric and photothermal signals for simultaneous, accurate, and visual quantitative detection of alkaline phosphatase (ALP) and butyrylcholinesterase (BChE). Specifically, the operation of this µPAD sensing platform is based on two sequential steps. Cobalt-doped mesoporous cerium oxide (Co-m-CeO2) with remarkable peroxidase-like activities under neutral conditions first catalytically decomposes H2O2 for effectively converting colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB). The subsequent addition of ALP or BChE to their respective substrates produces a reducing substance that can somewhat inhibit the oxTMB transformation for compromised colorimetric and photothermal signals of oxTMB. Notably, these two-step bioenzyme-nanozyme cascade reactions strongly support the straightforward and excellent processability of this platform, which exhibit lower detection limits for ALP and BChE with a detection limit for BChE an order of magnitude lower than those of the other reported paper-based detection methods. The practicability and efficiency of this platform are further demonstrated through the analysis of clinical serum samples. This innovative platform exhibits great potential as a facile yet robust approach for simultaneous, accurate, and on-site visual detection of multiple enzyme activities in authentic samples.

Genetic Modulation of Biosynthetic Gas Vesicles for Ultrasound Imaging.

Gas vesicles (GVs) from microorganisms are genetically air-filled protein nanostructures, and serve as a new class of nanoscale contrast agents for ultrasound imaging. Recently, the genetically encoded GV gene clusters have been heterologously expressed in Escherichia coli, allowing these genetically engineered bacteria to be visualized in vivo in a real-time manner by ultrasound. However, most of the GV genes remained functionally uncharacterized, which makes it difficult to regulate and modify GVs for broad medical applications. Here, the impact of GV proteins on GV formation is systematically investigated. The results first uncovered that the deletions of GvpR or GvpU resulted in the formation of a larger proportion of small, biconical GVs compared to the full-length construct, and the deletion of GvpT resulted in a larger portion of large GVs. Meanwhile, the combination of gene deletions has resulted in several genotypes of ultrasmall GVs that span from 50 to 20 nm. Furthermore, the results showed that E. coli carrying the ΔGvpCRTU mutant can produce strong ultrasound contrast signals in mouse liver. In conclusion, the study provides new insights into the roles of GV proteins in GV formation and produce ultrasmall GVs with a wide range of in vivo research.

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPß, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

The effects of combined acupuncture anesthesia and serratus anterior plane block with ropivacaine on postoperative analgesia in patients undergoing chest surgery.

OBJECTIVE: To investigate the effects of combined acupuncture anesthesia and ropivacaine on postoperative analgesia and neuro-related factors in patients undergoing chest surgery. METHODS: The analgesic drug dosage, postoperative PCIA pressing times, VAS scores at rest and during activity at 6 h (T1), 12 h (T2), 18 h (T3), and 24 h (T4) postoperatively. RESULTS: The analgesic drug dosage and postoperative PCIA pressing times were lower in the observation group than in the control group (p < 0.05). The VAS scores at T1-T4 postoperatively were lower in the observation group than in the control group (p < 0.05). The SAS scores at T1-T4 postoperatively were lower in the observation group than in the control group (p < 0.05). The levels of IL-6 and IL-10 on postoperative day 1 were higher than those on preoperative day 1 in both groups, with a smaller change in the observation group (p < 0.05). The levels of S100ß protein on postoperative day 1 were higher than those on preoperative day 1 in both groups, while the BDNF levels were lower, with a smaller change in the observation group (p < 0.05). There was no significant difference in the incidence of adverse reactions between the control group (11.36%) and the observation group (15.56%) (p > 0.05). CONCLUSION: Combined acupuncture anesthesia and ropivacaine can effectively improve postoperative analgesia and agitation in patients undergoing chest surgery, reduce the dosage of analgesic drugs, regulate the levels of inflammatory factors and neurotrophic factors in patients, and do not increase the risk of adverse reactions related to patients.

Chiral molecule induced valley polarization enhancement of MoS2.

Monolayers of transition metal dichalcogenides (TMDCs) are atomically thin direct-bandgap semiconductors with potential applications in nanoelectronics, opto-electronics, and electrochemical sensing. Recent theoretical and experimental results have suggested that they are ideal systems for exploiting the valley degrees of freedom of Bloch electrons. Here, we report detailed studies of the opto-valleytronic properties of a chiral histidine molecule embedded in monolayer MoS2 single crystals grown via chemical vapor deposition. By irradiating MoS2 with circularly polarized light and measuring the resulting spatially resolved circularly polarized emission, we find the existence of a significantly increased circular polarization for D-histidine doped MoS2. The increased valley contrast is attributed to the selective enhancement of both the excitation and emission rates having one particular handedness of the circular polarization. These results provide a promising pathway to enhance the valley contrast for monolayer TMDCs at room temperature.

Suicidal ideation in Chinese adults with schizophrenia: associations with neurocognitive function and empathy.

BACKGROUND: Suicidal ideation is common among people diagnosed with schizophrenia spectrum disorders and may be related to neurocognitive, social cognitive, and clinical variables. This study aimed to investigate the relationships between suicidal ideation and both neurocognitive function and empathy. METHODS: The sample for this cross-sectional study comprised 301 schizophrenic patients aged 18-44 years. All participants were administered the Beck Scale for Suicide Ideation-Chinese Version (BSI-CV), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Interpersonal Reactivity Index (IRI), and the Positive and Negative Syndrome Scale (PANSS). The demographic and clinical data of the patients were also collected. RESULTS: In total, 82 patients reported suicidal ideation. Compared to patients without suicidal ideation, patients with suicidal ideation showed significant differences in the IRI-Personal Distress subscale, PANSS-General Psychopathology symptom scores, and suicide attempts. Moreover, there were moderating effects of neurocognitive function and empathy on the relationship between suicide attempts and suicidal ideation. CONCLUSIONS: These results indicate that the personal distress component of empathy, general psychopathology symptoms and suicide attempts are independent risk factors for suicidal ideation in Chinese adults with schizophrenia. Moreover, neurocognitive function may also be related to suicidal ideation through a moderating relationship. In order to reduce suicidal ideation among patients with schizophrenia, early screening of empathy and neurocognitive function is essential.

Value of cytopathology in the diagnosis of adenoid cystic carcinoma and an analysis of misdiagnoses.

BACKGROUND: The diagnosis of adenoid cystic carcinoma (ACC) by cytopathology can be challenging. This study was aimed at testing the effectiveness of this technique and at assessing possible differences in the coincidence rate of fine-needle aspiration cytology(FNAC) and brush exfoliation. METHODS: The pathology database of Southwest Medical University( Luzhou, China) was searched for patients who had undergone surgery or biopsy for ACC between January 2017 and January 2022 and had preoperative cytopathologic results. Their cytologic and histologic data were then analyzed retrospectively and the coincidence rates of cytopathology in the diagnosis of ACC were calculated. RESULTS: Compared with histopathology, the total coincidence rate of the cytologic diagnosis of ACC was 76.8%, that of FNAC was 78.9%, and that of brush exfoliation was 55.6%. CONCLUSION: In the diagnosis of ACC, cytopathology is an effective tool; this is especially true of FNAC, which plays an important role in the diagnosis of ACC. The authors further suggest that it is advisable for diagnosticians to master the cytopathological features of ACC to reduce the possibility of preoperative misdiagnoses.

Enhanced Photocatalytic Hydrolysis Performance of Chiral Molecule Loaded Titanium Disulfide Nanosheets.

The photoelectrochemical (PEC) water decomposition is a promising method to produce hydrogen from water. To improve the water decomposition efficiency of the PEC process, it is necessary to inhibit the generation of H2 O2 byproducts and reduce the overpotential required by cheap catalysts and a high current density. Studies have shown that coating the electrode with chiral molecules or chiral films can increase the hydrogen production and reduce the generation of H2 O2 byproducts. This is interpreted as the result of a chiral induced spin selectivity (CISS) effect, which induces a spin correlation between the electrons that are transferred to the anode. Here, we report the adsorption of chiral molecules onto titanium disulfide nanosheets. Firstly, titanium disulfide nanosheets were synthesized via thermal injection and then dispersed through ultrasonic crushing. This strategy combines the CISS with the plasma effect caused by the narrow bandgap of two-dimensional sulfur compounds to promote the PEC water decomposition with a high current density.

Endovascular Treatments for Coarctation of the Aorta with Concurrent Poststenotic Aneurysms in Adults.

BACKGROUND: Coarctation of the aorta with poststenotic aneurysms is rare and complex. Here we report a relatively large group of endovascular treatments for the disease. MATERIALS AND METHODS: Fifteen patients from two centers between 2006 and 2019 were included in the study. The patients were retrospectively divided into two groups. Patients in the complex group had insufficient proximal landing zone (<2 cm) or the zigzag shape of aorta. Their demographics, clinical manifestations, endovascular procedures, and follow-up results were analyzed. RESULTS: There were 7 patients in the simple group and 8 patients in the complex group. Eleven patients were symptomatic. Despite the unfavorable anatomy in the complex group, technical success reached 100%. The diameter of coarctation increased from 8.6 mm to 16.7 mm with poststenotic aneurysms successfully excluded at the same time. In patients without sufficient proximal landing zone, left subclavian artery was covered by the stent grafts and then sacrificed (three patients) or revascularized (four patients). Other than one patient who suffered iliac artery rupture and received open repair, there was no other perioperative complications. Computed tomography angiography repeated at mean 42 months postoperation confirmed patency of stents and the exclusion of aneurysms with no aortic wall injury. Mild endoleaks occurred in two patients in the complex group and were left to observation. During 55.0 months follow-up, except for one patient who received secondary left subclavian artery fenestration, all other patients remained asymptomatic. CONCLUSIONS: Endovascular treatments for coarctation of the aorta with poststenotic aneurysm showed a high technical success and could be an alternative solution for such disease.

Window anastomosis technique for repair of supracardiac total anomalous pulmonary venous connection in infants.

Outcomes of operations for total anomalous pulmonary venous connection (TAPVC) have improved. However, postoperative pulmonary venous obstruction remains the most significant complication with high morbidity and mortality. We introduce a window anastomosis technique for repair of supracardiac TAPVC in infants. The mainstay of the surgical technique is to resect the anterior wall of the pulmonary vein confluence and part of the posterior wall of the left atrium to form a large and undistorted "window to window" anastomosis.

Application of nanotechnology in the diagnosis and treatment of bladder cancer.

Bladder cancer (BC) is a common malignancy in the genitourinary system and the current theranostic approaches are unsatisfactory. Sensitivity and specificity of current diagnosis methods are not ideal and high recurrence and progression rates after initial treatment indicate the urgent need for management improvements in clinic. Nanotechnology has been proposed as an effective method to improve theranosis efficiency for both non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). For example, gold nanoparticles (AuNPs) have been developed for simple, fast and sensitive urinary sample test for bladder cancer diagnosis. Nanoparticles targeting bladder cancers can facilitate to distinguish the normal and abnormal bladder tissues during cystoscopy and thus help with the complete removal of malignant lesions. Both intravenous and intravesical agents can be modified by nanotechnology for targeted delivery, high anti-tumor efficiency and excellent tolerability, exhibiting encouraging potential in bladder cancer treatment. Photosensitizers and biological agents can also be delivered by nanotechnology, intermediating phototherapy and targeted therapy. The management of bladder cancer remained almost unchanged for decades with unsatisfactory effect. However, it is likely to change with the fast-developed nanotechnology. Herein we summarized the current utility of nanotechnology in bladder cancer diagnosis and treatment, providing insights for the future designing and discovering novel nanoparticles for bladder cancer management.

Effect of Ferrous Ion on Heat-Induced Aroma Deterioration of Green Tea Infusion.

Aroma deterioration is one of the biggest problems in processing tea beverages. The aroma of tea infusion deteriorates fast during heat sterilization and the presence of ferrous ion (Fe2+) aggravates it. The underlying mechanism remains unveiled. In this study, Fe2+ was verified to deteriorate the aroma quality of green tea infusion with heat treatment. Catechins were necessary for Fe2+-mediated aroma deterioration. By enhancing the degradation of catechins, Fe2+ dramatically increased the production of hydrogen peroxide (H2O2). Fe2+ and H2O2 together exacerbated the aroma of green tea infusion with heat treatment. GC-MS analysis revealed that the presence of Fe2+ enhanced the loss of green/grassy volatiles and promoted the formation of new volatiles with diversified aroma characteristics, resulting in a dull scent of green tea infusion. Our results revealed how Fe2+ induced aroma deterioration of green tea infusion with heat treatment and could help guide tea producers in attenuating the aroma deterioration of tea infusion during processing.

A core-skirt designed artificial cornea with orthogonal microfiber grid scaffold.

Artificial cornea is an effective treatment option for cases of severe corneal loss. In this study, we prepared a core-skirt designed artificial cornea with orthogonal microfiber grid scaffold. We fabricated PCL orthogonal microfiber grid scaffolds by a direct writing technique, and then combined them with compressed collagen (CC) to obtain a sandwich-like CC/P (where P is used to represent the PCL microfiber grid scaffold). PHEMA hydrogel and the CC/P served as the core and the skirt, respectively, with the P also serving as an intermediate between the two. The physical properties of the artificial cornea, including the morphology, the mechanical properties and the light transmittance, were evaluated. SEM images showed an effective connection and a lack of phase separation at the interface between the core and the skirt, and the skirt formed a highly porous scaffold that promoted tissue biointegration. In addition, we used the skirt structure to construct a corneal tissue model containing two cells types: corneal stromal stem cells (CSSCs) and mouse hippocampal neurons. The results showed that the cells could grow and differentiate well, and the orthogonal microfiber grid scaffold fibers were good guides for the structural growth of CSSCs and neuronal axons.

Adiponectin reduces brain injury after intracerebral hemorrhage by reducing NLRP3 inflammasome expression.

Background and Purpose: Intracerebral hemorrhage (ICH) is a severe disease without effective therapeutic means. Adiponectin (APN) is strongly expressed in human brain tissue and cerebrospinal fluid and may play an anti-inflammatory role following ICH. NLR family pyrin domain-containing protein 3 (NLRP3) is a member of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family. Following ICH, activation of the NLRP3 inflammasome promotes neuroinflammation and brain edema. Here, we examined the effect of APN and the NLRP3 inflammasome on brain injury in an autologous blood model of ICH in rats and assessed whether APN could provide neuroprotection against inflammation by inhibiting NLRP3 activity.Methods: The ICH model was produced by injection of 50 µl fresh autologous blood into brain, we used lentiviral-mediated overexpression of APN to determine the efficacy and mechanism of APN therapy in ICH injury.Results: APN decreased interleukin-1ß(IL-1ß) and interleukin-18 (IL-18) production, attenuated neurological deficits, and reduced perihematomal brain edema 24 h after ICH. In rats with ICH, the protective effect of APN was associated with the reduced expression of NLRP3. APN and MCC950 (an NLRP3 inhibitor) both showed the same neuroprotective effect of reducing the expression of NLRP3, IL-1ß and IL-18.Conclusions: These results indicated that APN and the NLRP3 inflammasome inhibitor, MCC950, played the similar function in reducing brain injury and improving prognosis. Although further research is needed to confirm this, our findings suggest that APN may regulate inflammation injury via NLRP3 signaling.

[Pathological variant of FBN2 gene identified in a pedigree affected with congenital contracture arachnodactyly].

OBJECTIVE: To detect pathological variant in a Chinese pedigree affected with congenital contractural arachnodactyly (CCA). METHODS: Next generation sequencing (NGS) was used to scan the whole exome of the proband. Potential variant of the FBN2 gene was also detected in all members of the pedigree and 100 healthy controls by Sanger sequencing. With the determination of the genotype, prenatal diagnosis was carried out by amniotic fluid sampling. RESULTS: A c.3528C>A (p.Asn1176Lys) variant was identified in the FBN2 gene of the proband, other patients from this pedigree, as well as the fetus. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. CONCLUSION: The c.3528C>A (p.Asn1176Lys) variant of the FBN2 gene probably underlies the pathogenesis of CCA in our case. The new variant has enriched pathological spectrum of the FBN2 gene.

Treatment models of cardiac rehabilitation in patients with coronary heart disease and related factors affecting patient compliance.

Coronary heart disease is a serious threat to human health. In China, medical care for the population has been focused on therapy with little follow-up of treated patients. The efficacy of therapy; however, is highly dependent on post-therapy recovery. Cardiac rehabilitation can significantly enhance patient physical strength and help delay and prevent the development of coronary atherosclerosis. Although the clinical significance of cardiac rehabilitation has been established, the compliance of patients is generally low. In efforts to improve patient compliance, domestic and foreign researchers have extensively studied and applied treatment models of cardiac rehabilitation according to the specific conditions and cultural background of each country. This study aimed to review the treatment models of cardiac rehabilitation in patients with coronary heart disease and related factors affecting patient compliance to provide a better perspective of how patients with coronary heart disease can benefit from cardiac rehabilitation.

Classifying and characterizing nicotine use disorder with high accuracy using machine learning and resting-state fMRI.

Cigarette smoking continues to be a leading cause of preventable morbidity and mortality. Although the majority of smokers report making a quit attempt in the past year, smoking cessation rates remain modest. Thus, developing accurate, data-driven methods that can classify and characterize the neural features of nicotine use disorder (NUD) would be a powerful clinical tool that could aid in optimizing treatment development and guide treatment modifications. This investigation applied support vector machine-based classification to resting-state functional connectivity (rsFC) data from individuals diagnosed with NUD (n = 108; 63 male) and matched nonsmoking controls (n = 108; 63 male) and multi-dimensional scaling to visualize the heterogeneity of NUD in individual smokers based on rsFC measures. Machine-based learning models identified five resting-state networks that played a role in distinguishing smokers from controls: the posterior and anterior default mode networks, the sensorimotor network, the salience network and the right executive control network. The classification method constructed classifiers with an average correct classification rate of 88.1 percent and an average area under the curve of 0.93. Compared with controls, individuals with NUD had weaker functional connectivity measures within these networks (P < 0.05, false discovery rate corrected). Further, multi-dimensional scaling visualization demonstrated that controls were similar to each other whereas individuals with NUD had less similarity to controls and to other individuals with NUD. Our findings build upon previous literature demonstrating that machine learning-based approaches to classifying rsFC data offer a valuable technique to understanding network-level differences in nicotine-related neurobiology and extend previous findings by improving classification accuracy and demonstrating the heterogeneity in resting-state networks of individuals with NUD.

Photodegradation of 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P) in coastal seawaters: Important role of DOM.

Benzotriazole UV stabilizers (BT-UVs) have attracted concerns due to their ubiquitous occurrence in the aquatic environment, and their bioaccumulative and toxic properties. However, little is known about their aquatic environmental degradation behavior. In this study, photodegradation of a representative of BT-UVs, 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P), was investigated under simulated sunlight irradiation. Results show that UV-P photodegrades slower under neutral conditions (neutral form) than under acidic or alkaline conditions (cationic and anionic forms). Indirect photodegradation is a dominant elimination pathway of UV-P in coastal seawaters. Dissolved organic matter (DOM) from seawaters accelerate the photodegradation rates mainly through excited triplet DOM (3DOM⁎), and the roles of singlet oxygen and hydroxyl radical are negligible in the matrixes. DOM from seawaters impacted by mariculture exhibits higher steady-state concentration of 3DOM⁎ ([3DOM⁎]) relative to those from pristine seawaters, leading to higher photosensitizing effects on the photodegradation. Halide ions inhibit the DOM-sensitized photodegradation of UV-P by decreasing [3DOM⁎]. Photodegradation half-lives of UV-P are estimated to range from 24.38 to 49.66 hr in field water bodies of the Yellow River estuary. These results are of importance for assessing environmental fate and risk UV-P in coastal water bodies.