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Developing nanomaterial-based enzyme mimics for DNA cleavage is an interesting challenge and it has many potential applications. Single-layered graphene oxide (GO) is an excellent platform for DNA adsorption. In addition, GO has been employed for photosensitized generation of reactive oxygen species (ROS). Herein, we demonstrate that GO sheets could cleave DNA as a nuclease mimicking nanozyme in the presence of UV or blue light. For various DNA sequences and lengths, well-defined product bands were observed along with photobleaching of the fluorophore label on the DNA. Different from previously reported GO cleavage of DNA, our method did not require metal ions such as Cu 2+ . Fluorescence spectroscopy suggested a high adsorption affinity between GO and DNA. For comparison, although zero-dimensional fluorescent carbon dots (C-dots) had higher photosensitivity in terms of producing ROS, their cleavage activity was much lower and only smeared cleavage products were observed, indicating that the ROS acted on the DNA in solution. Based on the results, GO behaved like a classic heterogeneous catalyst following substrate adsorption, reaction, and product desorption steps. This simple strategy may help in the design of new nanozymes by introducing light.

Background: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. Methods: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient’s tumor and engineered cell lines. Results: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient’s tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). Conclusion: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.

Germline mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, tumor hypermutation, and predispose to hereditary colorectal and endometrial cancer. In this work, we used a multiprong approach to demonstrate that mutations that alter the amino acid charges in the DEDD motif of exonuclease domains could lead to proofreading deficiency. This novel mutation class, which is currently classified as a variant of uncertain significance, should be reclassified as likely pathogenic. Background: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. Methods: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient’s tumor and engineered cell lines. Results: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient’s tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). Conclusion: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.

Evacuations are a common practice to mitigate the potential risks and damages made by natural disasters. However, without proper coordination and management, evacuations can be inefficient and cause negative impact. Local governments and organizations need to have a better understanding of how the population responds to disasters and evacuation recommendations so as to enhance their disaster management processes. Previous studies mostly examine responses to evacuations at the individual or household level by using survey methods. However, population flows during disasters are not just the aggregation of individuals’ decisions, but a result of complex interactions with other individuals and the environment. We propose a method to model evacuation flows and reveal the patterns of evacuation flows at different spatial scales. Specifically, we gathered large-scale geotagged tweets during Hurricane Irma to conduct an empirical study. First, we present a method to characterize evacuation flows at different geographic scales: the state level, considering evacuation flows across southern states affected by Irma; the urban/rural area level, and the county level. Then we demonstrate results on the predictability of evacuation flows in the most affected state, Florida, by using the following environmental factors: the destructive force of the hurricane, the socioeconomic context, and the evacuation policy issued for counties. Feature analyses show that distance is a dominant predictive factor with counties that are geographically closer generally having larger evacuation flows. Socioeconomic levels are positively related to evacuation flows, with popular destinations associated to higher socioeconomic levels. The results presented in this paper can help decision makers to better understand population evacuation behaviors given certain environmental features, which in turn will aid in the design of efficient and informed preparedness and response strategies.

To evaluate the effectiveness and safety of CT/ultrasound dual-modality guided posterior approach in the management of upper abdominal cancer pain. Clinical research study. A total of 19 patients (7 men and 12 women) who had advanced carcinomatous epigastric pain and match the selection criteria were recruited in this study. All the patients proceed the bilateral Splanchnic Nerve Neurolysis (SNN) under Computed Tomography (CT) guided and Ultrasound. The pain Numerical Rating Scale (NRS) at different times (T0: preprocedure, T1: 1 day after-procedure, T2: 1 weeks, T3 and T4: 4 and 8 weeks after-procedure and drug taken dosages were recorded. The incidence of complications was also assessed. All the patients were successfully completed procedures under CT/Ultrasound dual-guided. NRS exhibited significant differences when comparing the preoperative time point (T0) with each of the following time intervals (T1-T4) (***P < 0.001). As the NRS gradually decreased, significant differences were observed between T2 and T3 (**P < 0.05). However, no significant difference was found between T3 and T4 regarding pain scores (p = 0.331). The consumption of morphine was significantly lower postoperatively than preoperatively, with the most pronounced reduction observed on the first day after surgery (***P < 0.001). Nevertheless, no statistically significant differences were observed at the other time intervals (P > 0.05). No severe complications during or after the surgery. Two patients (10.5%) felt burning pain in the abdomen for 2 days, 1 patient had transient backache for 3 days, and 12 (63.2%) patients had diarrhea for 1 week and disappear. The CT/Ultrasound dual-guided SNN procedure is regarded as a efficacy and safety treatment for managing abdominal cancer pain. It increases constant visualization in the operation and reduces radiation exposure.

Schizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families. The analysis of 51 SCZ trios with both unaffected parents identified 22 exonic and 1 splice-site de novo mutations (DNMs) on a total of 23 genes, and showed that 12 genes carried rare protein-altering compound heterozygous mutations in more than one trio. In addition, we identified 26 exonic or splice-site single nucleotide polymorphisms (SNPs) on 18 genes with nominal significance ( P  < 5 × 10 −4 ) using a transmission disequilibrium test (TDT) in all the families. Moreover, TDT result confirmed a SCZ susceptibility locus on 3p21.1, encompassing the multigenetic region NEK4-ITIH1-ITIH3-ITIH4 . Through several different strategies to predict the potential pathogenic genes in silico, we revealed 4 previous discovered susceptibility genes ( TSNARE1 , PBRM1 , STAB1 and OLIG2 ) and 4 novel susceptibility loci ( PSEN1 , TLR5 , MGAT5B and SSPO ) in Han Chinese SCZ patients. In summary, we identified a list of putative candidate genes for SCZ using a family-based WES approach, thus improving our understanding of the pathology of SCZ and providing critical clues to future functional validation.

Renal interstitial fibrosis (RIF) is a common pathological feature contributing to chronic injury and maladaptive repair following acute kidney injury. Currently, there is no effective therapy for RIF. We have reported that locked nuclear acid (LNA)-anti-miR-150 antagonizes pro-fibrotic pathways in human renal tubular cells by regulating the suppressor of cytokine signal 1 (SOCS1)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. In the present study, we aimed to clarify whether LNA-anti-miR-150 attenuates folic acid-induced RIF mice by regulating this pathway and by reducing pro-inflammatory M1/M2 macrophage polarization. We found that renal miR-150 was upregulated in folic acid-induced RIF mice at day 30 after injection. LNA-anti-miR-150 alleviated the degree of RIF, as shown by periodic acid–Schiff and Masson staining and by the expression of pro-fibrotic proteins, including alpha-smooth muscle actin and fibronectin. In RIF mice, SOCS1 was downregulated, and p-JAK1 and p-STAT1 were upregulated. LNA-anti-miR-150 reversed the changes in renal SOCS1, p-JAK1, and p-STAT1 expression. In addition, renal infiltration of total macrophages, pro-inflammatory M1 and M2 macrophages as well as their secreted cytokines were increased in RIF mice compared to control mice. Importantly, in folic acid-induced RIF mice, LNA-anti-miR-150 attenuated the renal infiltration of total macrophages and pro-inflammatory subsets, including M1 macrophages expressing CD11c and M2 macrophages expressing CD206. We conclude that the anti-renal fibrotic role of LNA-anti-miR-150 in folic acid-induced RIF mice may be mediated by reducing pro-inflammatory M1 and M2 macrophage polarization via the SOCS1/JAK1/STAT1 pathway.

Introduction ‘Let’s Talk About Children’ is a brief family focused intervention developed to improve mental health outcomes of children of parents with mental illness (COPMI). This study aims to assess the efficacy of LTC in improving mental health of children of parents with schizophrenia or bipolar disorder in China. Methods The planned study is a multicentre parallel group randomized wait-list controlled trial. A total of 400 eligible families with children aged 8 to 18 years will be recruited, 200 each for families with parental schizophrenia or bipolar disorder. The intervention group will receive Let’s Talk About Children delivered by a trained therapist, while the control group will receive treatment as usual. The primary outcomes are child mental health measured by the strengths and difficulties questionnaire and parent–child communication measured using the parent-adolescent communication scale. Parental mental health and family functioning are secondary outcomes. This study also plans to explore mediating factors for the effect of Let’s Talk About Children on child mental health, as well as conduct a cost-effectiveness analysis on using Let’s Talk About Children in China. Conclusion The present study will provide evidence for the efficacy of Let’s Talk About Children in families with parental schizophrenia and bipolar disorder in China. In addition, it will evaluate potential mechanisms of action and cost-effectiveness of Let’s Talk About Children, providing a basis for future implementation. Trial registration ChiCTR2300073904.

Background Younger age at onset is generally thought to be a predictor of poor outcome in Early Onset Schizophrenia (EOS), but there is a paucity of epidemiological data supporting this belief. This study aims to describe long-term outcomes and predictors of patient functioning in EOS, with a focus on the effect of age at onset. Methods We consecutively enrolled 118 EOS patients who were hospitalized in 2006. Mean age at baseline was 13.3 ± 2.3 years. Sixty-five subjects were successfully interviewed. Mean length of follow up was 10.4 ± 0.3 years. Baseline data were collected from inpatient medical records, while follow up was conducted primarily through telephone interviews of patient relatives. WHODAS 2.0 was used to measure global functioning at follow up. Outcomes included education, employment, marriage status, physical health, subsequent diagnoses and treatment, and patient functioning. Univariate and multivariate regression models were used to assess predictors of outcome, while propensity scores were used to adjust for confounding in analyzing the effect of age at onset on functional outcome. Results Of the 65 subjects where follow-up data were available, 3 were deceased at follow up. Five (8%) discontinued treatment. Diagnostic stability was 76%. Nearly a quarter (24%) were using clozapine at follow up. In male and female patients, 61 and 55% respectively were overweight, while 29 and 32% respectively were obese. Sixteen (26%) were economically self-sufficient, while 34 (55%) were unemployed. Thirteen (21%) patients had ever been married. The median WHODAS score was 15 (IQR 2 to 35), roughly corresponding to the 78th percentile on population norms. Extroverted personality ( p  = 0.01), suspicious personality ( p  = 0.02), and high level of education ( p  = 0.001) predicted better functioning. Age of onset was not associated with function in either the univariate model ( p  = 0.24), full model ( p  = 0.17) or the final risk factor model ( p  = 0.11), nor after using propensity scores to further adjust for confounders. Conclusion The long-term functional outcome of EOS is more optimistic than generally believed. Age at disease onset does not predict long-term functional outcome in EOS populations.

Kallistatin or kallikrein-binding protein (KBP) has been reported to regulate angiogenesis, inflammation and tumor progression. Autoimmune uveitis is a common, sight-threatening inflammatory intraocular disease. However, the roles of kallistatin in autoimmunity and autoreactive T cells are poorly investigated. Compared to non-uveitis controls, we found that plasma levels of kallistatin were significantly upregulated in patients with Vogt-Koyanagi-Harada (VKH) disease, one of the non-infectious uveitis. Using an experimental autoimmune uveitis (EAU) model induced by human interphotoreceptor retinoid-binding protein peptide 651-670 (hIRBP 651-670 ), we examined the effects of kallistatin on the pathogenesis of autoimmune diseases. Compared to wild type (WT) mice, kallistatin transgenic (KS) mice developed severe uveitis with dominant Th17 infiltrates in the eye. In addition, the proliferative antigen-specific T cells isolated from KS EAU mice produced increased levels of IL-17A, but not IFN-γ or IL-10 cytokines. Moreover, splenic CD4 + T cells from naïve KS mice expressed higher levels of Il17a mRNA compared to WT naïve mice. Under Th17 polarization conditions, KS mice exhibited enhanced differentiation of naïve CD4 + T cells into Th17 cells compared to WT controls. Together, our results indicate that kallistatin promotes Th17 differentiation and is a key regulator of aggravating autoinflammation in EAU. Targeting kallistatin might be a potential to treat autoimmune disease.