Discovery of a Long Half-Life AURKA Inhibitor to Treat MYC-Amplified Solid Tumors as a Monotherapy and in Combination with Everolimus.

Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors, that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC-overexpressing xenografts including SCLC, triple-negative breast cancer, hepatocellular carcinoma, and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC-driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC and/or N-MYC.

Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors.

A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STINGR232 knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents.

Dissolved Oxygen and Water Temperature Drive Vertical Spatiotemporal Variation of Phytoplankton Community: Evidence from the Largest Diversion Water Source Area.

In order to study the vertical distribution characteristics of phytoplankton in the Danjiangkou Reservoir, the water source of the Middle Route Project of the South-North Water Diversion, seven sampling sites were set up in the Reservoir for quarterly sampling from 2017 to 2019, and water environment surveys were conducted simultaneously. The results showed that 157 species (including varieties) were identified, belonging to 9 phyla and 88 genera. In terms of species richness, Chlorophyta had the largest number of species, accounting for 39.49% of the total species. The Bacillariophyta and Cyanobacteria accounted for 28.03% and 13.38% of the total species, respectively. From the whole Danjiangkou Reservoir, the total phytoplankton abundance varied from 0.09 × 102 to 20.01 × 106 cells/L. In the vertical distribution, phytoplankton were mainly observed in the surface-thermospheric layer (I-II layer) and the bottom layer, while the Shannon-Wiener index showed a trend of gradually decreasing from the I-V layer. The Surfer model analysis showed that there was no significant stratification in the Q site's water temperature (WT) and dissolved oxygen (DO) levels in the water diversion area during the dynamic water diversion process. A canonical correspondence analysis (CCA) showed that DO, WT, pH, electrical conductivity (Cond), chemical oxygen demand (CODMn), total phosphorus (TP), ammonia nitrogen (NH4+-N), and total nitrogen (TN) had significant effects on the vertical distribution of phytoplankton (p < 0.05). A partial Mantel analysis showed that the vertical distribution of the phytoplankton community was related to WT, and the phytoplankton community structure at the other sites, except for Heijizui (H) and Langhekou (L), was affected by DO. This study has positive significance for exploring the vertical distribution characteristics of a phytoplankton community in a deep-water dynamic water diversion reservoir.

The aberrant overexpression of hsa_circ_0078607 in colorectal cancer tissues and serum and its clinical significance / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探究hsa_circ_0078607在结直肠癌组织和患者血清中的表达水平及其与结直肠癌患者临床病理特征的关系，评价其能否作为结直肠癌潜在的分子诊断标志物及治疗靶标。方法：收集2018年6月至2022年1月于柳州市人民医院胃肠外科接受结直肠癌切除手术患者的58对癌及癌旁组织标本，收集2020年1月至2022年12月于柳州市人民医院初次确诊的结直肠癌患者、结直肠息肉患者及健康人体检血清共152例；从结直肠癌差异表达circRNA谱中挑选特异性高表达的hsa_circ_0078607作为候选标志物，采用qPCR法检测其在结直肠癌细胞、组织、患者血清及结直肠息肉患者血清中的相对表达量，分析其与临床病理特征的关系。采用ROC曲线评估hsa_circ_0078607对结直肠癌及结直肠息肉的诊断价值。通过Circular RNA Interactome数据库预测与hsa_circ_0078607结合的miRNA，并用Cytoscape 3.9.1软件构建circRNA-miRNA-mRNA调控网络，同时通过GO/KEGG富集分析进一步了解其功能。结果：与癌旁组织或健康人血清相比，hsa_circ_0078607在结直肠癌细胞、组织和血清及息肉患者血清中呈高表达（P<0.001），其中有52例（89.7%）患者癌组织中表达上调，6例（10.3%）表达下调。结直肠癌组织中hsa_circ_0078607的相对表达量与肿瘤位置（P=0.029）、分化程度（P=0.046）和远处转移（P=0.043）有关联。ROC结果显示，在结直肠癌组织和血清中其诊断结直肠癌的AUC分别为0.845 7[95%CI（0.772 8，0.918 6），P<0.000 1]和0.868 3[95%CI（0.790 7，0.945 9），P<0.000 1]；在息肉患者血清中，hsa_circ_0078607诊断结直肠息肉的AUC为0.710 1 [95%CI（0.610 0，0.810 1）]。GO/KEGG富集分析结果表明，hsa_circ_0078607下游的miRNA可能参与RNA聚合酶Ⅱ启动子转录调控、蛋白K48-连锁泛素化、Wnt、Hippo及MAPK信号通路调控等多个生物过程。结论：Hsa_circ_0078607在结直肠癌细胞、组织和血清中呈高表达，其在结直肠癌组织中的表达水平与肿瘤位置、分化程度和远处转移有关联，提示其可作为结直肠癌潜在的分子诊断标志物；其还可能介导结直肠癌的发生发展过程，对发现结直肠癌潜在的治疗靶点有重要意义。

Influence of Atmospheric Phosphorus and Nitrogen Sedimentation on Water Quality in the Middle Route Project of the South-to-North Water Diversion in Henan Province.

In order to understand the potential effects of atmospheric nitrogen and phosphorus deposition on the water quality of the Middle Route Project of the South-to-North Water Diversion Project, samples of dry and wet deposition of atmospheric nitrogen and phosphorus, meteorological factors, and water quality factors were analyzed out to investigate in the Middle Route Project of the South-to-North Water Diversion in Henan Province from October 2018 to October 2020. The variation characteristics of atmospheric nitrogen and phosphorus deposition with time in the Henan section of the main canal are revealed, and the influence of atmospheric dry and wet deposition on the water quality of the middle line is discussed. It was found that the total nitrogen (TN) sedimentation flux has obvious seasonal variation, which was consistent with the variation trend of rainfall, and increased with the increase of rainfall. Nitrogen and phosphorus deposition was significantly correlated with water factors. The effects of meteorological factors and nitrogen and phosphorus deposition on water quality variation reached 18%. The contribution rate and ecological impact of atmospheric nitrogen and phosphorus deposition on water pollution of main channels will be increasing, which needs to be paid enough attention to.

The Drosha-Independent MicroRNA6778-5p/GSK3ß Axis Mediates the Proliferation of Gastric Cancer Cells.

Background: Gastric cancer (GC) is a primary cause of cancer death around the world. Previous studies have found that Drosha plays a significant role in the development of tumor cells. Soon after, we unexpectedly found that the expression of microRNA6778-5p (miR6778-5p) is unconventionally high in the gastric cancer cells low-expressing Drosha. So, we designed the Drosha interference sequence and recombined it into a lentiviral vector to construct Drosha knockdown lentivirus and transfected the Drosha knockdown lentivirus into gastric cancer cells to establish Drosha knockdown gastric cancer cell lines. We aimed to explore the effect of microRNA6778-5p on the proliferation of gastric cancer cells with Drosha knockdown and its intrinsic mechanism. Methods: We designed the Drosha interference sequence and recombined it into a lentiviral vector to construct Drosha knockdown lentivirus and transfected the Drosha knockdown lentivirus into gastric cancer cells to establish Drosha knockdown gastric cancer cell lines. After transfecting miR6778-5p mimics and inhibitor into gastric cancer cell lines with Drosha knockdown, the expression levels of miR6778-5p mimics in Drosha low-expressing gastric cancer cells increased, while miR6778-5p inhibitor decreased the expression levels of miR6778-5p. The Cell Counting Kit-8 (CCK-8) experiment was used to detect the proliferation ability of gastric cancer cells after overexpression or knockdown of miR6778-5p and bioinformatics predicted the relationship between miR6778-5p and glycogen synthase kinase-3ß (GSK3ß). Results: After infection with the Drosha knockdown lentivirus, Drosha's mRNA and protein levels were significantly downregulated in gastric cancer cells. The expression levels of miR6778-5p mimics in Drosha low-expressing gastric cancer cells increased, while miR6778-5p inhibitor decreased the expression levels of miR6778-5p. Overexpression of miR6778-5p significantly enhanced the proliferation ability of Drosha low-expression gastric cancer cells; on the contrary, knocking down miR6778-5p weakened the proliferation ability of Drosha low-expression gastric cancer cells. Bioinformatics predicted that miR6778-5p targeted glycogen synthase kinase-3ß (GSK3ß) and the mRNA and protein levels of GSK3ß decreased significantly after overexpression of miR6778-5p. Conclusion: miR6778-5p promotes the proliferation of Drosha low-expressing gastric cancer cells by targeting GSK3ß.

MOF-templated synthesis of photoluminescent MoS2 QDs.

Fabricating MoS2 QDs using porous metal-organic frameworks (MOFs) as templates remains a great challenge, because the MOF structure is prone to collapse during solvothermal reactions, resulting in a loss of the function of the template. In the present work, the production of homogeneous photoluminescent MoS2 QDs was achieved by using the structurally stable MOF MIL-101 as limited nanoreactors. The process developed opens up a new route for fabricating other photoluminescent QDs and their derived nanomaterials.

AKT phosphorylation as a predictive biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR companion proteins in small cell lung cancer.

BACKGROUND: Constitutive activation of PI3K signaling has been well recognized in a subset of small cell lung cancer (SCLC), the cancer type which has the most aggressive clinical course amongst pulmonary tumors. Whereas cancers that acquire a mutation/copy gain in PIK3CA or loss of PTEN have been implicated in enhanced sensitivity to inhibitors targeting the PI3K/AKT/mTOR pathway, the complexities of the pathway and corresponding feedback loops hamper clear predictions as to the response of tumors presenting these genomic features. METHODS: The correlation between the expression profile of proteins involved in the PI3K/AKT/mTOR signaling and cell viability in response to treatment with small molecule inhibitors targeting isoform-specific PI3Ks, AKT, and mTOR was assessed in 13 SCLC cancer cell lines. Athymic nude mice were used to determine the effect of PI3K/mTOR dual inhibition on the growth of xenograft SCLC tumors in vivo. The activation of caspase signaling and proteolytic cleavages of mTOR companion proteins were assessed using recombinant caspases assays and Western blot analyses. RESULTS: Our results indicate that the sensitivity of these SCLC cell lines to GSK2126458, a dual PI3K/mTOR inhibitor, is positively correlated with the expression levels of phosphorylated AKT (p-AKT) at Thr308 and Ser473. Inhibition of pan-class I PI3Ks or PI3K/mTOR dual inhibition was shown to induce proteolytic cleavage of RICTOR and RPTOR, which were respectively dependent on Caspase-6 and Caspase-3. A combination of a clinically approved PI3Kα-selective inhibitor and an mTORC1 inhibitor was shown to have synergistic effects in inducing the death of SCLC cells with high p-AKT. We observed no clear correlation between PTEN levels and the survival of SCLCs in response to PI3K/mTOR dual inhibition; however, PTEN depletion was shown to increase the susceptibility of low p-AKT SCLC cells to dual PI3K/mTOR inhibitor-induced cell death as well as the proteolytic cleavage of RICTOR. CONCLUSIONS: These results suggest the level of p-AKT can be a companion diagnostic biomarker for the treatment of SCLC involving the combinational use of clinically approved isoform-specific PI3K and mTOR inhibitors.

Fabrication and Characterization of a Self-Powered n-Bi2Se3/p-Si Nanowire Bulk Heterojunction Broadband Photodetector.

In the present study, vacuum evaporation method is used to deposit Bi2Se3 film onto Si nanowires (NWs) to form bulk heterojunction for the first time. Its photodetector is self-powered, its detection wavelength ranges from 390 nm to 1700 nm and its responsivity reaches its highest value of 84.3 mA/W at 390 nm. In comparison to other Bi2Se3/Si photodetectors previously reported, its infrared detection length is the second longest and its response speed is the third fastest. Before the fabrication of the photodetector, we optimized the growth parameter of the Bi2Se3 film and the best Bi2Se3 film with atomic steps could finally be achieved. The electrical property measurement conducted by the physical property measurement system (PPMS) showed that the grown Bi2Se3 film was n-type conductive and had unique topological insulator properties, such as a metallic state, weak anti-localization (WAL) and linear magnetic resistance (LMR). Subsequently, we fabricated Si NWs by the metal-assisted chemical etching (MACE) method. The interspace between Si NWs and the height of Si NWs could be tuned by Ag deposition and chemical etching times, respectively. Finally, Si NWs fabricated with the Ag deposition time of 60 s and the etching time of 10 min was covered by the best Bi2Se3 film to be processed for the photodetector. The primary n-Bi2Se3/p-Si NWs photodetector that we fabricated can work in a self-powered mode and it has a broadband detection range and fast response speed, which indicates that it can serve as a promising silicon-based near- and mid-infrared photodetector.

Deformation of the nucleus by TGFß1 via the remodeling of nuclear envelope and histone isoforms.

The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFß1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFß1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, clustering at the nuclear periphery and reintegrating into the nucleoplasm. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFß1-induced compositional changes in the chromatin and nuclear lamina.

Association of ERBB4 genetic polymorphism with the risk and prognosis of non-small cell lung cancer in Chinese Han population: A population-based case-control study.

ABSTRACT: The aim of this study was to explore the association of rs1836724 single-nucleotide polymorphism (SNP) of ERBB4 with risk and prognosis of non-small cell lung cancer (NSCLC) in the Chinese Han population.The genotype of rs1836724 SNP of ERBB4 from 258 patients with NSCLC and 200 noncancer controls were detected the TaqMan-MGB probes real-time fluorescence polymerase chain reaction. The distribution of genotype and alleles between the 2 groups was compared, and the association between clinicopathological characteristic and rs1836724 SNP was analyzed. Prognosis and influencing factors were analyzed by Kaplan-Meier and Cox regression analysis.There were significant differences in the genotype and allele distribution of ERBB4 rs1836724 between the NSCLC group and control group (P < .05). And CC genotype of rs1836724 was associated with increased risk of NSCLC in the Chinese Han population. Rs1836724 SNP was associated with TNM stage and lymph nodal metastasis (P = .001, P = .007). The median follow-up was 29 months, and the progression-free survival and overall survival of 258 NSCLC patients were 27.91% and 31.39%, respectively. Patients with GG genotype of rs1836724 had poor progression-free survival and overall survival. Rs1836724 SNP was an independent prognostic marker of NSCLC patients, CC genotype had a high risk of poor prognosis (odds ratio = 1.587, 95% confidence interval: 1.079-2.335, P = .019).In Chinese Han populations, rs1836724 SNP of ERBB4 may contribute toward the increased risk and poor prognosis of NSCLC.

Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.

Transcriptionomic Study on Apoptosis of SKOV-3 Cells Induced by Phycoerythrin from Gracilaria lemaneiformis.

OBJECTIVE: To investigate the effects of Phycoerythrin (PE) on the human ovarian cancer cell line SKOV-3 and its antitumor mechanisms from a transcriptional point of view. METHODS: SKOV-3 cells were exposed to different concentrations of phycoerythrin. The efficiency of this treatment was evaluated through cell growth inhibition, changes in cell morphology, apoptosis and intracellular ROS levels. High throughput sequencing (RNA-seq) was performed to screen Differentially Expressed Genes (DEGs), which was verified using RT-PCR and Western blotting. RESULTS: PE showed a significant inhibitory effect on the growth of SKOV-3 cells in a time- and dose-dependent manner. H&E staining, electron microscopy and flow cytometry revealed that PE induced apoptosis in SKOV-3 cells. Transcriptome analysis showed that 2963 genes were differentially expressed between untreated or PEtreated cells. GO and KEGG pathway analyses identified 16 classical pathways that were enriched. We verified 8 DEGs including, JNK, GADD45A, EDEM2, RAD23, UBQLN, CAPN1, XBP1, and OS9. These results were consistent with the results from transcriptional sequences. CONCLUSION: The inhibitory effect of PE on SKOV-3 cells was a result of interaction with multiple pathways and signaling molecules. Among these, the ROS/JNK/Bcl-2 signaling pathway, upregulation of JNK, GADD45A and RAD23 as well as downregulation of XBP1 and OS9 played a critical role in the PE -induced apoptosis in human ovarian cancer cells.

[Application of transcranial Doppler in prognosis assessment of nerve function in patients with acute cerebral infarction after intracranial mechanical thrombectomy].

OBJECTIVE: To investigate the application value of transcranial Doppler (TCD) in the prognosis assessment of nerve function in patients with acute cerebral infarction (ACI) after intracranial mechanical thrombectomy. METHODS: A retrospective analysis was conducted. The clinical data of 43 patients with acute anterior circulation cerebral infarction who received intra-arterial mechanical thrombotomy for recanalization admitted to Taizhou Central Hospital from January 2018 to December 2019 were analyzed. The modified Rankin scale (mRS) score of patients were followed up by telephone at 3 months after surgery to evaluate the prognosis of neurologic outcome. Patients with mRS score 0-2 were enrolled in the good prognosis group, while those with a score of 3-6 were enrolled in the poor prognosis group. The gender, age, past history, underlying diseases, occluded arteries, atherosclerotic stenosis and bridging treatment, time from onset to reperfusion, blood flow dynamics under TCD at 1 day after thrombectomy, and National Institutes of Health stroke scale (NIHSS) scores before and 1, 7, and 14 days after thrombectomy were compared between the two groups. Multivariate Logistic regression analysis was used to screen the prognostic factors of nerve function at 3 months after mechanical thrombectomy in patients with ACI. The receiver operating characteristic (ROC) curve was drawn to evaluate the prognostic value for neurological function assessed by TCD. RESULTS: Forty-three patients were enrolled in the final analysis, with 23 patients in the good prognosis group and 20 in the poor prognosis group. The recanalization was successfully achieved in both groups without complications. However, the hemodynamics of intracranial arteries evaluated by TCD 1 day after operation in both groups still showed partial or complete occlusion, and the hemodynamics of patients in the poor prognosis group was worse than that in the good prognosis group (poor blood flow: 40.0% vs. 0%, inadequate blood flow: 30.0% vs. 17.4%, good blood flow: 30.0% vs. 82.6%), and the differences were statistically significant (all P < 0.01). Before thrombotomy, there was no significant difference in NIHSS score between the two groups. After thrombotomy, the NIHSS score of the two groups gradually decreased with the extension of time, but the NIHSS score at 14 days after operation of the poor prognosis group was still significantly higher than that of the good prognosis group (10.55±2.93 vs. 4.65±1.70, P < 0.01). Univariate analysis showed that compared with the good prognosis group, the proportion of patients with diabetes and arteriosclerosis stenosis in the poor prognosis group were significantly increased (30.0% vs. 4.3%, 45.0% vs. 17.4%, both P < 0.05), and the time from onset to reperfusion was prolonged (minutes: 385.9±96.2 vs. 294.5±95.1, P < 0.01). Multivariable Logistic regression analysis showed that the therosclerosis stenosis [odds ratio (OR) = 9.334, 95% confidence interval (95%CI) was 1.092-79.775, P = 0.041] and the reperfusion time (OR = 1.016, 95%CI was 1.006-1.027, P = 0.002) were associated with prognosis of nerve function at 3 months after mechanical thrombectomy in patients with ACI. ROC curve analysis suggested that the evaluation of intracranial hemodynamics by TCD might be able to predict the prognosis of neurological function in patients with ACI after 3 months of intracranial mechanical thrombectomy, the area under ROC curve (AUC) was 0.768 (95%CI was 0.620-0.917), the sensitivity was 65.0%, the specificity was 87.0%, the positive predictive value was 82.6%, and the negative predictive value was 70.0%. CONCLUSIONS: The evaluation of intracranial hemodynamics assessed by TCD is helpful in early judging the prognosis of neurological function in patients with ACI after intracranial mechanical thrombectomy.

Clinical features related to hospital expenses for non-cystic fibrosis bronchiectasis in China.

OBJECTIVE: Bronchiectasis is a common chronic airway disease. We investigated the economic burden and associated factors of bronchiectasis in China. METHODS: In this multicenter retrospective cohort study, we reviewed medical records of patients admitted to 18 tertiary hospitals during 2010 to 2014 with a bronchiectasis-related diagnosis. RESULTS: A total 5469 patients with bronchiectasis were admitted, accounting for 3.13% ± 1.80% of all discharged patients with any diagnosis during the same period; 13 patients died upon discharge. The median hospitalization cost was RMB 8421.52 (RMB 5849.88-12,294.47). Risk factors associated with hospitalization costs included age at admission (>70 vs. <40 years, odds ratio (OR) = 1.221, 95% confidence interval (CI) = 1.082-1.379; >80 vs. <40 years, OR = 1.251, 95% CI = 1.089-1.438), smoking (≤15 packs/year vs. non-smokers, OR = 1.125, 95% CI = 1.006-1.271; >15 packs/year vs. non-smokers, OR = 1.127, 95% CI = 1.062-1.228), length of hospitalization (OR = 1.05, 95% CI = 1.046-1.054), combination antibiotic treatment (OR = 1.089, 95% CI = 1.033-1.148), cough (OR = 0.851, 95% CI = 0.751-0.965), dyspnea (OR = 0.93, 95% CI = 0.878-0.984), chronic obstructive pulmonary disease (OR = 0.935, 95% CI = 0.878-0.996), respiratory failure (OR = 0.923, 95% CI = 0.862-0.989), cor pulmonale (OR = 0.919, 95% CI = 0.859-0.982), and death (OR = 1.816, 95% CI = 1.113-2.838). CONCLUSIONS: Age, smoking status, symptoms, and respiratory comorbidities were associated with hospitalization costs of bronchiectasis.

Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis.

Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson-Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle-specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole-body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)-associated protein involved in heat production, is upregulated in progerin-expressing and Lmna knockout (Lmna-/- ) skeletal muscle. The depletion of Sln accelerated the early death of Lmna-/- mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin-expressing myoblasts presented enhanced store-operated Ca2+ entry, as well as increased co-localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER-associated proteins, resulting in thermogenic and metabolic abnormalities.

Sun1 Mediates Interkinetic Nuclear Migration and Notch Signaling in the Neurogenesis of Zebrafish.

Interkinetic nuclear migration (INM) is a process by which nuclei oscillate between the basal and apical surfaces of epithelial cells in coordination with the cell cycle. The cytoskeletal machinery including microtubules and actin has been reported to drive apical INM; however, the role of nuclear proteins in this process has yet to be fully elucidated. Here, we investigated the function of a SUN-domain protein, Sun1, in zebrafish. We found that zebrafish sun1 is highly expressed in the ventricular zone of the brain. Knocking down sun1 with antisense morpholino oligonucleotides reduced the abundance of nestin- and gfap-expressing neural stem cells and progenitor cells. The live-cell imaging results showed that sun1 morphant cells migrated toward the basal side during the S phase but failed to migrate apically during the G2 phase. On the contrary, the passive stochastic movement during the G2 phase was unaffected. Furthermore, down regulation of sun1 was shown to reduce the expression of genes associated with the Notch pathway, whereas the expression of genes in the Wnt pathway was less perturbed. Findings from this research suggest that the Sun1-mediated nucleo-cytoskeletal interaction contributes to apical nuclear migration, and may thus affect exposure to Notch signal, thereby altering the composition of the progenitor pool in the embryonic neurogenesis of zebrafish.

Determining the number of chemical species in nuclear magnetic resonance data matrix by taking advantage of collinearity and noise.

The number of chemical species is crucial in analyzing pulsed field gradient nuclear magnetic resonance spectral data. Any method to determine the number must handle the obstacles of collinearity and noise. Collinearity in pulsed field gradient NMR data poses a serious challenge to and fails many existing methods. A novel method is proposed by taking advantage of the two obstacles instead of eliminating them. In the proposed method, the determination is based on discriminating decay-profile-dominant eigenvectors from noise-dominant ones, and the discrimination is implemented with a novel low- and high-frequency energy ratio (LHFER). Its performance is validated with both simulated and experimental data. The method is mathematically rigorous, computationally efficient, and readily automated. It also has the potential to be applied to other types of data in which collinearity is fairly severe.

Therapeutic effect evaluation of reteplase on acute pulmonary embolism.

Thrombolysis is the main therapeutic method of acute pulmonary embolism (APE). In order to investigate the efficacy of reteplase on APE and the changes of cytokines in the progression of APE, 72 patients with APE were randomized into reteplase group and urokinase group which received reteplase thrombolysis and urokinase thrombolysis, respectively. The clinical symptoms, blood pressure, heart rate (HR), blood gas index and cytokines of patients were observed before and after therapy for assessing the thrombolysis effect of each group; blood level of high sensitive C-reactive protein (hs-CRP), TNF-α, IL-1ß, IL-6 and IL-10 was detected at 0h, 2h, 6h, 12h and 24h after thrombolysis. After treatment, the clinical symptoms of both groups were alleviated obviously; PaO2, PaCO2, blood pressure and HR in both groups were significantly improved than those before treatment (p<0.001), and reteplase group showed a more obvious improvement than urokinase group (p<0.001). Since 6h after therapy, the content of hs-CRP, IL-1ß and IL-6 in patients of reteplase group declined significantly (p<0.05 or 0.01). In conclusion, therapeutic effect of reteplase is better than urokinase, hs-CRP, IL-1ß and IL-6 can be used to monitor the thrombolysis efficacy of APE patients.