Use of observing system simulation experiments in the United States

Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 101(8), (2020): E1427-E1438, https://doi.org/10.1175/BAMS-D-19-0155.1.The NOAA Science Advisory Board appointed a task force to prepare a white paper on the use of observing system simulation experiments (OSSEs). Considering the importance and timeliness of this topic and based on this white paper, here we briefly review the use of OSSEs in the United States, discuss their values and limitations, and develop five recommendations for moving forward: national coordination of relevant research efforts, acceleration of OSSE development for Earth system models, consideration of the potential impact on OSSEs of deficiencies in the current data assimilation and prediction system, innovative and new applications of OSSEs, and extension of OSSEs to societal impacts. OSSEs can be complemented by calculations of forecast sensitivity to observations, which simultaneously evaluate the impact of different observation types in a forecast model system

Small RNAs Targeting Transcription Start Site Induce Heparanase Silencing through Interference with Transcription Initiation in Human Cancer Cells

Heparanase (HPA), an endo-h-D-glucuronidase that cleaves the heparan sulfate chain of heparan sulfate proteoglycans, is overexpressed in majority of human cancers. Recent evidence suggests that small interfering RNA (siRNA) induces transcriptional gene silencing (TGS) in human cells. In this study, transfection of siRNA against −9/+10 bp (siH3), but not −174/−155 bp (siH1) or −134/−115 bp (siH2) region relative to transcription start site (TSS) locating at 101 bp upstream of the translation start site, resulted in TGS of heparanase in human prostate cancer, bladder cancer, and gastric cancer cells in a sequence-specific manner. Methylation-specific PCR and bisulfite sequencing revealed no DNA methylation of CpG islands within heparanase promoter in siH3-transfected cells. The TGS of heparanase did not involve changes of epigenetic markers histone H3 lysine 9 dimethylation (H3K9me2), histone H3 lysine 27 trimethylation (H3K27me3) or active chromatin marker acetylated histone H3 (AcH3). The regulation of alternative splicing was not involved in siH3-mediated TGS. Instead, siH3 interfered with transcription initiation via decreasing the binding of both RNA polymerase II and transcription factor II B (TFIIB), but not the binding of transcription factors Sp1 or early growth response 1, on the heparanase promoter. Moreover, Argonaute 1 and Argonaute 2 facilitated the decreased binding of RNA polymerase II and TFIIB on heparanase promoter, and were necessary in siH3-induced TGS of heparanase. Stable transfection of the short hairpin RNA construct targeting heparanase TSS (−9/+10 bp) into cancer cells, resulted in decreased proliferation, invasion, metastasis and angiogenesis of cancer cells in vitro and in athymic mice models. These results suggest that small RNAs targeting TSS can induce TGS of heparanase via interference with transcription initiation, and significantly suppress the tumor growth, invasion, metastasis and angiogenesis of cancer cells

Cortical Surface Thickness in the Middle-Aged Brain with White Matter Hyperintense Lesions

Background and purpose: Previous voxel-based morphometry (VBM) studies have suggested that cortical atrophy is regionally distributed in middle-aged subjects with white matter hyperintense (WMH) lesions. However, few studies have assessed cortical thickness in middle-aged WMH subjects. In this study, we examined cortical thickness as well as cortical morphometry associated with the presence of WMH lesion load in middle-aged subjects.Participants and methods: Thirty-six middle-aged subjects with WMH lesions (WMH group) and without clinical cognitive impairment, and 34 demographically matched healthy control subjects (HCS group) participated in the study. Cortical thickness was estimated using an automated Computational Anatomy Toolbox (CAT12) as the distance between the gray-white matter border and the pial surface. Individual WMH lesions were manually segmented, and WMH loads were measured. Statistical cortical maps were created to estimate differences in cortical thickness between groups based on this cortex-wide analysis. The relationship between WMH lesion loads and cerebral cortical thickness was also analyzed in CAT12.Results: Cortical thickness was significantly lower in the WMH group than in the controls in multimodal integration regions, including the right and left dorsal anterior cingulate cortex (dACC), right and left frontal operculum (fO), right and left operculum parietale (OP), right and left middle temporal gyrus (MTG), and left superior temporal gyrus (STG; P < 0.01, family-wise error (FWE)-corrected). Additionally, cortical thickness was also lower in the recognition regions that contained the right temporal pole (TP), the right and left fusiform gyrus, and the left rolandic operculum (RO; P < 0.01, FWE-corrected). The results revealed that in the left superior parietal lobule (SPL), cortical thickness was higher in the WMH group than in the HCS group (P < 0.01, FWE-corrected). A voxel-wise negative correlation was found between cortical thickness and WMH lesion loads in the right orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex (DLPFC), and right subcallosal cortex (P < 0.01, FWE-corrected).Conclusion: The main findings of this study suggest that middle-aged WMH subjects are more likely to exhibit cortical thinning, especially in multimodal integration and recognition- and motor-related regions. The current morphometry data provide further evidence for WMH-associated structural plasticity

NR4A1 is Involved in Fibrogenesis in Ovarian Endometriosis

Background/Aims: Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis. Methods: Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining. Results: The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo. Conclusion: NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis

Alteration of osteocalcin mRNA expression in ovine osteoblasts in dependence of sodium fluoride and sodium selenite medium supplementation

Objective of this study was to assess the quantification of osteocalcin (OCN) expression by ovine osteoblasts cultured with different concentrations of sodium fluoride (F) and sodium selenite (Se) to evaluate the interaction of these agents on OCN expression in vitro . We wanted to demonstrate a possible protective effect of selenium on the toxic effect of fluoride. Osteoblasts were isolated by complete trypsin and collagenase digestion from ovine calvarial bone and cultured in DMEM supplemented with 15% FBS at 37 °C in a humidified 5% CO 2 incubator. Identified osteoblasts were divided into one control group (C) and eight experimental groups, which were exposed to different concentrations of sodium fluoride (F; 0, 0.5, 1 mM) sodium selenite (Se; 0, 0.1, 1 μM). At different time points after treatment total RNA was extracted and reverse transcribed into first-strand cDNA. OCN mRNA was indirectly measured by real-time fluorescent quantitative PCR (qPCR). OCN mRNA expression in F 1 mM with Se 1 μM group was found to have a high peak at day seven and was lower before and afterwards. Expression of OCN mRNA in all groups except control could be promoted by F and/or Se showing a general upregulation. Furthermore, the toxicity from excessive exposure of osteoblast with F could be circumvented by usage of moderate concentration of Se. Osteoblasts cultured in vitro may have stressful responses to F and Se at the first few days. Low concentrations of Se inhibit the toxic effects of high concentrations of F. Therefore, F and Se could be used as antagonistic factors, which could regulate osteocalcin expression

Alteration of Regional Homogeneity within the Sensorimotor Network after Spinal Cord Decompression in Cervical Spondylotic Myelopathy: A Resting-State fMRI Study

There is a lack of longitudinal research to evaluate the function of neurons’ adaptive changes within the sensorimotor network (SMN) following recovery after cervical cord decompression. Regional homogeneity (ReHo) may provide information that is critical to fully understand CSM-related functional neural synchrony alterations. The purpose of this study was to assess the ReHo alterations of resting state-functional MRI (rs-fMRI) within pre- and postdecompression CSM and healthy controls (HC) and its correlations with clinical indices. Predecompression CSM demonstrated a significantly lower ReHo in the left primary sensory cortex and primary motor cortex (PostG/PreG) but enhanced ReHo in the right superior parietal lobule (SPL) compared with HC. In comparison with predecompression CSM, the postdecompression CSM showed increased ReHo in the left PostG/PreG but significantly lower ReHo in the right SPL compared with HC patients. Abnormal ReHo regions in pre- or postdecompression CSM showed no significant correlation with the Japanese Orthopaedic Association (JOA) scores, Neck Disability Index (NDI) scores, and disease duration (P>0.05). This result demonstrated disrupted regional homogeneity within SMN in CSM. This adaptive change in the brain may favor the preservation of sensorimotor networks before and after cervical cord decompression and clinical symptoms independent of ReHo within SMN

Predicting long-term multicategory cause of death in patients with prostate cancer: random forest versus multinomial model.

The majority of patients with prostate cancer die of non-cancer causes of death (COD). It is thus important to accurately predict multi-category COD in these patients. Random forest (RF), a popular machine learning model, has been shown useful for predicting binary cancer-specific deaths. However, its accuracy for predicting multi-category COD in cancer patients is unclear. We included patients in Surveillance, Epidemiology, and End Results-18 cancer registry-program with prostate cancer diagnosed in 2004 (followed-up through 2016). They were randomly divided into training and testing sets with equal sizes. We evaluated prediction accuracies of RF and conventional statistical/multinomial models for 6-category COD by data-encoding types using the 2-fold cross-validation approach. Among 49,864 prostate cancer patients, 29,611 (59.4%) were alive at the end of follow-up, and 5,448 (10.9%) died of cardiovascular disease, 4,607 (9.2%) of prostate cancer, 3,681 (7.4%) of non-prostate cancer, 717 (1.4%) of infection, and 5,800 (11.6%) of other causes. We predicted 6-category COD among these patients with a mean accuracy of 59.1% (n=240, 95% CI, 58.7%-59.4%) in RF models with one-hot encoding, and 50.4% (95% CI, 49.7%-51.0%) in multinomial models. Tumor characteristics, prostate-specific antigen level, and diagnosis confirmation-method were important in RF and multinomial models. In RF models, no statistical differences were found between the accuracies of training versus cross-validation phases, and those of categorical versus one-hot encoding. We here report that RF models can outperform multinomial logistic models (absolute accuracy-difference, 8.7%) in predicting long-term 6-category COD among prostate cancer patients, while pathology diagnosis itself and tumor pathology remain important factors

The Effects of Preoperative Oral Carbohydrate on Frequency of T and NK Cells in Patients with Cervical Cancer Treated Using Neoadjuvant Chemotherapy and Surgery: A Prospective Cohort Study

Background. Immune dysfunction can occur after neoadjuvant chemotherapy (NAC) and surgery for cancer. We investigated whether preoperative oral carbohydrate affected the postoperative percentages of T cells (CD4+ and CD8+) and natural killer (NK) cells in patients with cervical cancer treated with NAC and surgery. Methods. This prospective cohort study enrolled consecutive patients with cervical cancer treated by radical hysterectomy with PLND at the Gynecologic Oncology Department of Fujian Provincial Cancer Hospital (China) between January 2018 and December 2018. Patients were divided into three groups according to the treatment method: NAC (two cycles, surgery 1 month later), NAC+CHO (chemotherapy and surgical methods same as with the NAC group but with 300 mL of oral carbohydrate administered 2 h before surgery), and non-NAC (surgery alone). Percentages of NK, CD3+, CD4+, and CD8+ cells were evaluated by flow cytometry the day after the first admission, just before surgery, immediately after tracheal tube removal, and the day after surgery. This trial is registered with NCT03872635 at clinicaltrials.com. Results. The final analysis included 77 patients (non-NAC group, n=26; NAC group, n=25; and NAC-CHO group, n=26). Baseline characteristics and preoperative NK, CD3+, CD4+, and CD8+ cell percentages were similar between groups. Postoperatively, all groups exhibited reductions in NK, CD3+, and CD4+ cell percentages and increases in CD8+ cell percentages (all P<0.05). The changes in NK, CD3+, CD4+, and CD8+ cell percentages were attenuated in the NAC-CHO group (P<0.05 vs. both other groups). Conclusion. Preoperative oral carbohydrate can improve the postoperative populations of NK and T cells after the treatment of cervical cancer by NAC and surgery