To evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B.
Our results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy.
Decreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.
Chemo- and radiotherapy combined with surgical removal of a tumor remain the most common treatment for cancer. However, this treatment is complicated by the development of drug resistance in cancer cells which leads to tumor recurrence [1, 2]. Therapy resistance can be attributed to a variety of mechanisms, such as DNA mutations, alterations in gene expression level, and abnormalities in pre-mRNA splicing [1–3]. The first two of these mechanisms are well studied, whereas the role of the pre-mRNA splicing regulation in development of chemotherapy resistance remains unclear .
Alternative pre-mRNA splicing is a process that affects more than 90% of multi-exon human genes. It allows cells to rapidly switch gene expression towards the production of various protein isoforms or noncoding transcripts and totally change the entire exome, proteome, and ultimately the cell phenotype [5–7]. Multiple pre-mRNA splicing abnormalities have been found in malignant cells leading to functional and nonfunctional changes in the proteome [8–11]. Further splicing perturbations were observed following chemotherapy. Several studies have described alternative splicing events that occur in cancer cells after treatment; however, most of these studies were focused on the function of specific genes rather than global changes in the transcriptome [12–17].
Most types of anticancer therapy frequently used in clinical practice are based on direct or indirect induction of DNA damage in target cells. The cellular response to DNA damage is a very complex process that includes stalling of RNA polymerase II, activation of multiple kinases (i.e., ATM, ATR, and DNA-PK), phosphorylation of histone H2AX, and cell cycle arrest [1, 18, 19]. These mechanisms allow tumor cells to repair DNA damage and survive following treatment. It has been recently reported that the splicing regulatory proteins may also play an important role in the DNA damage response and promote resistance to genotoxic stress by combining both splicing-dependent and splicing-independent mechanisms [20, 21].
Several small molecule splicing inhibitors were proposed lately to treat different types of cancer such as chronic lymphocytic leukemia, breast adenocarcinoma, prostate cancer, ovarian adenocarcinoma, and colon adenocarcinoma [22–24]. The most commonly used splicing inhibitors are pladienolide B and spliceostatin A. Both compounds bind to SF3B1 complex, blocking the spliceosome . These small molecules were confirmed to effectively eliminate cancer cells both in vitro and in vivo; however, phase I clinical trials revealed multiple side effects due to high toxicity of the compounds .
In this study, we analyzed transcriptome data from patient-derived xenograft tumors and cancer cell lines to detect global changes in pre-mRNA splicing induced by multiple anticancer drugs. In addition, we comprehensively explored alterations in spliceosomal proteins. Particular, we used (I) mRNA microarray gene expression data from 101 cell lines derived from a variety of cancers, (II) quantitative phosphoproteome data, and (III) proteomic datasets of cells affected by various stress stimuli. We also tested the effect of the small molecule splicing inhibitor pladienolide B on the sensitivity of cancer cells to cisplatin.
Unprocessed RNA-Seq reads were downloaded from the NCBI Gene Expression Omnibus (GEO) data repository (accession numbers GSE69405 and GSE89127; Table 1) . To increase read quality before mapping, paired reads were trimmed using Trimmomatic (v. 0.35). The rMATS splicing tool  requires reads with a fixed length, so we trimmed reads from datasets GSE69405 and GSE89127 to the lengths of 96 and 90, respectively. We mapped trimmed RNA-Seq reads to hg19 of Gencode using STAR (v. 2.5.2b) according to recommendations from the STAR manual 2.4.0.1 with the following parameters: the maximum number of mismatches for paired reads was 4% of the read length, the maximum number of multiple alignments allowed for a read was 10, non-canonical junctions were removed, the minimum number of allowed splice overhangs was 8 for unannotated junctions and 1 for annotated junctions, the minimum intron length was 20, the maximum intron length was 1,000,000, and the number of "spurious" junctions was reduced. To compare splicing events before and after chemotherapy, we ran rMATS  splicing tool using the following parameters recommended by the developers: -c 0.0001 and -novel SS1 (multi-align reads are ignored as a default). Minor splicing differences were filtered out by thresholds of FDR < 0.05 and IncLevelDifference value > 5%. Splicing events were considered identical if they had the same coordinates and IncLevelDifference values had the same sign.
In total, 26 microarray datasets (for dataset accession numbers see Table 1 and Additional file 1) were loaded from two repositories: NCBI GEO  and EMBL-EBI ArrayExpress . Raw microarray data from Affymetrix microarrays (CEL files) were processed using the affy R/Bioconductor package  with the following parameters: normalization—quantiles, background correction—rma, probe specific correction—pmonly, and summary method—medianpolish. The final data were already log-transformed. The lumi  and limma  R/Bioconductor packages were used to process the data obtained from Illumina Beadchips. The parameters were as follows: variance stabilization—log2 and normalization—quantiles. Before that, an initial detection p value threshold of 0.05 was chosen based on Illumina recommendations. rMeanSignal and gMeanSignal were taken as the values of the Agilent microarray signal. For further analysis of the data obtained from Agilent microarrays, the logarithm of the rMeanSignal-to-gMeanSignal ratio was normalized using the quantile normalization method.
Gene expression was compared between two group of cells (intact cells and exposed to stress: chemotherapy, radiotherapy, or hypoxia) using the limma R/Bioconductor package .
The advantage of our analysis was that we combined p values of separate datasets with the use of Wilkinson's method  for meta-analysis of significance values from metap R/Bioconductor package . First, we considered p values of differentially expressed genes using the limma R/Bioconductor package , and then, we combined p values with the method of Wilkinson and made a correction for multiple testing with the FDR method. Methods for combining p values gives a statistician flexibility, since they require minimal information and assumptions from gene expression studies, and thus, we did not account for the variability in the datasets or microarray platforms.
Meta-analysis of cisplatin, hypoxia, and topoisomerase inhibitor actions (Table 1, Additional file 1) were processed according to the above scheme of meta-analysis with a p value cutoff threshold of 0.05. We picked only those genes that were exclusively up or downregulated in all the studies compared to their corresponding controls. Gene expression levels were combined between studies on different platforms using RefSeq ID obtained from the microarray annotation file. To analyze the effect of paclitaxel (Table 1, Additional file 1), all corresponding samples were combined into one set as these data came from the same source using Affymetrix GeneChip Human Genome U133 Plus 2.0 software. Differentially expressed genes were identified without meta-analysis techniques using only the limma R/Bioconductor package . We could not find a sufficient number of datasets for the effect of radiation and tyrosine kinase inhibitors' effect in public repositories, and therefore, differentially expressed genes were independently identified for each separate dataset using only the limma R/Bioconductor package .
Human ovarian (SKOV3), breast (MCF7), colorectal (HT29), cervix (Hela) adenocarcinoma, lung carcinoma (A549), hepatocellular carcinoma (HepG2), and glioblastoma (U87MG) cell lines were grown in DMEM (Sigma) supplemented with a 1% penicillin/streptomycin mixture (Gibco), 2 mM glutamine (Gibco), and 10% fetal bovine serum (HyClone) in a humidified 5% CO2 incubator at 37 °C. The cells were checked for signs of mycoplasma contamination.
The LC-MS/MS analysis of SKOV3 cell lysates was performed in three replicates using a TripleTOF 5600+ mass spectrometer with a NanoSpray III ion source (ABSciex) coupled to a NanoLC Ultra 2D+ nano-HPLC system (Eksigent). The HPLC system was configured in trap-elute mode. For sample loading buffer and buffer A, we used a mixture of 98.9% water, 1% methanol, and 0.1% formic acid (v/v). Buffer B was 99.9% acetonitrile and 0.1% formic acid (v/v). Samples were loaded on a Chrom XP C18 trap column (3 μm, 120 Å, 350 μm × 0.5 mm; Eksigent) at a flow rate of 3 μl/min for 10 min and eluted through a 3C18-CL-120 separation column (3 μm, 120 Å, 75 μm × 150 mm; Eksigent) at a flow rate of 300 nl/min. The gradient was increased from 5 to 40% buffer B over 90 min followed by 10 min at 95% buffer B and 20 min of reequilibration with 5% buffer B. Between different samples, two blank 45-min runs consisting of 5 to 8 min waves (5% B, 95%, 95%, 5%) were required to wash the system and prevent carryover.
The information-dependent mass spectrometry experiments included one survey MS1 scan followed by 50 dependent MS2 scans. The following MS1 acquisition parameters were used: the mass range for MS2 analysis was 300–1250 m/z, and the signal accumulation time was 250 ms. The ions used for the MS2 analysis were selected based on intensity with a threshold of 200 cps and a charge state from 2 to 5. The following MS2 acquisition parameters were used: the resolution of the quadrupole was set to UNIT (0.7 Da), the measurement mass range was 200–1800 m/z, and the signal accumulation time was 50 ms for each parent ion. Collision-activated dissociation was performed using nitrogen gas and by ramping collision energy from 25 to 55 V within a signal accumulation time of 50 ms. Analyzed parent ions were sent to a dynamic exclusion list for 15 s to obtain MS2 spectra at the chromatographic peak apex. A β-galactosidase tryptic solution (20 fmol) was run with a 15-min gradient (5–25% buffer B) between samples to calibrate the mass spectrometer and control overall system performance, stability and reproducibility.
Descriptions of further bioinformatics (pathway analysis, time clusterization analysis, co-regulation analysis, LC-MS/MS protein identification) and experimental methods (SDS-PAGE, in-gel trypsin digestion, cell proliferation assay, flow cytometry, immunofluorescence analysis and western blotting) are provided in Additional file 2.
To determine how pre-mRNA splicing in cancer cells is affected by chemotherapy, we analyzed publicly available transcriptome datasets (GSE89127) that represent melanoma, lung cancer, gastric carcinoma, and bladder carcinoma cell lines (A375, A549, H3122, N87, PC9, RT112) treated with multiple kinase inhibitors (erlotinib, crizotinib, trametinib, lapatinib, vemurafenib, BGJ398)  (Table 1). In total, we detected 12,203 altered alternative splicing events in intact cells and cells exposed to kinase inhibitors. Interestingly, among them, 367 splicing events were observed in at least half of the cell lines after the therapy (Additional file 3A). Analysis of genes affected by alternative splicing revealed significant number of genes from the pre-mRNA splicing pathway (Fig. 1a). Thus, we assumed a regulatory feedback mechanism between the spliceosomal proteins and their targets. In other words, therapy-induced alterations in pre-mRNA splicing affect spliceosomal genes, which in turn may provoke further splicing perturbations. To assess possible effects of splicing changes on gene expression, we investigated types of alternative splicing events that occurred after therapy. Our analysis revealed two common splicing alterations: exon skipping (184 events) and intron retention (46 events) (Fig. 1b). In contrast to exon skipping, intron retention was observed more frequently after the therapy, i.e., in most cases the intron inclusion level was higher in treated samples than in untreated control cells (Fig. 1c). Analysis of transcripts with retained introns demonstrated that all of them contain multiple in frame stop codons (Additional file 3B). Therefore, they could not be translated into functional proteins [35, 36]. Our data indicate that the spliceosome pathway might be suppressed by chemotherapy.
To further examine our hypothesis in a more clinically relevant model, we analyzed a publicly available transcriptome dataset (GSE69405) that represents 12 lung adenocarcinoma patient-derived xenograft (PDX) tumors prior to and after treatment with chemotherapeutic drugs, including carboplatin, docetaxel, afatinib, BEZ235, BKM120, DAPT, erlotinib, tivantinib, and selumetinib (Table 1). These data were used in the original study to compare gene expression levels without paying attention to mRNA splice variants . Strikingly, we found that different drugs induced similar alterations in pre-mRNA splicing. This trend was further confirmed by PCA clustering of inclusion level differences between treated and untreated samples (Additional file 4: Figure S1). We detected 824 altered alternative splicing events in treated cells (Fig. 1b), and, similar to the previous dataset, the most frequent type of alternative splicing variants was intron retention. In total, more than half of samples had 47 common splicing events and 39 of them involved in intron retention (Fig. 1b, Additional file 3C, D).
As in the experiments conducted on cancer cell lines, in patient-derived tissues, a chemotherapy induces splicing alterations in genes involved in the spliceosome pathways (Fig. 1a). We observed intron retention in several essential splicing factors, including RBM6, HNRNPA2B1, RBM39, RBM5, SRRM1, SRSF5, and SRSF7 (Fig. 1d, Additional file 3E). Interestingly, treatment of cancer cells with different chemotherapeutic drugs resulted in retention of the same introns in each of these genes.
Having discovered that significant changes in pre-mRNA splicing in response to the action of various types of chemotherapeutic drugs, we next examined global changes in gene expression. We decided to perform analysis of mRNA levels in the same dataset that was used previously for evaluation of alternative splicing differences (GSE89127). It has revealed a significant downregulation of splicing-related gene levels in all cancer cell lines after chemotherapy (Fig. 1e). To expand this result to larger number of samples and multiple types of cancers, we performed six meta-analyses of mRNA microarray gene expression profiles of different cell lines exposed to various stress stimuli, including DNA-damaging agents (i.e., platinum-based drugs, gamma irradiation, and topoisomerase inhibitors), tyrosine kinase inhibitors, and taxanes (Fig. 2a). A detailed description of these datasets is presented in Table 1 and Additional file 1.
Our meta-analysis (Fig. 2b (top panel) and Additional file 5) revealed multiple downregulated and upregulated pathways, which were exclusively observed for certain drugs. For example, platinum-based compounds promoted the expression of genes responsible for apoptosis and those involved in the platinum drug resistance pathway (Additional file 5). While topoisomerase and tyrosine kinase inhibitors provoked the expression of apoptotic, lysosomal, and MAPK signaling genes. The only two pathways that were commonly affected in all tested datasets regardless of the treatment used were the cell cycle regulation (especially M phase regulation) and the pre-mRNA splicing pathways. The level of gene expression in these two pathways was significantly downregulated after treatment with anticancer drugs.
In clinical practice, platinum-based drugs are often combined with taxanes [38–40]. The cytostatic effect of taxanes is mainly associated with enhanced microtubule formation and stabilization . The stimulation of microtubule formation temporarily activates CDK1 and triggers the G2/M transition, which is followed by mitotic arrest . It is in line with our meta-analysis of paclitaxel-treated cancer cells. The levels of genes involved in M phase were significantly upregulated, while those associated with the S phase and the G1/S transition were downregulated (Fig. 2b (bottom panel), Additional file 5). These data are consistent with previous findings [41, 43]. Interestingly, we also observed a substantial increase in the transcription levels of genes involved in spliceosome assembly and regulation and in RNA transport.
Next, we studied the response of cancer cells to hypoxia, which is one of the natural stress factors for cancer cells. The result of corresponding dataset analysis was not so surprising: the spliceosomal and cell cycle progression genes were found in the cluster of downregulated pathways (Fig. 2b (top panel), Additional file 5). In particular, the level of transcripts associated with M phase of the cell cycle were significantly downregulated (Fig. 2b (bottom panel)).
Taken together, in our analysis of gene expression in 101 cell lines that were affected by six different types of stress, we identified only two pathways that were altered in all tested samples. The downregulation of cell cycle-related pathways was expected since it has recently been shown that stress induces retardation or arrest of specific cell cycle phases [43, 44]. Surprisingly, in addition to cell cycle changes, we consistently observed concerted changes in the expression of spliceosomal genes. To the best of our knowledge, this phenomenon has not been reported previously.
To understand the dynamics of changes in the expression of spliceosomal genes following exposure to different stress factors, we implemented soft clustering (i.e., fuzzy c-means clustering). We analyzed two datasets containing at least four time points after the beginning of the treatment: an ovarian cancer cell line treated with cisplatin (E-GEOD-8057) and a glioma cell line subjected to hypoxia (E-GEOD-18494). For both datasets, the cluster analysis clearly showed that spliceosomal gene levels were gradually downregulated (Fig. 3 a, b; Additional file 6). In spliceosomal gene clusters, we also found genes that were associated with the cell cycle and DNA replication pathways (Additional file 6). In particular, cell cycle genes involved in M and S phase transitions were significantly downregulated. The simultaneous decrease in the expression levels of cell cycle- and spliceosome-related genes indicates that the downregulation of splicing is not a consequence of cell cycle arrest. It is more likely represents an independent mechanism of the cell response to stress.
Next, we were interested whether the concerted downregulation of spliceosomal and cell cycle genes is unique to cancer cells. Therefore, we conducted the soft clustering analysis of the transcriptome of gamma-irradiated normal skin fibroblasts (dataset E-GEOD-59861) (Fig. 3c, Additional file 6). Strikingly, results showed that spliceosomal genes were significantly downregulated in gamma-irradiated fibroblasts and the clusters enriched with spliceosomal genes also contained genes involved in DNA replication and M and S phase cell cycle transitions. Our results imply that observed concerted downregulation of expression levels of genes involved in splicing and cell cycle regulation is not specific for cancer cells.
Since spliceosomal genes and genes involved in the M phase of the cell cycle were changed in a concerted manner, we wondered whether these genes were regulated by the same transcription factors. To answer this question, we performed a co-expression analysis of genes differentially expressed in cancer cells exposed to chemotherapeutic drugs and created a co-regulatory network based on ChIP-seq from the ReMap database. We selected four datasets (E-GEOD-66493, GSE13525, GSE66493, and GSE47856) that describe the effects of platinum agents on gene expression in different cancer cell lines.
For each dataset, we independently identified differentially expressed splicing- and mitotic-related genes and chose pairs with Spearman correlation coefficients greater than 0.7 and FDR-corrected p value < 0.05. Next, we determined transcription factors that bind to the promoter regions of the co-expressed genes in chosen pairs (for more detail see Additional file 2). Our analysis revealed three transcription factors that were common for all datasets, namely, SOX2, GFI1B, and TARDBP (Fig. 3d, Additional file 4: Figure S2A, B). We assumed that these factors might be responsible for concerted gene expression changes in spicing- and mitotic-related genes.
In addition to the transcriptional control of gene expression, the activity of spliceosomal proteins can also be regulated at the proteome level by post-translational modifications. It has been shown that splicing can be inhibited by the phosphorylation of spliceosomal proteins as negatively charged phosphate groups obstruct binding between proteins and negatively charged RNA molecules [45–47]. Therefore, we analyzed three publicly available phosphoproteomes of cancer cells that were subjected to DNA damage (gamma irradiation or neocarzinostatin) [48–50] and compared proteins that were phosphorylated before and after treatment. According to our analysis, spliceosomal proteins were significantly phosphorylated after the therapy. In total, we identified 66 spliceosomal proteins with high post-treatment phosphorylation levels (Fig. 4a). These data favor the possibility that DNA damage may suppress the catalytic activity of spliceosomal proteins in cells.
In addition, several studies have shown that following exposure to chemo-  or radiotherapy  cancer cells specifically secrete spliceosomal proteins into the extracellular space. Consistent with these observations, we have previously identified multiple spliceosomal proteins in ovarian cancer ascites (extracellular fluids that serve as a natural medium for cancer cells) obtained from patients after treatment . The proteins for which secretion increased more than twofold after radiotherapy of glioblastoma cells in vitro  and after chemotherapy of ovarian cancer cells both in vitro (cisplatin treatment) and in vivo (ascites from patients after combined course of chemotherapy)  are shown on Fig. 4b. In these datasets, we identified more than 30 spliceosomal proteins that could be exported from cancer cells in response to therapy. We validated these data by western blotting with antibodies against several spliceosomal proteins U2AF65, U2AF35, and RBM11 (Additional file 4: Figure S3).
To experimentally confirm the results of our meta-analyses, we performed LC-MS/MS-based proteome profiling of SKOV3 ovarian cancer cells before and 24 h after treatment with cisplatin. In total, 3578 proteins were identified in our experiment (Fig. 4c, Additional file 7). Proteins were considered differentially present if their abundance was changed by more than twofold. We found that the abundance of 366 proteins were increased and the abundance of 922 proteins were decreased after cisplatin treatment. Data analysis using the KEGG database revealed that only three pathways were significantly altered in the treated cells (Fig. 4d). Interestingly, the spliceosome-related pathway proteins were substantially downregulated in accordance with our results of gene expression analyses.
Based on the results on our transcriptomic and proteomic analyses, we conclude that alterations in pre-mRNA splicing are induced by multiple mechanisms during therapy: altered gene expression, pre-mRNA splicing dysregulation, protein post-translational modification and secretion. However, our analysis does not explain the biological reason for these changes. The role of the spliceosome in the DNA damage response has lately been demonstrated in several studies [53, 54]. Paulsen and colleagues performed full-genomic siRNA screening of human cells and identified that downregulation of genes involved in pre-mRNA splicing induced the highest level of H2AX phosphorylation , which serves as an early marker of the DNA damage response [55, 56]. We collated the results of siRNA screening for histone H2AX phosphorylation  with the results of our meta-analysis of gene expression and proteomic data [51, 52] (Fig. 4e). Fisher's test showed that the proteins secreted by DNA-damaged cells are encoded by genes for which insufficient expression is perceived by the cell as a DNA repair signal (Fig. 4e). Therefore, the downregulation of several spliceosomal proteins that was observed during therapy may activate DNA reparation.
Based on these data, we proposed that the changes in alternative splicing and downregulation of spliceosomal transcripts and proteins that were observed after therapy may help cancer cells survive after genotoxic stress. To test this hypothesis, we treated ovarian (SKOV3), breast (MCF7), colorectal (HT29), cervix (Hela) adenocarcinoma, lung carcinoma (A549), hepatocellular carcinoma (HepG2), and glioblastoma (U87MG) cell lines with sublethal doses of the small molecule splicing inhibitor pladienolide B for 2 days. After treatment, we evaluated the sensitivity of these cells to the DNA damaging drug cisplatin using an MTT assay (Fig. 5a, Additional file 4: Figure S4A). This experiment revealed that nanomolar concentrations of pladienolide B significantly increase the sensitivity of cancer cells to cisplatin (Fig. 5b, Additional file 4: Figure S4B).
To determine how splicing inhibitors affect cancer cells, we analyzed RNA sequencing data from ovarian adenocarcinoma cells (TOV21G; E-GEOD-67770)  treated with pladienolide B and cervix adenocarcinoma cells (Hela; GSE72156)  treated with another potent splicing inhibitor spliceostatin A with the same mechanism of action as pladienolide B. Figure 5e demonstrates that both inhibitors predominantly affect splicing of genes involved in the cellular stress response and cell cycle regulation. We confirmed these data through cell cycle analysis of HT29 and SKOV3 cells treated with pladienolide B (Additional file 4: Figure S4C).
Tressini and colleagues have recently demonstrated that spliceosomal complexes play an important role in the activation of ATM kinase and subsequent DNA repair . This signaling pathway is activated by ATM autophosphorylation on Ser1981 . Therefore, having obtained data indicating that pladienolide B impairs cell response to stress, we decided to investigate its effect on the level of phosphorylated ATM after DNA damage. FACS analysis and immunofluorescence microscopy demonstrated that pretreatment with pladienolide B dramatically decreases cisplatin-induced ATM phosphorylation in SKOV3, Hela, HT29, and A549 cells (Fig. 5c, d and Additional file 4: Figure S4D). Based on these data, we conclude that regulation of pre-mRNA splicing is important for ATM-dependent DNA damage response while dysregulation of spliceosomal machinery induced by a splicing inhibitor impairs ATM signaling and increases the sensitivity of cancer cells to genotoxic stress.
Dysregulation of pre-mRNA splicing can lead to the appearance of protein isoforms that contribute to the initiation and progression of tumors and cancer resistance to chemotherapy [5, 59, 60]. In addition to the imbalance in splicing regulation that is inherent to cancer cells (as opposed to normal cells) [35, 61–63], the effectiveness and precision of pre-mRNA splicing are further affected by chemotherapy [4, 64]. Recent global analysis of splicing changes in tumor samples in comparison with normal tissues from TCGA collection revealed that aberrant alternative splicing often affected the functional domains of proteins, which frequently mutated in cancer . The origin of cancer-related splicing changes remains mostly unknown. On the one hand, the global tendency of splicing dysregulation in cancer has been demonstrated in several excellent studies that revealed various cancer-associated mutations in spliceosomal genes that impair pre-mRNA splicing [5, 65, 66]. However, even in the absence of mutations in splicing factors, more intron retention events occur in cancer tissues than in normal cells . On the other hand, many splicing factors are frequently overexpressed in multiple cancers . Intriguingly, a growing number of studies demonstrates the functions of spliceosomal proteins that are not directly related to the splicing process such as DNA repair , R-loop formation , telomere elongation , mRNA export from the nucleus , and M-phase regulation [71, 72].
Here, we comprehensively studied differences in alternative splicing and changes in the expression of spliceosomal genes in cancer cells following treatment with a variety of chemotherapeutic drugs. We analyzed publicly available poly(A)+ RNA-sequencing data and demonstrated that the most frequent alternative splicing event after chemotherapy was intron retention. Inefficient intron removal indicates less intense pre-mRNA splicing. It is important to note that poly(A)+ RNA-sequencing data could underestimate the extent of alternative splicing events because poly(A)+ RNA-seq depletes some fraction of intronic reads ; therefore, the real intron retention might be even higher then detected during our analysis. Our data strongly support the results of the meta-analyses, in which we observed a decrease in the expression of spliceosomal genes following exposure to several types of stress stimuli. To the best of our knowledge, this is the first study demonstrating an increase in the number of intron retention events in various cancer cells following different types of chemotherapy. Recently, one group of studies tried to recognize the regulation of one or a few transcripts following therapy [12–17]. Other studies focused only on exon inclusion/skipping events using splicing-sensitive microarrays. For example, it has been shown that camptothecin altered alternative splicing of genes involved in splicing regulation in MCF-7 and HCT116 cell lines [64, 74, 75]. Only a few works interrogated entire transcriptome changes after stress response. It has been reported that hypoxia and cisplatin treatment also affected the splicing of spliceosomal genes in breast cancer cell line [4, 76]. In our systematic analysis, we observed a similar enrichment pattern of alternative splicing changes across various cancer cell lines derived from different tumor types after exposure to various chemotherapeutic drugs. We showed that genes most affected by intron retention were genes that encodes spliceosomal proteins. Intron retention usually leads to RNA degradation and may therefore provide an additional mechanism by which downregulation of spliceosomal proteins is facilitated within the cell.
Intriguingly, the results of our meta-analyses of gene expression and the results of time clustering showed that spliceosomal genes and genes involved in the mitotic part of the cell cycle were simultaneously downregulated in different cell lines following exposure to various stresses. The only exception was the effect of taxanes. This group of drugs stimulates the G2/M transition and as a result upregulates genes involved in M phase. Importantly, we observed a simultaneous increase in spliceosomal genes after treatment with taxanes. Therefore, we observed concerted changes in the expression of spliceosomal and cell cycle-related genes following all types of treatment. An interplay between the cell cycle and the spliceosome has been demonstrated in many organisms, including yeast [77–82], fruit flies [83, 84], chickens , mice , and humans [54, 72, 86–90]. In human cells, inhibition of spliceosomal gene expression using siRNA led to multiple defects in cell cycle progression, most of which were related to mitosis [72, 86–88]. In addition, it has been shown that a lack of spliceosomal components causes cell cycle arrest in S and G2 phases [91, 92]. Furthermore, a connection between alternative splicing and cell cycle regulation has been demonstrated by Tsai and colleagues, who showed that alterations in pre-mRNA splicing are correlated with expression changes of genes involved in cell cycle regulation in cancer cells . Therefore, there is a strong interplay between pre-mRNA splicing and proper cell cycle progression.
Our results show that the key transcription factors that regulate the concerted changes in the expression of spliceosomal and cell cycle genes were the proto-oncogenes SOX2 and GFI1B and the transcriptional repressor TARDBP. Changes in these transcription factors may play an oncogenic role in tumor formation [94–96]. SOX2 has been implicated in growth, tumorigenicity, drug resistance, and metastasis in at least 25 different cancers , TARDBP is involved in apoptosis and cell division, while GFI1B positively regulates c-Myc expression and increases the proliferation rate of cancer cells .
We showed that the amount of spliceosomal proteins in cells decreased after treatment with chemotherapeutic drugs through different molecular mechanisms. In addition to reduced expression and disturbances in splicing of spliceosomal genes, cancer cells secrete spliceosomal proteins into the extracellular space after a course of chemotherapy. Consistent with this observation, our LC-MS/MS-based proteomic profiling revealed a significant decrease in spliceosomal proteins inside cancer cells after chemotherapy. Interestingly, we also observed DNA damage-induced hyperphosphorylation of spliceosomal proteins. This post-translational modification is known to inhibit splicing catalysis [45–47]. Therefore, these data demonstrate that four independent mechanisms are activated in response to therapy-induced stress to decrease the number of spliceosomal proteins. These processes act at different levels (i.e., affecting gene expression, pre-mRNA splicing, protein post-translational modification and secretion) and are likely complementary to each other. In other words, they occur simultaneously in response to strong cellular stress and may affect more than two thirds of all spliceosomal proteins within the cell  (Fig. 4f).
However, it is important to note that downregulation of spliceosomal proteins does not always lead to decreased splicing efficiency. Alternative splicing is regulated by an intricate network of enhancing and inhibiting splicing factors. Therefore, downregulation of a splicing inhibitor protein may in fact lead to increased splicing efficiency. Moreover, multiple studies have demonstrated that depending on context the same protein may both repress and activate splicing, giving rise to complex regulatory relationships . We believe that the therapy-induced downregulation of spliceosomal proteins may lead to highly specific alterations in pre-mRNA splicing and promote the survival of cancer cells after treatment. In our study, we utilized a small molecule splicing inhibitor that impairs the function of spliceosomal machinery. We speculate that it induces dysregulation of pre-mRNA splicing and therefore does not allow cells to fine tune their splicing in response to genotoxic stress. Failure to adjust splicing after DNA damage may in turn promote cell death. In agreement with this hypothesis, we demonstrated that pladienolide B significantly increases cisplatin-induced apoptosis and impedes DNA reparation. This synergetic effect of pladienolide B with cisplatin may allow the use of lower doses of both compounds in cancer treatment and therefore overcome side effects observed in patients during therapy .
Several previously published studies have shown that removal of spliceosomal proteins may activate DNA repair in cancer cells. Most recently, the U2/U5/U6 ribonucleoprotein complex of the spliceosome, which participates in the last stage of splicing, was found to dissociate from chromatin in response to UV radiation . In addition, a lack of spliceosomal proteins inside the cell leads to a high level of histone H2AX phosphorylation, which serves as a signal for subsequent DNA repair . However, the exact mechanism of interplay between spliceosomal proteins and DNA repair remains unknown. It is important to mention that a reduction in splicing efficiency does not indicate a total loss of functional transcripts. Cells contain many protein-coding genes that possess only few or even no introns. Multiple studies have shown that mainly intron-poor genes are activated upon exposure to different stresses . Hence, genes with few introns can be efficiently spliced even in the presence of a small number of functional spliceosomes, whereas the expression of genes with a higher number of introns or with weak splicing sites might be downregulated .
Our analysis revealed a novel stress response mechanism that was observed in 101 cell lines under 12 different conditions. After treatment of cancer cells with various drugs, we detected a reduction in the level of active spliceosomal proteins induced by different pathways, such as intron retention, decreased gene expression, phosphorylation, and extracellular export. These processes act at multiple levels and are likely complementary to each other, i.e., they occur in parallel following stress insults and can collectively affect more than two thirds of all spliceosomal proteins within the cell. The downregulation of spliceosomal components through these processes may promote cancer cells survival following therapy. This stress response mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin, and therefore, pladienolide B is a candidate drug to improve the efficiency of cancer therapy.
We thank Dr. Grigory Stepanov for providing helpful comments about the manuscript. We thank Dr. Dmitry B. Staroverov for assistance with FACS experiments. We thank Dr. Veronika Boychenko for critical reading and editing the manuscript.
This work was supported by the Russian Science Foundation project nos. 17-75-20205 (K.S.A; for the LС-MS/MS analysis) and 14-50-00131 (G.P.A.; for the in vitro experiments); the Russian Foundation for Basic Research projects nos. 18-34-00622 (K.S.A.), 16-04-01414 (V.O.S.), 17-00-00172 (M.A.L.), 16-04-01209 (M.S.P.), and 17-29-06056 (M.S.P.), the Scholarship of the President of the Russian Federation SP-4811.2018.4 (V.O.S.), the Grant of the President of the Russian Federation МК-6894.2018.4 (G.P.A.), the Program of the Presidium of the Russian Academy of Sciences "Molecular and Cellular Biology" project no. 0101-2015-0027 (M.S.P.).
All data generated or analyzed during this study are included in this published article and its supplementary information files. The datasets used in this study are listed in Table 1 and Additional file 1. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE  partner repository with the dataset identifier PXD007615 and https://doi.org/10.6019/PXD007615.
KSA, VOS, GPA, MSP, MAL, MIS, and VMG designed the research. KSA and GPA analyzed the data. KSA, VOS, MSP, PVS, and IOB performed the research. KSA, VOS, GPA, and MSP wrote the paper. All authors read and approved the final manuscript.
Mizui Y, Sakai T, Iwata M, Uenaka T. Pladienolides, new substances from culture of streptomyces platensis Mer-11107. The Journal of. jstage.jst.go.jp; 2004; Available from: https://www.jstage.jst.go.jp/article/antibiotics1968/57/3/57_3_188/_article/-char/ja/.
Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang YA, Williams E, et al. ArrayExpress update—simplifying data submissions. Nucleic Acids Res. 2014; Available from: https://0-academic-oup-com.brum.beds.ac.uk/nar/article/43/D1/D1113/2436935.
Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. Oxford Univ Press; 2004; Available from: https://0-academic-oup-com.brum.beds.ac.uk/bioinformatics/article/20/3/307/185980.


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Michelle Mangione
About Michelle...
With her band, cajon (box drum), drums and acoustic guitar, songwriter Michelle Mangione challenges the world of live music to rise to a very intimate and honest level. Her music is written from personal experiences and observations, and invites the listener to find personal connection to the songs.
She has released numerous Independent CDs and videos.
She is frequently seen playing guitar and "feet drums" at the same time, a skill she learned out of necessity. "I couldn't afford to pay a drummer, and needed the percussive edge in our acoustic shows, so I devised a pedal driven drum set that I could play with my feet", says Mangione.
Her signature blend of percussion-infused acoustic music has been featured on Radio, TV and in film.
Michelle has co-written songs with artists including Grace Slick (Jefferson Airplane) and Exene Cervenka (X). "The Edge of Madness", which was her second collaboration with rock icon Grace Slick (Jefferson Airplane) was chosen as one of Rolling Stone Magazine's "Top Singles". The single featured many artists who donated their performances for the cause. All of the proceeds were been donated to victims of the Gulf Coast disasters.
A familiar face in the Los Angeles music scene, Mangione first polished her chops playing drums for such greats as saxophonist Buddy Collette and guitarist Robben Ford. An accomplished drummer by age 16, Mangione taught herself to play guitar, bass and piano while growing up in Los Angeles. She studied under legendary jazz teacher/drummer Kay Carlson before going on to graduate at a young age from Percussion Institute of Technology in Hollywood. She later taught at PIT and then hit the road.
Mangione frequently uses her music in her activism for social justice. In addition to "The Edge of Madness", the artist has used her music to raise awareness and funding for many different projects including Writers for the Storm, Music to Vote By, God Save the World, MusicHugs and more.
Most of her recordings are created primarily by Mangione in her home studio – from writing to arrangements, & production. In addition to most of the acoustic and electric guitar work on the records, she plays drums, piano and percussion. "Financial constraints" translates to "get as creative as you can with what you have"
Michelle Mangione's music is available on her website and on iTunes, as well as other outlets that she probably doesn't know about, so please buy from this official site if you choose to purchase downloads:)
Michelle Mangione ©2010

redpajama_set_name: RedPajamaCommonCrawl


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Your side by side is a handy tool to have around, helping you run fence, check livestock, or getting you to your favorite hunting or fishing locations. With all the versatility that your machine offers you might find yourself longing for a helping hand when it comes to the organization of the cab and the bed of your UTV. Nothing is worse than trying to get to your destination and having tools bouncing around the bed of your machine, and not to mention the room some tools can take up leaving less room for others. Here at Side By Side Stuff we offer you a solution with the UTV Roll Bar Tool Mount by Hornet Outdoors, and with this tool mount you�ll be able to carry more tools and stay more organized.
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Robot Flick 'Chappie' Features Dev Patel, Hugh Jackman
Chappie features an all-star cast that includes Hugh Jackman and Slumdog Millionaire's Dev Patel.
The sci-fi adventure film from Columbia follows the ups and downs of the title character, an experimental humanoid robot who has the ability to think and feel. Kidnapped by criminals during "birth," he eventually finds a home when he is adopted by an eccentric and dysfunctional family. As a child he is impressionable when it comes to his surroundings. A gifted prodigy, Chappie is set apart from the crowd in more ways than one. This part human-part machine hybrid faces many struggles as he grows into manhood, but he promises to pave the way to changing the world's perception of robots and people forever.
Starring as Chappie is Sharlto Copley, who was last seen on the big screen in the hit fantasy Maleficent. Patel plays the young scientist responsible for the Artificial Inteligence breakthrough. Jackman is cast against type as a hostile anti-A.I. emissary intent on destroying Chappie. The cast also includes Sigourney Weaver, Brandon Auret (Elysium) and Robert Hobbs (Mandela: Long Walk to Freedom).
The film was written and directed by Neill Blomkamp, best known for writing and directing the high-profile sci-fi features District 9 and Elysium. Blomkamp collaborated on the screenplay with writing partner and wife Terri Tatchell.
Chappie will be released in theaters nationwide on March 6, 2015.
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Sonam Kapoor and Anand Ahuja wedding: Arjun Kapoor's fun video from preparations
Amidst Sonam Kapoor and Anand Ahuja's wedding preparations, cousins, Arjun Kapoor and Anshula gather to celebrate it. Sister Rhea Kapoor shares a video on her Instagram account
A still of Arjun Kapoor from the video shared by Rhea Kapoor on her Instagram story
After making it official that Sonam Kapoor and Anand Ahuja are getting hitched on May 8, the wedding preparations have been in full swing. On Wednesday, Sonam's sister and filmmaker Rhea Kapoor shared a video of cousins Arjun Kapoor and Anshula Kapoor visiting the bride-to-be.
The video showed behind-the-scenes from Sonam Kapoor's wedding preparations. Rhea shared the video on her Instagram account, wherein, Arjun Kapooris seen standing at the door with sister Anshula, assumingly all set to go home.
Rhea Kapoor's voice echoes, addressing Arjun Kapoor as 'Chaach'. She asks, "What are you saying, Chaach?" To which he replies, "It's like I am watching Veere Di Wedding live. The reality… Like aur kitne tareefan chahiye tainu? Sonu, you are not even listening, you not interested."
Later, Sonam replies, "No, no… I am just figuring something out."
On Tuesday, both Kapoors and Ahujas released a joint statement announcing the wedding date. It read, "The Kapoor & Ahuja families, take great joy and pride, in announcing the marriage of Sonam & Anand. The wedding will take place on the 8th of May in Mumbai. Since it is an intimate affair, we request you to respect the family's need for privacy. Thank you for all your blessings and love, as we celebrate this special moment in our lives."
With the year's big fat Punjabi wedding of Sonam Kapoor and Anand Ahuja, there is much excitement within the industry folks. The who's who from the glamour world will be gracing the special occasion on May 8.
Also Read: Sonam Kapoor-Anand Ahuja's Wedding Invite Is Out; More Details Inside
Posted by entertainment	No Responses » Tagged with: Anand Ahuja, Arjun Kapoor, Rhea Kapoor, Sonam Kapoor
Sonam Kapoor denies rumours of a catfight
Actress Sonam Kapoor is livid over gossip around an alleged 'cat fight' on the sets of her film 'Veere Di Wedding', which features an ensemble of actresses including Kareena Kapoor Khan, Swara Bhasker and Shikha Talsania. Sonam's reaction came following a 'blind item' posted by an entertainment portal.
In a Twitter post, Sonam wrote: "Dear websites, you can put out as many 'blind items' (aka gossip you were too lazy to fact-check) as you like pitting women against each other. It may get you clicks but it won't be the truth. Must you insist on shoving this tired patriarchal concept of women cat fighting into our film (which is not about a road trip) as if grown, intelligent women have nothing better to do.
"We will continue to be actual friends and try and make a kick-ass movie and prove that women can work with each other, get along and have a blast. Because we can, we are and we will continue to. And on schedule. Please keep in mind how outdated, irresponsible, and harmful your narrative is and frustrating for a culture of women who actually want to work together. There is no place for it anymore. Sincerely, The cast and crew of 'Veere Di Wedding'."
Produced by Rhea Kapoor and Ekta Kapoor, the film's first schedule was wrapped in Delhi. It is directed by Shashanka Ghosh. Sonam and Rhea's father and veteran actor Anil Kapoor also shot down the gossip item. "Veeres stand together, through 'blind stories', false accusations and smear campaigns. That's true friendship."
Posted by entertainment	No Responses » Tagged with: Actress Sonam Kapoor, Kareena Kapoor Khan, Rhea Kapoor, Shikha Talsania
Kareena Kapoor Khan finally speaks on Taimur being a part of 'Veere Di Wedding'
Kareena Kapoor Khan with son Taimur
Kareena Kapoor Khan has put speculation to rest about Taimur being part of Veere Di Wedding. In a video shared by the film's Instagram handle yesterday, the actor says, "No, but his mother is in the film.
I think that's enough na? It's either me or him. Rhea (Kapoor, producer) can't afford both." The video also has Rhea say, "It's out of my budget." As the nine-month-old accompanies Bebo on the set, there was talk of him doing a cameo.
Watch video: Sussanne Khan slams Kangana Ranaut, calls her allegations 'evil'
Download the new mid-day android app to get updates on all the latest and trending stories on the go https://goo.gl/8Xlcvr
Posted by entertainment	No Responses » Tagged with: Kareena Kapoor Khan, Rhea Kapoor, Sussanne Khan, Veere Di Wedding
Rhea Kapoor to style uncle Sanjay Kapoor for a television show
Sanjay Kapoor and Rhea Kapoor
Sanjay Kapoor, who is back on the small screen after over a decade, has niece Rhea Kapoor styling him. The actor plays a widower attracted to a young girl in the upcoming show Ishq Gunaah. Rhea also styles sister Sonam Kapoor, so expect some fancy threads.
Watch video: Riya Sen's shocking controversies: MMS scandal to smooching a girl
Posted by entertainment	No Responses » Tagged with: Ishq Gunaah, Rhea Kapoor, Riya Sen, Sanjay Kapoor
Arjun Kapoor's sister Anshula looks unrecognisable in this childhood photo
Arjun Kapoor, who is very active on social media, always treats his fans with throwback photos of him with his family and cousins, including actress Sonam Kapoor.
And, all the pictures gives an idea that how close these two are.
Today, the 'Mubarakan' star shared an endearing throwback photo f the duo on Instagram.
In the picture, all the cousins are posing for the camera. Sonam is all smiles while Arjun looks on innocently.
The photo also includes Rhea Kapoor, Anshula Kapoor, Harshvardhan Kapoor, Shanaya Kapoor.
On the work front, Sonam will be seen next in 'Veere Di Wedding'. Helmed by Shashanka Ghosh, the chick flick also stars Kareena Kapoor Khan, Swara Bhaskar and Shikha Talsania.
On the other hand, Arjun was last seen in 'Mubarakan' alongside Anil Kapoor, Ileana D'Cruz and Athiya Shetty. The movie performed well at the box office.
Watch video: Mandana Karimi hides her private parts with Snapchat filter
Posted by entertainment	No Responses » Tagged with: Athiya Shetty, Harshvardhan Kapoor, Rhea Kapoor, Sonam Kapoor
Anil Kapoors daughter to launch online chat show
Anil Kapoor's younger daughter Rhea Kapoor, who has always been involved with film production, has decided to launch a new celebrity chat show titled 'On the Bench'. Hosted by Cyrus Sahukar, the show will be aired on the internet and Youtube unlike Simi Garewal's Rendezvous and Karan Johar's Koffee With Karan which were aired on television.
The show promises to be sarcastic and on the face but all in good humour. However, as per the format of the show, the celebrities will be sitting on a wooden bench which will be carried by the unit to different locations for the interview. We also hear that two episodes of the show have already been shot with Anil Kapoor and Farah Khan as the guests. Sonam is also supposed to be one of the guests on the show.
Posted by BollywoodHungama.com News	No Responses » Tagged with: Anil Kapoor, Anil Kapoors, Cyrus Sahukar, Rhea Kapoor


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Dr. Ekaterina Bessmeltseva - Huntington Beach School of Music
D.M.A. (Doctor of Musical Arts in Piano Performance) from University of Nevada, Las Vegas
Performing at Weill Recital Hall at Carnegie Hall in New York
Piano instructor at University of Nevada, Las Vegas
Ekaterina Bessmeltseva is a concert pianist whose performances span North America,
Europe and Russia. Dr. Bessmeltseva has appeared as a soloist and a chamber player at Weill
Recital Hall at Carnegie Hall (New York, 2013 and 2014), Elebash Concert Hall (New York,
2009), Artemus W. Ham Concert Hall ( Las Vegas, 2016), Los Angeles Valley College ( Los
Angeles, 2018), Rimsky-Korsakov Museum ( St. Petersburg, Russia, 2003).
Dr. Bessmeltseva strives constantly to expand her artistic boundaries by performing
unusual and non-standard repertoire. She has an affinity for the music of women composers such
as Mel Bonis, Amy Beach, Amanda Maier, Louise Forrenck, Nadia Boulanger, Clara Schumann
augmenting her repertoire beyond that of the standard literature.
Furthermore, Ekaterina is also active performer of contemporary classical music. She
collaborated with composer David del Tredici (City University of New York) performing his
solo piano work Aeolian Ballade, as well as with composer Prof. Beth Mehocic ( University of
Nevada, Las Vegas) performing her Piano concerto.
Dr. Bessmeltseva has appeared as a soloist with Las Vegas Symphony Orchestra
( 2016 ) and the Neue World Orchestra (2018).
As an educator Ekaterina Bessmeltseva was invited as an adjudication for Nevada Music
Ed Junior Festival and Roger Bushell Competition. In 2016 and 2017 she was a piano instructor
at University of Nevada, Las Vegas.
Currently, residing in Los Angeles area Ekaterina performs regularly as a soloist and a
chamber player. She holds a large private piano studio at South Bay area.
Years Teaching: 11 years teaching
Message To You: ekaterinabessmeltseva.com
https://www.youtube.com/watch?v=S8kpHHwPY5Y
https://www.youtube.com/watch?v=A_LYb_25S80


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Sheikh Zayed Desert Learning Centre
The Sheikh Zayed Desert Learning Centre (SZDLC) is an integral part of the development of the vast Al Ain Wildlife Park & Resort. The overall project involves the redevelopment of the 40-year old Al Ain Zoo to include a wildlife themed safari, destination resort, retail and residential communities. The Desert Learning Centre is a tribute to the late Sheikh Zayed and is an exploration of the natural and cultural history of the Arabian deserts, as well as deserts worldwide.
The SZDLC is both a museum and a science centre containing interactive displays about the UAE's wildlife and culture. Visitors fly over the Arabian Desert, travel back in time to witness different geological eras, understand the values that drove Sheikh Zayed's conservation principles, experience traditional Bedu life, and measure the impact of their ecological footprints on the fragile ecosystem.
The SZDLC is one of the pilot projects of the UAE's new Estidama environmental design standard and is the first building to achieve a Five Pearl rating at the design phase. The exhibit lighting is designed to meet the new standard and reduce over-all heat loading, energy consumption and maintenance requirements. The design goals were achieved in the exhibit galleries with a combination of daylighting and LSI SPT4-39 and MHLN303 Series ceramic metal halide track-mounted luminaires.
Architect: Chalabi Architects and Partners, Vienna
Exhibit Lighting Design: Eos Lightmedia
Interpretive Planning & Exhibit Design: Aldrich Pears Associates, Vancouver
Exhibit Fabricator: Beck Interiors, London
Lighting Supply & Installation: SI Electric, London
Surface Track (120/250V)
EOS Lightmedia


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Home/NY Islanders News
NY Islanders Hudson Fasching proving to be a "real-deal" NHLer
Florida Panthers v New York Islanders / Bruce Bennett/GettyImages
When the NY Islanders signed Hudson Fasching this summer to a one-year, $750K contract, no one believed it to be anything more than a depth move. Fasching is on his fourth NHL team in his seven-year professional career. He started with the Los Angeles Kings who drafted him in the fourth round of the 2013 NHL draft, however, never dressed for an NHL game until he was with the Buffalo Sabres in the 2015-16 season. In the previous two seasons, Fasching was part of the Arizona Coyotes organization and now, the Islanders have given him a chance to showcase his talents and he's run away with the opportunity.
In his seven-year AHL career, Fasching never lit the league up in terms of scoring. He's a multi-30-plus point collector with a career-best 37 points (14 goals, 23 assists) last season with the Tuscon Roadrunners. At the NHL level, he won't be much of a point collector, either, but he's proven he can net the occasional point while providing plenty of other elements necessary in a bottom-six role.
The Islanders recalled Fasching with a number of injuries piling up for the varsity squad. Cal Clutterbuck and Kyle Palmieri remain missing from the forward group, and Simon Holmstrom is the latest to go down with an injury. Fasching has mostly replaced Clutterbuck in his checking role on the fourth line and has fit in like a glove. Fasching has brought that fourth-line energy we all know and love from the MC^2 line, making things hard for his opponent in the Islanders zone, skating the puck away from danger, and being unafraid to throw his body around when necessary. His most physical game came against the Vegas Golden Knights when he totaled five hits.
It wasn't long before Fasching found the back of the net, too. In his second game with the Islanders, Fasching scored the Isles third goal of the game in what appeared to be the start of a comeback against the St. Louis Blues who had fouund the back of the net five times in two-plus periods. It wasn't enough to help the Islanders mount a comeback, but it was a goal in a moment when the Islanders really needed one. His second goal, however, was a pretty one. In that same game where he threw five hits against the Golden Knights, Fasching scored an aggressive, highlight worthy goal to give the Islanders a 2-1 lead in the second period en route to a 5-2 Isles victory.
Just give it to Fasching and let him do the work😤
Isles lead 2-1 pic.twitter.com/YQZOW8JKaq
— Isles on MSGSN (@IslesMSGN) December 18, 2022
In Tuesday night's contest against the Pittsburgh Penguins, the injury bug bit again as the Islanders lost Oliver Wahlstrom early in the first period. Lane Lambert mixed and matched his lines while short a man and Fasching found his way to Mathew Barzal's wing. It was another moment where Fasching made the most of his opportunity, winning a puck battle below the blue line, feeding the puck to the slot for a high-danger scoring chance, and Barzal finding it and cashing in to give the Islanders a 2-1 lead. The Isles went on to win 5-1.
Fasching said: "It was fun. Obviously the first shift, we score within the first 30 seconds. It was a lot of fun. (Bailey and Barzal) are really creative players, Barzy is a special player. It was fun to try and figure out how to play with him and find those spaces. It's definitely a bit of a different game playing with that line, but I take fun in that challenge."
If you didn't think this would go the analytics route, think again. Fasching's short sample is proving to be a productive one. He's accruing positive scoring chances and helping create high-danger ones to boot. He's totaled a 54.07 CF%, 51.11xGF%, 54.76 HDCF%, and 71.43 HDGF% in 100:51 of time on ice according to NaturalStatTrick. In the Islanders' last nine games, Fasching is a top-10 player on the Isles in all categories.
Fasching has certainly helped light a spark in the Islanders lineup who have now won back-to-back 5-1 games over the Panthers and the Penguins. He's continued to show up and put in the work to remain in the lineup and provide an impact. He hasn't stuck in the NHL quite yet, but he's making a case for himself in the Islanders lineup and Lambert has certainly taken notice.
"He's done a good job over time. I've only known him for a short period of time. Tremendous person first and foremost. When you have that going for you, your ability to come through certain adversities and continue to push forward shows itself. He's done a really good job for us playing whatever position or whatever role we've asked of him at this point."


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10-year-old Jordyn simply thought she wasn't feeling well. She had a fever that lasted for six days before she began experiencing severe pain on her right side. They took her to the doctor and ran a battery of tests. Appendicitis was ruled out. Many of the tests were extremely invasive, but she endured them all. Her family had to travel a couple of hours to Oakland, CA to a kidney specialist who confirmed that Jordyn was born with an extra ureter and her right kidney was only functioning about 80%. Her family decided that surgery was necessary. The plan was to remove the extra ureter and reconnect it, but when the surgeon observed that the procedure would be more complicated because the extra ureter was so swollen. Five hours later, her surgery was complete and she woke up with more bandages than anticipated. Initially, she was supposed to have a catheter in for 6 weeks but to everyone's surprise, she was up walking after the first day and they were even able to remove it completely. The medical team was shocked because she had just undergone major surgery! Jordyn comes from a very supportive family, and loves Wizards of Waverly, Taylor Swift, and Hannah Montana. She has a smile that will light up any room and a positive attitude that is contagious!


These new view are now centered on your exact location.
The base imagery and radar overlays are high-resolution.
These views have been incredible popular in their simplicity and the value of the visual information they provide.
You can view Satellite imagery and radar (where available) by clicking Local Radar / Imagery… from the View Menu.
On larger screens if you make the default Swackett window taller a mini- Satellite strip will pop out and always be visible. Click on that to view multiple imagery views.
High-resolution satellite and radar imagery was refined and improved for greater Florida, including Tampa, Jacksonville and Orlando.
These new radars are now available in all Swackett apps.
High-resolution satellite and radar imagery was refined and improved for San Francisco Bay Area, Milwaukee, Wisconsin and Dallas, Texas.
Select Swackett apps are experiencing "stuck" local radar imagery in different parts of the country.
If your local radar does not present as an animated radar image for your location — or you see a gray placeholder page — please let by know by submitting a tech support ticket. We are able to work with you to flush the page and get your local radar running again.
We're sorry for an inconvenience caused by this issue — and we appreciate your patience.


Facebook has been doing a lot of work to improve its mobile experiences, most notably the release of a faster, rebuilt native Facebook for iOS app in August and the more-recently promised timed release cycles for its mobile apps.
Facebook has historically had a small, nimble engineering team with separate groups dedicated to desktop and mobile experiences. In fact, the first core iOS app was originally built and maintained by one person, and later developed by a single small team…Within the last year, our engineering teams have taken ownership of their product experiences across both desktop and our mobile apps. These teams know their product, features, and users better than anyone and are sensitive to the nuances of developing and adapting these experiences across multiple platforms.
Not every feature from the standalone apps makes sense for the core app, so as the Facebook for iOS PM, one of my jobs is to make sure that the features we share across apps result in the best user experience. So while the swipe gesture to reveal the camera roll works really well within the Camera app – we chose not to include this in the core app because the gesture doesn't make sense with our persistent top navigation bar. To make it into the core app, a feature has to add significant value to the integrated experience, regardless of how critical it is in one of our standalone apps.
The core app is not just composed of features from standalone apps – there are many teams that own key portions of the core app and continue to iterate on them. Timeline, Groups and Events are sections that are completely owned and maintained by their respective teams.
As we continue to develop Facebook across platforms, we will continue to use our standalone apps to push the limits of each product and leverage new, battle-tested features to create the best possible core app experiences on every platform.
Apple updated its iTunes Connect Mobile app today that allows developers to keep an eye on their app sales stats and related data from iTunes Connect. Among the new features are "enhanced product detail views for your entire catalog," the ability to view app ratings and reviews from customers, a new advanced search feature, and user-interface refinements on the iPad. Developers will also now be able to reject apps submitted for review and release approved updates from within the app. The updated iTunes Connect Mobile app is available on the App Store now.
Apple changes its rules in Taiwan to allow users 7 days to test an app?
We haven't gotten official word on this but the Economic Times of India is reporting that Apple changed its return policy on Apps from minutes to 7 days. We reported earlier this month that Taiwan gave both Apple and Google two weeks to comply withits consumer protection mandate.
An official said the lack of a return and refund mechanism violated the Consumer Protection Act. In an example of the problem the city government is trying to prevent, Yeh cited a case of software bought on Apple Store on Thursday that did not work, but left the buyer without recourse.


Since 1952, J.F. Kiely Construction Co., of Long Branch, New Jersey, has built a successful utility installation business by focusing on safety, reliability, and efficiency. While keeping focused on that three-pillared formula, Kiely willingly embraces new technologies that provide a competitive edge.For example, in 1986 J.F. Kiely got a head start on the competition when it became the first excavation contractor in New Jersey to perform directional drilling for the utility industry, safely and efficiently applying the new technology for installing gas lines, water lines, and electrical conduit.
More recently, the company's early adoption of ground-penetrating radar (GPR) systems helped J.F. Kiely stay one step ahead of the crowd while addressing all three of its operational strategies. "We're always open to new technology, as long as it improves our safety, reliability, and efficiency. Ground-penetrating radar addresses all three of those objectives—it's an excellent tool to have in your toolbox," says John M. Kiely, president and third generation of Kiely family leadership.
"Our company is committed to improvement," he adds. "The idea of ground-penetrating radar made a lot of sense when it was first introduced, and it's gotten better with each succeeding generation of equipment.
J.F. Kiely Construction Co. was an early adopter of ground-penetrating radar (GPR) systems. It currently uses four GPR systems from US Radar, including this 500 Series model, designed for locating utilities up to 15 feet below the surface.
The company dispatches any of its four dual-frequency US Radar units to jobsites before the work begins. The cart-based, walk-behind systems employ radar frequencies that discover buried infrastructure components, construction remnants, and various sub-surface anomalies to enhance the safety, reliability, and efficiency of new excavations and installation of new utility network components. Each unit incorporates a portable computer that analyzes the radar signals and displays the results on a screen, easily visible to the GPR unit operator.
"GPR is a value-added service," Kiely explains. "It's not required on every job, but we rely on it to address challenging circumstances." The benefits are numerous. "With GPR, we get a better idea of the unknown," Kiely says. "The more we know about what's underground, the better. It goes back to our focus on safety, reliability, and efficiency. One of the biggest benefits in using GPR is finding unmarked lines, and giving that information to the crew to help prevent damage. It's a damage-reduction and avoidance technology." The company's GPR operators are specialists who not only understand the technology and know how to use it, but also have interpretive skills in analyzing the results.
J.F. Kiely Construction serves utility companies throughout New Jersey and eastern Pennsylvania. The company employs union workers and operates from four full-service shop locations throughout New Jersey. Its fleet encompasses mobile equipment, covering every category of equipment required for utility excavation and installation.
A self-described turnkey provider of underground utility services, J.F. Kiely Construction specializes in the installation of underground utilities, including natural gas, water, telecommunications, electric, and sewer. In addition to excavation, installation, and restoration of underground utilities, the company also offers pressure testing, welding, plastic fusion, and high-pressure tapping and stopping services.
In 2013, J.F. Kiely Construction provided 12,412 hours of training to its workforce. Those hours included courses in more than 15 categories, such as general safety, operator qualification, trench and excavation (competent person) training, hazardous materials operations, fire extinguisher, natural gas emergency response, forklift safety, work zone safety, confined space operations, and pipeline facility locating.
A continued strategic reliance on cutting-edge technologies—such as US Radar sub-surface imaging systems—will remain key to J.F. Kiely's future growth and success.


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A Soldiers View on the Bombing of Cassino Monastery
In battles spanning the months from late 1943 to May 1944, Italian locals and British, Polish, American and German servicemen witnessed the effects of steady attrition on the town of Cassino and the razing to the ground of one of the great centres of the Christian world.
Douglas Lyne, age 20, was a gunner in the Royal Artillery, acting as Observation Post Assistant in the 57th Field Regiment, part of X Corps. To him the destruction of the Cassino Monastery had a special significance, his ancestor Father Ignatius of Llanthony having founded a Benedictine monastery in Wales based on this very edifice.
Douglas Lyne, one of many cheering the fall of the monastery but who would later work for reconciliation and restoration.
Suffice it to say that by the end of January, beginning of February, no real progress had been made towards the capture of Cassino Monastery, without which it was impossible to proceed along the road to Rome. It was about this time that my own regiment of artillery was posted into the line there, in support of the 201st Guards Brigade. Monte Cassino was on the height of about 1,500 feet and we had to climb up to an observation post at about 2,500 feet. From there we could see across the valley, whenever weather permitted, this shining monument of Cassino Monastery, which, I must say, did look in a way menacing and odd, in so far as it was the only un-destroyed object in a vast waste of destruction. It was rather like seeing Buckingham Palace in the middle of Passchendaele. On 15 February we'd been up there about a week and were feeling absolutely miserable, it was terrible weather. In the occasional breaks in the clouds we saw this monastery all the time, and it got on our nerves, to be quite frank. It became, from being a thing of beauty, a thing of monstrosity, an excrescence, and somehow it was the thing which was holding up all our lives and keeping us away from home. It became identified in an obsessional way with all the things we detested. Remember, I had been about two years in almost continuous action, and action is barbarising and our sensibilities were blunted. Suddenly out of the mist of the south, on this really rather nice morning, just after breakfast at about 9.30 hours, appeared this vast armada a huge bomber force, mainly Flying Fortresses, some 250 of them.
Polish gunners prime shells during an attack on Monte Cassino.
We were wondering where on earth this vast armada was going, when all of a sudden, the bombs started dropping out of these things, and came bashing down on the jolly old mother of monasteries of St Benedict, about ten miles away over the valley. I must confess it was a gigantically stimulating sight, to suddenly see this sort of Barnum and Bailey's kind of Brock's benefit, it must have been comparable to seeing the early Christians being eaten by lions in the Coliseum, I suppose. We all started cheering wildly and hugging each other. We went mad and everybody thought it was the greatest thing since the eruption over Pompeii. But there was, with me, a remarkable Welshman called Tom Roberts, who'd been my constant guide, philosopher and friend since the earliest days when we went around the Cape of Good Hope to get to Suez. He was a man of great spiritual merit who knew all about my connection with Father Ignatius of Llanthony. After I'd stopped trembling and the laughter and hysterical gaiety faded, he sat me down at one side and said, 'Steady on Doug, I mean, it's all very well, but are we really in this war for the business of bombing monasteries. What would old Father Ignatius think of that?' Suddenly, I had a sort of complete bloody double-take. I thought, 'What the hell are we doing, up on this bloody hill and surrounded by destruction and mayhem, and everything gone to pot? What are we fighting for or against? Here we are, cheering the destruction of one of the great monuments of Christendom. One's mood changed from exultation to a peculiar sort of horror and self questioning, which was very disturbing ...
Sergeant Herbert Parkin with the 2nd Battalion of the London Irish Rifles was based at a holding position high on a mountainside, facing Cassino. His company depended totally on mule trains getting through for all their supplies. Herbert Parkin of the London Irish Rifles was involved in the Cassino struggle from the early days.
We landed at Taranto naval base towards the end of 1943 and we reformed just outside Taranto to move forwards through Italy. The terrain wasn't easy, it was all valleys and ridges and you couldn't advance too fast in case that you had no back-up. We came out of the line at a place called Inferno Valley, which was a mule point. Inferno Valley was the start line and from there we got into position on a mountain facing Cassino. We were well within firing distance of the enemy. The Germans were up in the monastery with a bird's eye view of everything. You couldn't move without them seeing you.
Mules carry all-important food and ammunition to the troops holding positions on the hill, as a means of supply it left a lot to be desired.
The Royal Engineers used to put up smoke screens from the valley pots and pots of smoke, but you could only blind the Germans for so long before the wind carried the smoke away. The Germans would let the ambulances through, but everything else was shelled. They used the old moaners, we called them 'Moaning Minnie's' which were six-barrelled mortars. There were six at a time and they moaned like anything. The Germans were pretty accurate with them, and they did a lot of damage. Our mortars were with different companies at the time. I was therefore acting as infantry on the forward slope, in case the Germans came through. Although the Germans were in the monastery, they were right the way around as well, dug in. You had no idea where they were. It was worst at night because, of course, you couldn't see anything in the dark. You had to listen and try and make out what the noise was. You couldn't start firing, though, because you didn't know if you were going to hit one of your own patrols. Everything came up to us by mules, our water, rations, first-aid everything. We could see the mules clearly from where we were, coming along the valley. If they got shelled or started misbehaving, they would dance about and sling their loads off their backs. It was uncomfortable on the mountain, but we always got our meals. Our cooks were very good. They would send hot food up to us in boxes and looked after us very well.
It may not be haute cuisine, but the chef of the Royal West Kent Regiment makes the best of facilities in a quarry on Monastery Hill.
We couldn't dig in to the soil because it was too stony and scrubby. We built sangars instead from the loose rocks. Although the ground was uncomfortable, you managed to sleep. You had a blanket and a ground sheet and you just put your haversack down and pulled your blanket over you and your tin hat over your head, and tried to get down. When the Poles came to take over from us, we picked up the rest of the battalion and marched across to Inferno Valley where we had a mug of tea and formed up to move back behind the lines.


The inflation rate in Poland between 2010 and today has been 14.34%, which translates into a total increase of zł14.34. This means that 100 zloty in 2010 are equivalent to 114.34 zloty in 2019. In other words, the purchasing power of zł100 in 2010 equals zł114.34 today. The average annual inflation rate has been 1.35%.


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Exclusive: FOX to "Sit Down" in Late Night This Fall
LOS ANGELES (thefutoncritic.com) -- FOX is reviving its short-lived animated series "Sit Down, Shut Up" as part of its late night lineup this fall.
Network sources have confirmed new episodes of the series, which lasted just four weeks earlier this year, will air Saturday nights at midnight/11:00c starting September 12.
Leading into the half-hour will be repeats of the departing "Talkshow with Spike Feresten" at 11:00/10:00c. Newcomer "The Wanda Sykes Show" will take over said hour as previously announced on November 7.
FOX still has nine episodes of "Sit Down" yet to air.
· SIT DOWN, SHUT UP (FOX)


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By LifePosts
The Strange Case of the Underfed National Service Strategy
02/04/2009 04:03 pm ET Updated May 25, 2011
During the campaign, Barack Obama proposed tripling AmeriCorps, the full-time community service program, at a cost of roughly $3 billion. John McCain, though less specific, also supported a large expansion in national service.
That consensus had grown around national service before the economic crisis -- which has only strengthened the argument for it. Franklin Roosevelt discovered during the Great Depression that the Civilian Conservation Corps got people fixing the country, earning wages and restoring dignity -- faster and at a fraction of the cost of traditional infrastructure projects. As I've written earlier, national service should again be viewed as an essential part of an economic recovery plan, as it gets young people useful work, rapidly and inexpensively.
So, when the Obama and the Democrats put forth their $900 billion recovery plan,how much did he put toward national service? Did he raise it to say $6 billion to create 300,000 service jobs? No, he instead proposed just $200 million, enough for about 12,000 service opportunities. How is it possible that a time when the Democrats are spending more rapidly on domestic programs than any time in history that both the House and Senate bills offered such a small increase for national service?
What I'm hearing from people familiar with the legislative dynamic is that some of the key House titans, such as Rep. David Obey, the chairman of the House Appropriations Committee, weren't wild about national service. Obey is typical of many traditional liberals who have resisted national service over the years on matters of principle. Some opposed it because they want only union jobs at union wages. Some feel that the fairest way to help the poor is to write them a check, not have an AmeriCorps member organize Habitat projects.
Bill Clinton faced similar resistance from the left when he proposed national service in 1993. So he made it clear it was a high priority -- and liberals (some reluctantly) went along.
In this case, the Obama administration, faced with this lack of enthusiasm, didn't push it. Perhaps they didn't want to embrace something without a strong congressional constituency or they sensed a looming Republican attack. Or maybe the White House staff substantively prefers a different approach -- aid for "social entrepreneurship" or using better web technology to improve volunteerism, a sort of Points of Light 2.0.
Whatever the reason, just as Obama allowed for dubious spending ideas to creep into the bill by outsourcing key decisions to Congressional Democrats, he also allowed important ideas -- campaign promises -- to get squeezed out by that same deference.
I was right in the middle of writing a tirade on this point when I read that the Senate Republicans have attacked even this piddling amount as "paid volunteers working at the Corporation for National Service," according to CNN.com. Grrrr.
First, that makes it sound like these are volunteers working for a government agency. The money was to go to states that would then give it to local non-profit groups (Red Cross, Teach for America, Big Brothers etc) and to the corps member.
The implication of the phrase is that we're paying them to do things that volunteers would do for free. In fact, most of the national service members work full time, often helping non-profits recruit and manage occasional unpaid volunteers. That's why so many Republican governors have supported AmeriCorps.
The smart thing for the Republicans would have been to shift money from non-job-creating social spending to cost-effective national service opportunities -- daring Obama to object to something he himself had proposed during the campaign. Come to think of it, Senator McCain, since you support national service and think some of the stimulus is wasteful, how about you stick it to the man by proposing a shift of some money toward national service?
Since the election, Michelle Obama has identified expanding national service as a personal priority. I expect that the White House will eventually turn back to its more ambitious national service plans, perhaps by backing the "Serve America Act" recently introduced by Senators Orrin Hatch and Edward Kennedy. My fear is that by the time Congress gets to it, the money will be gone.
More from Steven Waldman here
Politics News Barack Obama Americorps Stimulus Package Service


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Q: Is it possible to require checkout in Alfresco? Is it possible to configure Alfresco to always require that a file be checked out before it can be updated?

A: Behaviours can do the trick. You definitely want to leverage  ContentServicePolicies.OnContentPropertyUpdatePolicy. You might need CheckOutCheckInServicePolicies.OnCheckIn as well.

redpajama_set_name: RedPajamaStackExchange


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We find two different categories here: Team Design and Case Study.
In Team Design the participants must build a real prototype following given specifications and limited materials provided to them. At the end, the prototype has to fulfill a set of characteristics and overcome several tests. The evaluation will take into account the originality, realism, functionality, materials used, their cost, etc.
A Case Study consists in solving theoretically a typical problem from a real company, be it on the technological aspect, logistical, environmental…Feasibility and the idea development will be valued, as well as originality and innovation. All the solutions from the different teams will be presented to a jury who will decide which team is the winner.
The competition is composed by three rounds (local, national, final), where the winners of each round will advance directly to the next stage.
They are celebrated in almost 90 Europeans universities and each of them is organized by the local group of the participant university.
The universities in which the local rounds take place gather forming National Groups (or Regional, in case there are not enough universities in one country and several of them have to group). The winners of the local rounds compete against each other in this stage.
EBEC Final is considered to be the biggest and most far-reaching project of BEST organization on European level, in which more than 6000 students start participating in the different local rounds, where they will have the chance to develop soft skills in the cultural field, communication, presentation, teamwork and practicing English, aside from creating ties with students from different countries and careers. A formation beyond what they have learned in the classroom through this unique opportunity.
Each year the Final is celebrated in one of the participant universities, having taken place in Ghent (2009), Cluj-Napoca (2010), Istanbul (2011), Zagreb (2012), Warsaw (2013), Riga (2014), Porto (2015), Belgrade (2016), Brno (2017). This year it will be located in Turin (Italy).
In this event, besides all the facilities needed to carry out this competition, the participants will enjoy several socio-cultural activities to further increase the experience provided.
Once again, Universidad Carlos III will be one of the 83 universities participating in the local rounds that form the base of the EBEC project pyramid. This way and by tenth consecutive year, students from all the degrees in Leganes campus will compete in one of the categories: Team Design or Case Study.
EBEC Madrid Carlos III will take place at Leganes campus (Superior Polytechnic School) in three days: one for team Design, one for Case Study and the last for the closing ceremony and the announcement of the winners.
The winning teams of both categories will pass to the second stage of the competition: EBEC Spain (national round) with all the expenses covered (transport, lodging, food…).


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Celebration of life: Toddlers 'graduate' from program at MetroHealth Medical Center
by: Roosevelt Leftwich
Posted: Oct 25, 2019 / 07:33 PM EDT / Updated: Oct 30, 2019 / 10:12 AM EDT
CLEVELAND — It's a graduation of sorts. But it's really a celebration of life.
For the past five years, infant mortality rates in Cleveland have been some of the highest in the state.
But, a two-year program to cut down those totals has turned into a partnership with nurses helping new parents like Sharita Taylor get their footing with their first child.
"The program helped me navigate through my first pregnancy and helped me overcome a lot — gives me a lot of knowledge about being a first time parent," Taylor said.
MetroHealth Medical Center, in conjunction with a grant from the Mt. Sinai Foundation, created the nurse family partnership.
It sends registered nurses into homes of expectant mothers to monitor their health and provide prenatal care and advice.
Once the baby is born, the nurses continue to follow up with mother and child. The approach is simple: Work to put the family in a position to succeed.
"We offer them education resources that are out in the community; we offer things like housing, just educating them on what it is to be the best parent possible, program coordinator Maria Cody said.
All of the children in the program are thriving. Many parents have been able to move their lives forward, as well.
Jeff Sigley says the nurse that's been helping his family is a great friend and she's taught all of them a lot.
"It's going to be tough; it's going to be hard. If you have people that are willing to give you help and listen to them you'll get through it and he has come a long way, farther than I thought, at this point," Sigley said.
The graduates are the first of more than 300 families who are being helped by the partnership. MetroHealth hopes to expand it, bringing in more families so that children — no matter where they start in life — get a chance to succeed.
41.49932-81.694361