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Our data expand the spectrum of mutations in the KRT5 gene underlying DDD.

Purpose The purpose of this study was to review the microbiological profile, in vitro antibiotic susceptibility and visual outcomes of paediatric microbial keratitis in Shanghai, China over the past 6 years. Methods Medical records of patients aged r16 years were reviewed, who were diagnosed as having bacterial keratitis between 1 January 2005 and 31 December 2010. Bacterial culture results and in vitro antibiotic susceptibility were analysed. A logistic regression analysis was conducted to evaluate the relationship between visual impairment and possible risk factors. Results Eighty consecutive cases of paediatric bacterial keratitis cases were included, among which 59 were identified as having positive culture. Staphylococcus epidermidis was the most commonly isolated organism (n ¼ 23; 39.0%), followed by Streptococcus pneumoniae (n ¼ 11; 18.6%) and Pseudomonas aeruginosa (n ¼ 6; 10.2%). Antibiotic sensitivities revealed that tested bacteria had low resistance rates to fluoroquinolones and aminoglycosides (8.3-18.4% and 12.5-24.4%, respectively). Multivariate logistic regression analysis proved that visual impairment was significantly associated with Gram-negative bacterial infection (odds ratio (OR) ¼ 7.626; P ¼ 0.043) and an increasing number of resistant antibiotics (OR ¼ 0.385; P ¼ 0.040). Conclusions S. epidermidis was the most common isolated organism in Shanghai paediatric keratitis. The fluoroquinolones and aminoglycosides remained good choices for treating these patients. Gram-negative bacterial infection and an increasing number of resistant antibiotics were associated with worse visual prognoses in paediatric keratitis.

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers. KeywordsCRISPR, Glioblastoma (GBM), Topoisomerase II poisons (TOP2: etoposide, doxorubicin), DNA damage and repair response, H2AX (gamma H2AX phosphorylation) FANCB, Protein Synthesis, Ribosomal proteins subunits: (RPS11, 16, and 18), APAF1, Pro-(BID, CASPASE3/7) and anti-apoptotic effectors (BCL2).

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A.AbstractThe standard approach in neuroscience research infers from the external stimulus (outside) to the brain (inside) through stimulus-evoked activity. Recently challenged by Buzsáki, he advocates the reverse; an inside-out approach inferring from the brain’s activity to the neural effects of the stimulus. If so, stimulus-evoked activity should be a hybrid of internal and external components. Providing direct evidence for this hybrid nature, we measured human intracranial stereo-electroencephalography (sEEG) to investigate how prestimulus variability, i.e., standard deviation, shapes poststimulus activity through trial-to-trial variability. We first observed greater poststimulus variability quenching in trials exhibiting high prestimulus variability. Next, we found that the relative effect of the stimulus was higher in the later (300-600ms) than the earlier (0-300ms) poststimulus period. These results were extended by our Deep Learning LSTM network models at the single trial level. The accuracy to classify single trials (prestimulus low/high) increased greatly when the models were trained and tested with real trials compared to trials that exclude the effects of the prestimulus-related ongoing dynamics (corrected trials). Lastly, we replicated our findings showing that trials with high prestimulus variability in theta and alpha bands exhibits faster reaction times. Together, our results support the inside-out approach by demonstrating that stimulus-related activity is a hybrid of two factors: 1) the effects of the external stimulus itself, and 2) the effects of the ongoing dynamics spilling over from the prestimulus period, with the second, i.e., the inside, dwarfing the influence of the first, i.e., the outside.B.Significance StatementOur findings signify a significant conceptual advance in the relationship between pre- and poststimulus dynamics in humans. These findings are important as they show that we miss an essential component - the impact of the ongoing dynamics - when restricting our analyses to the effects of the external stimulus alone. Consequently, these findings may be crucial to fully understand higher cognitive functions and their impairments, as can be seen in psychiatric illnesses. In addition, our Deep Learning LSTM models show a second conceptual advance: high classification accuracy of a single trial to its prestimulus state. Finally, our replicated results in an independent dataset and task showed that this relationship between pre- and poststimulus dynamics exists across tasks and is behaviorally relevant.

Skeletal muscle denervation eventually causes atrophy as a result of interrupted nerve conduction and the lack of nutritional factors. Myogenin is a myogenic regulatory factor that plays a key role in myoblast differentiation. Changes in myogenin expression in denervated rat skeletal muscle have been demonstrated, but myogenin expression in denervated human skeletal muscle has not been reported. Human muscle samples were analysed at different time-points post-denervation to evaluate changes in myogenin expression and their relationship with skeletal muscle atrophy. Post-denervation, myogenin mRNA levels peaked at 7 months and were 37.5 times the normal level. Expression levels then declined to 21 and 11 times the normal level at 12 and 26 months postdenervation, respectively. Prolonged denervation resulted in pathological changes characterized by decreased numbers of intact muscle fibres.

Background: Cisplatin (DDP)-based chemotherapy is the mainstay of first-line therapeutic strategy for the treatment of advanced non-small cell carcinoma (NSCLC). However, the anticancer efficacy of DDP is often limited by the existence or development of chemoresistance. Thus, we investigated the effect of interferon-γ on DDPresistant A549 cell. Methods: Semi-quantitative RT-PCR was used to compare the differences of SOCS3 mRNA expression in both cisplatin-resistant A549 (A549/DDP) cell and the parental A549 cell. The cellular sensitivity to cisplatin, cell viability and apoptosis were detected by MTT, flow cytometry and Western blotting. Results: Semi-quantitative RT-PCR and western blotting showed that SOCS 3 expression was significantly down-regulated in A549/DDP cell compared to the parental A549 and normal human bronchial epithelial cells BEAS-2B. IFN-γ treatment could restore SOCS3 expression, resulting in an increased sensitivity of these resistant A549 cells to DDP. In addition, p53 and Bcl-2 signaling pathways were also involved in regulating IFN-γ-induced cell death in DDP-resistant A549 cells. Conclusion: Our study indicates that SOCS 3 may play a crucial role in the progress of cisplatin resistance of A549. Moreover, IFN-γ could induce SOCS3 expression and potentiate the re-sensitization of these resistant A549 cells to DDP.