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This paper presents an all-optical time-extended optical code division multiplexing (TE-OCDM) system using two different optical en/decoders (E/Ds). The proposed system configuration alleviates the rigorous requirement for transmitter specifications in TE-OCDM systems. We numerically evaluate the use of PAM-4 with TE-OCDM for the first time by optimizing chip period to reduce inter-symbol interference (ISI). We utilize an analytical model and simulations to investigate the bit error rate (BER) in back-to-back scenario as a function of extinction ratio (ER) and total power contrast ratio (PCR). The fiber simulation with inline amplifications shows that 8 TE-OCDM PAM-4 signals at 12.5 Gbaud using 1274 nm could reach up to $8\times 30$ km. The total bit rate is equivalent to 200 Gbps (8 TE-OCDM users $\times 12.5$ Gbaud $\times 2$ bits/symbol) per wavelength. Further analysis of the scalability of TE-OCDM over the entire O-band through the optical E/D spectral periodicity, suggests that the feasible total bit rate that can be achieved is approximately 3 Tbps.

This paper explores, through the utilization of analytical models and simulations, the bit error rate (BER) of 400GBASE-LR8/ER8 in back-to-back configuration, considering various extinction ratio (ER) values and photodetector types. Simulation of transmission over fiber is carried out to measure chromatic dispersion (CD) penalty in each scenario. To increase the distance, we simulated a multi-span transmission with inline optical amplifiers (OAs). We mitigated the effects of CD-induced power fading by employing equalization such that the channel under test (CUT) at 1274 nm could reach $7\times 30$ km. The effects of fiber nonlinearity were also investigated for both single-channel and 3 wavelength division multiplexing (WDM) at various channel spacings. Moreover, the relationship between ER and peak-to-average-power ratio (PAPR) at different distances was investigated. An ER optimization for a highly accumulated CD multi-span fiber link with amplification was effective in improving the BER. Finally, we successfully transmitted a 26.56 GBaud 4-level pulse amplitude modulation (PAM-4) signal up to $8\times 30$ km with the optimal ER of 5 dB.

Abstract The management of wavelength routed optical mesh networks is complex with many potential light path routes and numerous physical layer impairments to transmission performance. This complexity can be reduced by applying the ideas of abstraction from computer science where different equipment is described in the same basic terms. The noise-to-signal ratio can be used as a metric to describe the quality of transmission performance of a signal propagated through a network element and accumulates additively through a sequence of such elements allowing the estimation of end-to-end performance. This study aims to explore the robustness of the noise-to-signal ratio metric in an installed fibre infrastructure. We show that the abstracted noise-to-signal ratio is independent of the observers and their location. We confirm that the abstracted noise-to-signal ratio can reasonably predict the performance of light-paths subsequently set in our network. Having a robust network element abstraction that can be incorporated into routeing engines allows the network management controller to make decisions on the most effective way to use the network resources in terms of the routeing and data coding format.

Abstract CYP3A5 is the primary CYP3A subfamily enzyme expressed in the human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between CYP3A5 expression and hypertension, however, most investigators have considered CYP3A5*1 as active and CYP3A5*3 as an inactive allele. Observations of gender specific differences in CYP3A5*3/*3 protein expression suggest additional complexity in gene regulation that may underpin an environmentally responsive role for CYP3A5 in renal function. Reconciliation of the molecular mechanism driving conditional restoration of functional CYP3A5*3 expression from alternatively spliced transcripts, and validation of a morpholino-based approach for selectively suppressing renal CYP3A5 expression, is the focus of this work. Morpholinos targeting a cryptic splice acceptor created by the CYP3A5*3 mutation in intron 3 rescued functional CYP3A5 expression in vitro, and salt-sensitive cellular mechanisms regulating splicing and conditional expression of CYP3A5*3 transcripts are reported. The potential for a G-quadruplex (G4) in intron 3 to mediate restored splicing to exon 4 in CYP3A5*3 transcripts was also investigated. Finally, a proximal tubule microphysiological system (PT-MPS) was used to evaluate the safety profile of morpholinos in proximal tubule epithelial cells, highlighting their potential as a therapeutic platform for the treatment of renal disease.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics.

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In order to develop new cancer therapeutics, rapid, reliable, and relevant biological models are required to screen and validate drug candidates for both efficacy and safety. In recent years, the zebrafish (Danio rerio) has emerged as an excellent model organism suited for these goals. Larval fish or immunocompromised adult fish are used to engraft human cancer cells and serve as a platform for screening potential drug candidates. With zebrafish sharing ~80% of disease-related orthologous genes with humans, they provide a low cost, high-throughput alternative to mouse xenografts that is relevant to human biology. In this review, we provide background on the methods and utility of zebrafish xenograft models in cancer research.

BACKGROUND: The aim of this study was to examine the value of various ultrasound and biochemical parameters for the prediction of successful expectant management of miscarriage. METHODS: This was a prospective observational study. Clinically stable women with an ultrasound diagnosis of miscarriage were offered expectant management. In all cases, gestational age, size of retained products of conception, serum HCG, progesterone, 17-hydroxyprogesterone, insulin growth factor-binding protein 1 (IGFBP-1), inhibin A and inhibin pro a-C RI levels were recorded. Follow-up continued until resolution of the pregnancy. Clinical data, ultrasound findings and biochemical markers were analysed using univariate analysis and decision tree analysis. RESULTS: Fify-four women underwent expectant management of miscarriage. Thirty-seven (69%) had successful expectant management and 17 (31%) required surgery. The size of retained products, serum HCG, progesterone, inhibin A and inhibin pro a-C RI were all significantly different in those pregnancies that resolved spontaneously (P<0.05). Serum inhibin A was the best predictor of a complete miscarriage. CONCLUSION: This study shows that novel biochemical markers may be used to predict the likelihood of successful expectant management of miscarriage. [ABSTRACT FROM AUTHOR]

In many patients with knee osteoarthritis (OA), the disease progresses, and there is loss of cartilage; in others, the disease stabilizes with time. Previous studies have demonstrated that concentrations of serum proteins that reflect joint tissue metabolism can identify knees that will deteriorate, leading to the suggestion that OA disease activity is phasic or cyclical. The aim of the current study was to determine whether longitudinal measurements of one such protein, serum cartilage oligomeric matrix protein (COMP), are related to disease outcome over a 5‐year period.Serum COMP levels were measured by enzyme‐linked immunosorbent assay at study entry and every 6 months thereafter in 115 patients with knee pain and OA of mainly the tibiofemoral joint. Cartilage loss was determined from knee radiographs taken at entry and at 24, 36, and 60 months. Disease progression was defined as either a reduction in the tibiofemoral joint space width by at least 2 mm or total knee replacement (TKR) in either knee at followup. COMP concentrations at baseline and the area under the curve (AUC) of measurements obtained over 5 years were compared between progressors and nonprogressors by Student's 2‐tailed t‐test. The patterns and probability of progression according to TKR or ≥2 mm of narrowing of the tibiofemoral joint space were analyzed by logistic regression models. The mean ± SD ages of the progressors and nonprogressors were 64.2 ± 7.8 years and 63.3 ± 10.6 years, respectively, and the proportion of females was 51% and 56%, respectively. Of the 37 patients whose OA progressed (22 by TKR and 15 by ≥2‐mm reduction in tibiofemoral joint space), 13 lost cartilage during the first 2 years, and 18 lost cartilage during the last 2 years. The mean ± SD serum COMP concentration at baseline was significantly higher in the progressors compared with the nonprogressors (14.12 ± 3.39 units/liter versus 12.62 ± 3.25 units/liter; P < 0.036). Serum COMP levels rose significantly after TKR; however, after allowing for the effect of TKR, the AUC/month was significantly higher in the progressors compared with the nonprogressors (12.52 ± 2.71 versus 10.82 ± 2.71; P < 0.003). Serum COMP concentrations were higher during periods of radiographic progression and identified periods of progression that were nonlinear. Logistic regression analysis showed that on average, a 1‐unit increase in serum COMP levels increased the probability of radiographic progression by 15%.The data suggest that serum COMP is related to progressive joint damage in knee OA. The patterns of progression for the early and late progressors are consistent with the hypothesis that knee OA progression is episodic or phasic. Large between‐subject variation precludes the use of individual values to predict progression with confidence. However, sequential measurements of serum COMP levels may identify patients whose OA is likely to progress over the next year or two. [ABSTRACT FROM AUTHOR]