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Background and Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc., Patients/methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC 0-inf,norm )., Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC 0-inf,norm was significantly greater for N9-GP than rFIXFc (ratio: 4.39; P  <   0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound., Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc., Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).

Objectives: To evaluate the safety of outpatient induction with dinoprostone insert in low-risk labour inductions for premature rupture of membranes or postdates gestation., Methods: This retrospective cohort study compared outpatient labour induction priming with inpatient induction in terms of neonatal safety, mode of delivery, and obstetrical parameters. The sample included all inductions for premature rupture of membranes or postdate gestation. The analysis used logistic regression. The statistical power of the sample was 80% to detect a difference of 5.6% for the composite neonatal safety outcome (5-minute Apgar score <7 and NICU admission for >12 hours or transfer to a level III nursery)., Results: Compared with the inpatient cohort (n = 568), the outpatient cohort (n = 611) included more postdate gestations (93% vs. 67%) with less cervical dilatation (0.5 cm vs. 1.0 cm) and larger infants (3705 g vs. 3551 g). There were no differences in measures of neonatal safety or mode of delivery. The outpatient cohort required more dinoprostone inserts (1.59 vs. 1.23) and were less likely to deliver within 24 hours (OR 0.24, 95% CI 0.17 to 0.34) but were also less likely to deliver by CS (OR 0.71, 95% CI 0.54 to 0.95), after adjusting for obstetrical parameters., Conclusion: An outpatient model of labour induction using dinoprostone inserts is feasible and safe., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Compartmentalization is essential in the organization of biological systems, playing a fundamental role in modulating biochemical activity. An appreciation of the impact that biological compartments have on chemical reactions and an understanding of the physical and chemical phenomena that affect their assembly and function have inspired the development of synthetic compartments. Organic compartments assembled from amphiphilic molecules or derived from biological materials, have formed the basis of initial work in the field. However, inorganic and hybrid organic-inorganic compartments that capitalize on the optical and catalytic properties of metal and semiconductor materials are emerging. Methods for arraying these microcompartment and nanocompartment materials in higher order systems promise to enable the scaling and integration of these technologies for industrial and commercial applications., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Neural chips, which are capable of simultaneous multisite neural recording and stimulation, have been used to detect and modulate neural activity for almost thirty years. As neural interfaces, neural chips provide dynamic functional information for neural decoding and neural control. By improving sensitivity and spatial resolution, nano-scale electrodes may revolutionize neural detection and modulation at cellular and molecular levels as nano-neuron interfaces. We developed a carbon-nanofiber neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes and demonstrated its capability of both stimulating and monitoring electrophysiological signals from brain tissues in vitro and monitoring dynamic information of neuroplasticity. This novel nano-neuron interface may potentially serve as a precise, informative, biocompatible, and dual-mode neural interface for monitoring of both neuroelectrical and neurochemical activity at the single-cell level and even inside the cell., From the Clinical Editor: The authors demonstrate the utility of a neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes. The new device can be used to stimulate and/or monitor signals from brain tissue in vitro and for monitoring dynamic information of neuroplasticity both intracellularly and at the single cell level including neuroelectrical and neurochemical activities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A better understanding of how confinement, crowding and reduced dimensionality modulate reactivity and reaction dynamics will aid in the rational and systematic discovery of functionality in complex biological systems. Artificial microfabricated and nanofabricated structures have helped elucidate the effects of nanoscale spatial confinement and segregation on biological behavior, particularly when integrated with microfluidics, through precise control in both space and time of diffusible signals and binding interactions. Examples of nanostructured interfaces for synthetic biology include the development of cell-like compartments for encapsulating biochemical reactions, nanostructured environments for fundamental studies of diffusion, molecular transport and biochemical reaction kinetics, and regulation of biomolecular interactions as functions of microfabricated and nanofabricated topological constraints., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cells offer natural examples of highly efficient networks of nanomachines. Accordingly, both intracellular and intercellular communication mechanisms in nature are looked to as a source of inspiration and instruction for engineered nanocommunication. Harnessing biological functionality in this manner requires an interdisciplinary approach that integrates systems biology, synthetic biology, and nanofabrication. Here, we present a model system that exemplifies the synergism between these realms of research. We propose a synthetic gene network for operation in a nanofabricated cell mimic array that propagates a biomolecular signal over long distances using the phenomenon of stochastic resonance. Our system consists of a bacterial quorum sensing signal molecule, a bistable genetic switch triggered by this signal, and an array of nanofabricated cell mimic wells that contain the genetic system. An optimal level of noise in the system helps to propagate a time-varying AHL signal over long distances through the array of mimics. This noise level is determined both by the system volume and by the parameters of the genetic network. Our proposed genetically driven stochastic resonance system serves as a testbed for exploring the potential harnessing of gene expression noise to aid in the transmission of a time-varying molecular signal.

A key to advancing the understanding of molecular biology in the post-genomic age is the development of accurate predictive models for genetic regulation, protein interaction, metabolism, and other biochemical processes. To facilitate model development, simulation algorithms must provide an accurate representation of the system, while performing the simulation in a reasonable amount of time. Gillespie's stochastic simulation algorithm (SSA) accurately depicts spatially homogeneous models with small populations of chemical species and properly represents noise, but it is often abandoned when modeling larger systems because of its computational complexity. In this work, we examine the performance of different versions of the SSA when applied to several biochemical models. Through our analysis, we discover that transient changes in reaction execution frequencies, which are typical of biochemical models with gene induction and repression, can dramatically affect simulator performance. To account for these shifts, we propose a new algorithm called the sorting direct method that maintains a loosely sorted order of the reactions as the simulation executes. Our measurements show that the sorting direct method performs favorably when compared to other well-known exact stochastic simulation algorithms.

We present a frequency domain Langevin approach for stochastic analysis that remains valid for many important gene circuit elements even as molecular populations approach zero. We begin by considering the case of low-rate transcription and show that the previously reported shot noise representation is exact at all mRNA population levels for a constant transcription rate. Next, we consider transcriptional control through protein-DNA interactions at an operator site within the gene promoter region. This analysis results in expressions for the dynamics and noise behavior of this important gene sub-circuit, including the spectral density of the intrinsic operator noise and the processing of extrinsic noise by this transcriptional regulation system. This analysis shows that mRNA synthesis noise is composed of wideband shot noise and band-limited operator binding generated noise components. We find that the bandwidth of operator noise and its ultimate effect on total mRNA and protein noise is controlled by operator binding and unbinding dynamics. The most substantial impact of the operator noise is seen at transcription rates just above basal expression. This analysis captures the full behavior of this transcriptional regulation system, and points to potentially serious flaws in simplified mathematical relationships often used to model transcriptional regulation.

The maximal activity of the enzymes hexokinase and 6-phosphofructokinase were measured in interscapular brown adipose tissue during ageing in the rat. The activity of these glycolytic enzymes increased markedly during the suckling-weaning transition (20-22 days of age), but from 30 to 100 days of age the activities per gram wet weight and per mg protein decreased. The rate of lipogenesis in brown adipose tissue was also increased over the suckling-weaning transition and the contribution of glucose to this fatty acid synthesis was greater in weaned animals especially under the influence of insulin.

Serum angiotensin-converting enzyme (SACE) levels were measured in 44 subjects six weeks after acute pulmonary histoplasmosis. All patients were infected in a common-source outbreak of histoplasmosis which occurred on one day. All patients had both strictly defined clinical and serologic evidence of infection. The SACE activity was elevated at six weeks compared to normal controls, and seven of the 44 had levels more than 2 SD above the normal mean. SACE levels were also measured at three and 24 weeks after acute infection in a smaller number of the same subjects. Serial observations demonstrated that all subjects (including those with normal and elevated SACE at six weeks) had a rise and fall in SACE activity following symptomatic acute pulmonary histoplasmosis. Our findings suggest that elevated SACE does not reliably separate sarcoidosis from histoplasmosis, although elevations in histoplasmosis are much less common and may occur only briefly following acute pulmonary histoplasmosis. More important, it seems that SACE activity rises acutely in all patients with symptomatic acute histoplasmosis and then falls gradually toward baseline over several months, coinciding temporally with the granulomatous response.

We conducted a single-blind trial of gamma-vinyl-GABA (GVG) in nine patients: seven with tardive dyskinesia, one with Meige syndrome, and one with Tourette syndrome. Five tardive dyskinesia patients completed the entire 11-week study and, as a group, demonstrated significant decreases in dyskinesia scores. Four of these five tardive dyskinesia patients showed clinically evident improvement, with approximately 30% reduction in dyskinetic symptoms. Other patients had no clinical benefit from GVG. Three patients had transient exacerbation of psychiatric symptoms after sudden withdrawal of GVG, and one patient experienced dose-related confusional episodes. Our results suggest that GABAergic drugs may have a role in treating patients with tardive dyskinesia.