Balanced familial translocation t(5;19)(q12;p or q11) with phenotypical abnormalities in a girl.

Human diploid fibroblasts cultured in Dulbecco's Modified Eagle's medium (DME) were exposed to different concentrations of 15 antibiotics to determine the limiting toxic concentration. The number of cells surviving after antibiotic treatment was given as the index of toxicity. No visible chromosomal damage could be detected when half the maximal toxic concentration was applied. The maximum limiting concentration was found to be the same for both the preconfluent and postconfluent phases.     

Characterization of pharyngeal resistance during sleep in a spectrum of sleep-disordered breathing.

Aims of the study were 1) to compare Hudgel's hyperbolic with Rohrer's polynomial model in describing the pressure-flow relationship, 2) to use this pressure-flow relationship to describe these resistances and to evaluate the effects of sleep stages on pharyngeal resistances, and 3) to compare these resistances to the pressure-to-flow ratio (DeltaP/V). We studied 12 patients: three with upper airway resistance syndrome (UARS), four with obstructive sleep hypopnea syndrome (OSHS), three with obstructive sleep apnea syndrome (OSAS), and two with simple snoring (SS). Transpharyngeal pressures were calculated between choanae and epiglottis. Flow was measured by use of a pneumotachometer. The pressure-flow relationship was established by using nonlinear regression and was appreciated by the Pearson's square (r(2)). Mean resistance at peak pressure (Rmax) was calculated according to the hyperbolic model during stable respiration. In 78% of the cases, the value of r(2) was greater when the hyperbolic model was used. We demonstrated that Rmax was in excellent agreement with P/V. UARS patients exhibited higher awake mean Rmax than normal subjects and other subgroups and a larger increase from wakefulness to slow-wave sleep than subjects with OSAS, OSHS, and SS. Analysis of breath-by-breath changes in Rmax was also a sensitive method to detect episodes of high resistance during sleep.     

The Contractile and Control Sites of Natural Actomyosin

The various contractile and control sites of natural actomyosin gel were studied by comparing the kinetics of ATP hydrolysis with those of gel contraction, measured as an increase in turbidity. Contraction of actomyosin gel seems to require the cooperative reaction of ATP (with Mg) at two different sites. One of these sites catalyzes the hydrolysis of ATP and most probably contributes the driving force for contraction; the binding of ATP to the other site appears to break certain links that retard movement of the gel components. At limiting concentrations of ATP, the rate of contraction seems to depend on the rate of breaking these links as well as on the rate of ATP hydrolysis. But when both sites are saturated, the rate of contraction appears to be limited only by the rate of ATP hydrolysis. In addition to these two contractile sites, there are also two different control sites. At one, the relaxing site, the binding of ATP with Mg inhibits ATP hydrolysis and gel contraction. At the other, the binding of calcium activates contraction by overcoming the inhibitory action of Mg and ATP at the relaxing site. This control system—inhibition by substrate and disinhibition by calcium—can be selectively inactivated by heat and reactivated by dithiothreitol, a disulfide-reducing agent. These observations on the isolated contractile system are discussed in relation to the contraction and relaxation of muscle.     

Essential fatty acid deficiency lowers the activity of the acetylated low density lipoprotein receptor of rat peritoneal macrophages.

We compared phospholipid fatty acid composition, cholesterol ester accumulation, and receptor-mediated binding, internalization, and degradation of acetylated low-density lipoprotein (acetyl-LDL) in cultured peritoneal macrophages from rats fed an essential fatty acid deficient or control diet. The deficient diet increased the 5,8,11-eicosatrienoic acid and decreased the omega 6 fatty acid content of macrophage phospholipid relative to control. The deficient diet did not affect macrophage uptake of [1-14C]oleate; however, it lowered the accumulation of intracellular labelled cholesteroyl oleate to 66% of the control. This effect was attributed to a diminution of the specific binding of acetyl-LDL, and not to acetyl-LDL internalization nor to degradation. The results demonstrate the sensitivity of the acetyl-LDL receptor to changes in its membrane environment, brought about through dietary means.     

Computer modeling of deployment and mechanical expansion of neurovascular flow diverter in patient-specific intracranial aneurysms

Flow diverter (FD) is an emerging neurovascular device based on self-expandable braided stent for treating intracranial aneurysms. Variability in FD outcome has underscored a need for investigating the hemodynamic effect of fully deployed FD in patient-specific aneurysms. Image-based computational fluid dynamics, which can provide important hemodynamic insight, requires accurate representation of FD in deployed states. We developed a finite element analysis (FEA) based workflow for simulating mechanical deployment of FD in patient-specific aneurysms. We constructed FD models of interlaced wires emulating the Pipeline Embolization Device, using 3D finite beam elements to account for interactions between stent strands, and between the stent and other components. The FEA analysis encompasses all steps that affect the final deployed configuration including stent crimping, delivery and expansion. Besides the stent, modeling also includes key components of the FD delivery system such as microcatheter, pusher, and distal coil. Coordinated maneuver of these components allowed the workflow to mimic clinical operation of FD deployment and to explore clinical strategies. The workflow was applied to two patient-specific aneurysms. Parametric study indicated consistency of the deployment result against different friction conditions, but excessive intra-stent friction should be avoided. This study demonstrates for the first time mechanical modeling of braided FD stent deployment in cerebral vasculature to produce realistic deployed configuration, thus paving the way for accurate CFD analysis of flow diverters for reliable prediction and optimization of treatment outcome.     

NetCooperate: a network-based tool for inferring host-microbe and microbe-microbe cooperation

Background

Host-microbe and microbe-microbe interactions are often governed by the complex exchange of metabolites. Such interactions play a key role in determining the way pathogenic and commensal species impact their host and in the assembly of complex microbial communities. Recently, several studies have demonstrated how such interactions are reflected in the organization of the metabolic networks of the interacting species, and introduced various graph theory-based methods to predict host-microbe and microbe-microbe interactions directly from network topology. Using these methods, such studies have revealed evolutionary and ecological processes that shape species interactions and community assembly, highlighting the potential of this reverse-ecology research paradigm.

Results

NetCooperate is a web-based tool and a software package for determining host-microbe and microbe-microbe cooperative potential. It specifically calculates two previously developed and validated metrics for species interaction: the Biosynthetic Support Score which quantifies the ability of a host species to supply the nutritional requirements of a parasitic or a commensal species, and the Metabolic Complementarity Index which quantifies the complementarity of a pair of microbial organisms’ niches. NetCooperate takes as input a pair of metabolic networks, and returns the pairwise metrics as well as a list of potential syntrophic metabolic compounds.

Conclusions

The Biosynthetic Support Score and Metabolic Complementarity Index provide insight into host-microbe and microbe-microbe metabolic interactions. NetCooperate determines these interaction indices from metabolic network topology, and can be used for small- or large-scale analyses. NetCooperate is provided as both a web-based tool and an open-source Python module; both are freely available online at http://elbo.gs.washington.edu/software_netcooperate.html.     

Facilitating the Recruitment of Minority Ethnic People into Research: Qualitative Case Study of South Asians and Asthma

Background

There is international interest in enhancing recruitment of minority ethnic people into research, particularly in disease areas with substantial ethnic inequalities. A recent systematic review and meta-analysis found that UK South Asians are at three times increased risk of hospitalisation for asthma when compared to white Europeans. US asthma trials are far more likely to report enrolling minority ethnic people into studies than those conducted in Europe. We investigated approaches to bolster recruitment of South Asians into UK asthma studies through qualitative research with US and UK researchers, and UK community leaders.

Methods and Findings

Interviews were conducted with 36 researchers (19 UK and 17 US) from diverse disciplinary backgrounds and ten community leaders from a range of ethnic, religious, and linguistic backgrounds, followed by self-completion questionnaires. Interviews were digitally recorded, translated where necessary, and transcribed. The Framework approach was used for analysis. Barriers to ethnic minority participation revolved around five key themes: (i) researchers'' own attitudes, which ranged from empathy to antipathy to (in a minority of cases) misgivings about the scientific importance of the question under study; (ii) stereotypes and prejudices about the difficulties in engaging with minority ethnic populations; (iii) the logistical challenges posed by language, cultural differences, and research costs set against the need to demonstrate value for money; (iv) the unique contexts of the two countries; and (v) poorly developed understanding amongst some minority ethnic leaders of what research entails and aims to achieve. US researchers were considerably more positive than their UK counterparts about the importance and logistics of including ethnic minorities, which appeared to a large extent to reflect the longer-term impact of the National Institutes of Health''s requirement to include minority ethnic people.

Conclusions

Most researchers and community leaders view the broadening of participation in research as important and are reasonably optimistic about the feasibility of recruiting South Asians into asthma studies provided that the barriers can be overcome. Suggested strategies for improving recruitment in the UK included a considerably improved support structure to provide academics with essential contextual information (e.g., languages of particular importance and contact with local gatekeepers), and the need to ensure that care is taken to engage with the minority ethnic communities in ways that are both culturally appropriate and sustainable; ensuring reciprocal benefits was seen as one key way of avoiding gatekeeper fatigue. Although voluntary measures to encourage researchers may have some impact, greater impact might be achieved if UK funding bodies followed the lead of the US National Institutes of Health requiring recruitment of ethnic minorities. Such a move is, however, likely in the short- to medium-term, to prove unpopular with many UK academics because of the added “hassle” factor in engaging with more diverse populations than many have hitherto been accustomed to. Please see later in the article for the Editors'' Summary     

Design,synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH₂-imidazole or CH₂-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC?=?12.5?μg/mL, 17a 50?μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2?Å. A model generated from a 1.5?Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.