Distinct requirements of wls, wnt9a, wnt5b and gpc4 in regulating chondrocyte maturation and timing of endochondral ossification

Formation of the mandible requires progressive morphologic change, proliferation, differentiation and organization of chondrocytes preceding osteogenesis. The Wnt signaling pathway is involved in regulating bone development and maintenance. Chondrocytes that are fated to become bone require Wnt to polarize and orientate appropriately to initiate the endochondral ossification program. Although the canonical Wnt signaling has been well studied in the context of bone development, the effects of non-canonical Wnt signaling in regulating the timing of cartilage maturation and subsequent bone formation in shaping ventral craniofacial structure is not fully understood.. Here we examined the role of the non-canonical Wnt signaling pathway (wls, gpc4, wnt5b and wnt9a) in regulating zebrafish Meckel's cartilage maturation to the onset of osteogenic differentiation. We found that disruption of wls resulted in a significant loss of craniofacial bone, whereas lack of gpc4, wnt5b and wnt9a resulted in severely delayed endochondral ossification. This study demonstrates the importance of the non-canonical Wnt pathway in regulating coordinated ventral cartilage morphogenesis and ossification

Avalanche-Induced Current Enhancement in Semiconducting Carbon Nanotubes

Semiconducting carbon nanotubes under high electric field stress (~10 V/um) display a striking, exponential current increase due to avalanche generation of free electrons and holes. Unlike in other materials, the avalanche process in such 1D quantum wires involves access to the third sub-band, is insensitive to temperature, but strongly dependent on diameter ~exp(-1/d^2). Comparison with a theoretical model yields a novel approach to obtain the inelastic optical phonon emission length, L_OP,ems ~ 15d nm. The combined results underscore the importance of multi-band transport in 1D molecular wires

Multi-Muscle FES Force Control of the Human Arm for Arbitrary Goals

We present a method for controlling a neuroprosthesis for a paralyzed human arm using functional electrical stimulation (FES) and characterize the errors of the controller. The subject has surgically implanted electrodes for stimulating muscles in her shoulder and arm. Using input/output data, a model mapping muscle stimulations to isometric endpoint forces measured at the subject’s hand was identified. We inverted the model of this redundant and coupled multiple-input multiple-output system by minimizing muscle activations and used this inverse for feedforward control. The magnitude of the total root mean square error over a grid in the volume of achievable isometric endpoint force targets was 11% of the total range of achievable forces. Major sources of error were random error due to trial-to-trial variability and model bias due to nonstationary system properties. Because the muscles working collectively are the actuators of the skeletal system, the quantification of errors in force control guides designs of motion controllers for multi-joint, multi-muscle FES systems that can achieve arbitrary goals

Accuracy of commercial geocoding: assessment and implications

BACKGROUND: Published studies of geocoding accuracy often focus on a single geographic area, address source or vendor, do not adjust accuracy measures for address characteristics, and do not examine effects of inaccuracy on exposure measures. We addressed these issues in a Women's Health Initiative ancillary study, the Environmental Epidemiology of Arrhythmogenesis in WHI. RESULTS: Addresses in 49 U.S. states (n = 3,615) with established coordinates were geocoded by four vendors (A-D). There were important differences among vendors in address match rate (98%; 82%; 81%; 30%), concordance between established and vendor-assigned census tracts (85%; 88%; 87%; 98%) and distance between established and vendor-assigned coordinates (mean ρ [meters]: 1809; 748; 704; 228). Mean ρ was lowest among street-matched, complete, zip-coded, unedited and urban addresses, and addresses with North American Datum of 1983 or World Geodetic System of 1984 coordinates. In mixed models restricted to vendors with minimally acceptable match rates (A-C) and adjusted for address characteristics, within-address correlation, and among-vendor heteroscedasticity of ρ, differences in mean ρ were small for street-type matches (280; 268; 275), i.e. likely to bias results relying on them about equally for most applications. In contrast, differences between centroid-type matches were substantial in some vendor contrasts, but not others (5497; 4303; 4210) p(interaction )< 10(-4), i.e. more likely to bias results differently in many applications. The adjusted odds of an address match was higher for vendor A versus C (odds ratio = 66, 95% confidence interval: 47, 93), but not B versus C (OR = 1.1, 95% CI: 0.9, 1.3). That of census tract concordance was no higher for vendor A versus C (OR = 1.0, 95% CI: 0.9, 1.2) or B versus C (OR = 1.1, 95% CI: 0.9, 1.3). Misclassification of a related exposure measure – distance to the nearest highway – increased with mean ρ and in the absence of confounding, non-differential misclassification of this distance biased its hypothetical association with coronary heart disease mortality toward the null. CONCLUSION: Geocoding error depends on measures used to evaluate it, address characteristics and vendor. Vendor selection presents a trade-off between potential for missing data and error in estimating spatially defined attributes. Informed selection is needed to control the trade-off and adjust analyses for its effects

An NgAgo tool for genome editing: did CRISPR/Cas9 just find a competitor?

AbstractWhile CRISPR/Cas9-mediated genome editing technology has been experiencing a rapid transformation during the past few years, a recent report on NgAgo-mediated single-stranded DNA-guided genome editing may offer an attractive alternative for genome manipulation. While it's too early to predict whether NgAgo will be able to compete with or be superior to CRISPR/Cas9, the scientific community is anxiously waiting for further optimization and broader applications of the NgAgo genome editing technology

Avoiding Breast Animation Deformity with Pectoralis-Sparing Subcutaneous Direct-to-Implant Breast Reconstruction

Summary: There is renewed interest in sparing the pectoralis major muscle in implant breast reconstruction, placing the implant in the subcutaneous position. This advance is made reliable by improvements in mastectomy skin flap quality, evolution of technique, and increased awareness of breast animation deformity. This retrospective review presents 13 patients (23 breasts) reconstructed immediately with placing the definitive implant in the subcutaneous space without disruption of the underlying chest muscles. None of the 13 patients had breast animation deformity postoperatively. One patient experienced an early hematoma, and 3 patients had small seromas that resolved uneventfully. One morbidly obese patient undergoing chemotherapy using a nearby chest port experienced infection requiring implant removal. This study describes an early experience, demonstrates feasibility, and discusses patient selection considerations that are important because we continue to evolve breast reconstruction approaches

The Association of Long-Term Exposure to Particulate Matter Air Pollution with Brain MRI Findings: The ARIC Study.

BACKGROUND: Increasing evidence links higher particulate matter (PM) air pollution exposure to late-life cognitive impairment. However, few studies have considered associations between direct estimates of long-term past exposures and brain MRI findings indicative of neurodegeneration or cerebrovascular disease. OBJECTIVE: Our objective was to quantify the association between brain MRI findings and PM exposures approximately 5 to 20 y prior to MRI in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: ARIC is based in four U.S. sites: Washington County, Maryland; Minneapolis suburbs, Minnesota; Forsyth County, North Carolina; and Jackson, Mississippi. A subset of ARIC participants underwent 3T brain MRI in 2011-2013 (n=1,753). We estimated mean exposures to PM with an aerodynamic diameter less than 10 or 2.5μm (PM RESULTS: In pooled analyses, higher mean PM CONCLUSIONS: Long-term past PM exposure in was not associated with markers of cerebrovascular disease. Higher long-term past PM exposures were associated with smaller deep-gray volumes overall, and higher P

Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis

Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis , especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery