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Functional profiling of CFTR-directed therapeutics offers the potential to provide significant benefits to young people with cystic fibrosis (CF). However, the development of 2D airway epithelial cell models for individual response tests in CF children remains a central task. The objective of this study was to determine the utility of EpiXTM technology for expansion of nasal epithelial cells for use in electrophysiological CFTR function measurements. An initial harvest of as few as 20,000 cells was sufficient to expand up to 50 million cells that were used to generate air-liquid interface (ALI) cultures for ion transport studies with the Ussing assay. CFTR function was assessed by measuring responses to forskolin and the CFTR potentiator VX-770 (ivacaftor) in ALI cultures generated from passage 3 and 4 cells. Short-circuit current (Isc) measurements of blocked CFTR currents (ΔICFTRinh) discriminated CFTR function between healthy control (wild type, WT) and patients with intermediate (F508del/R117H-7T: 56% WT) and severe (F508del/F508del: 12% WT) CF disease. For the mixed genotypes, CFTR activity for F508del/c.850dupA was 12% WT, R334W/406-1G>A was 24% WT, and CFTRdele2,3(21 kb)/CFTRdele2,3(21 kb) was 9% WT. The CFTR correctors VX-809 (lumacaftor) and VX-661 (tezacaftor) significantly increased CFTR currents for F508del/R117H to 73 and 67% WT, respectively. Cultures with the large deletion mutation CFTRdele2,3(21 kb) unexpectedly responded to VX-661 treatment (20% WT). Amiloride-sensitive sodium currents were robust and ranged between 20-80 μA/cm2 depending on the subject. In addition to characterizing the electrophysiological profile of mutant CFTR activity in cultures for five genotypes, our study exemplifies the promising paradigm of bed-to-bench side cooperation and personalized medicine.

We present an ecosystem approach to analyze open‐source data to identify populations vulnerable to human trafficking and to reveal underlying causal relationships. In the case of Bangladesh, our analysis suggests combinations of indicators that are highly predictive of human trafficking. The traditional narrative that poverty and unemployment are the main drivers for human trafficking may be an oversimplification. We find many areas where vulnerability is highest within lower‐middle to middle‐class societies with (a) moderate levels of income and education, (b) adherence to traditional gender norms of a male‐dominated patriarchal society, and (c) access to an urban center. [ABSTRACT FROM AUTHOR]

SS -precursor imaging is used to image sharp interfaces within Earth's mantle. Current SS -precursor techniques require tightly bandpassed signals (e.g. 0.02–0.05 Hz), limiting both vertical and horizontal resolutions. Higher frequency content would allow for the detection of finer structure in and around the mantle transition zone (MTZ). Here, we present a new SS -precursor deconvolution technique based on multiple-taper correlation (MTC). We show that applying MTC to SS -precursor deconvolution can increase the frequency cut-off up to 0.5 Hz, which potentially sharpens vertical resolution to ∼10 km. Furthermore, the high-pass frequency can be lowered (≪ 0.01 Hz), allowing more long-period energy to be included in the calculation, to better constrain the signal and reduce side lobes. Our method is benchmarked on full-waveform synthetic seismograms computed via AxiSEM3D for the PREM 1-D Earth model. We apply our novel MTC- SS -precursor deconvolution to ∼7000 seismograms recorded at broad-band borehole sensors of the Global Seismographic Network with source–receiver bounce points in the North-Central Pacific Ocean. The MTZ in this region appears to be thin, which agrees with previous results. We do not observe the 520-km discontinuity in our SS -precursor estimates. Additionally, we detect a low-velocity zone above the MTZ to the north of the Hawaiian Islands that has previously been inferred from asymmetry in side lobe amplitudes. Our high-frequency analysis demonstrates this feature to be a sharp interface (≤ 10-km thickness), rather than a thick wave speed gradient. [ABSTRACT FROM AUTHOR]

Lately, the premier ateliers of contemporary architecture - such as Herzog de Meuron, or the Office of Metropolitan Architecture - are showing increasing interest in hospital design, once the realm of highly specialized architectural firms. This trend towards reevaluating hospital design and architecture is most opportune, as the COVID-19 pandemic urges us all to rethink the ways in which our healthcare institutions can be better designed. This commentary is a discussion on the emerging issues of contemporary hospital architecture, especially as reinforced by the pandemic. For instance, while hospital architecture today focuses on individualized care, providing each patient with hotel-like rooms, the pandemic has reminded us of the issue of capacity and inequality in these limited and costly spaces. To what extent should hospitals be centralized or decentralized? Specialized or despecialized? This commentary discusses how COVID-19 has provided insight into some of contemporary hospital architecture's greatest problems; specifically, it argues that the hospital of the future must exist on a more decentralized platform, both physically and digitally, and be more flexible in function. [ABSTRACT FROM AUTHOR]

Tomographic images of the distribution of shear-wave speed beneath the northwestern Pacific delineate the configuration of the subducted oceanic lithosphere beneath the western Aleutian arc. At ~100 km depth, a fast shear-wave speed anomaly is beneath the Aleutian arc everywhere east of 173[degrees]E. Between 164[degrees]E and 173[degrees]E, however, seismic velocities at this depth are slow relative to the surrounding mantle. The lateral termination of the fast shear-wave speed anomaly at depth coincides with a gap in deep seismicity beneath the Aleutians. The absence of these two distinctive traits of subducting slabs leads us to conclude that this segment of the Aleutian arc overlies a very large window in the otherwise continuous lithospheric slab that we term a 'slab portal.' This portal is likely to facilitate the production of distinctive volcanic rocks (adakites or high-Mg# andesites) by partially melting the adjacent edges of the slab. The Miocene age of most adakites in the westernmost Aleutians where no slab is present may indicate that the portal formed relatively recently. The chemistry of western Aleutian adakites approximates that of typical continental crust, so their genesis and subsequent lateral transport toward Kamchatka is a plausible mechanism for new continent formation. Keywords: adakites, Aleutians, mantle structure, seismic tomography, slab melting.

Author(s): Vadim Levin (corresponding author) [1]; Nikolai Shapiro [1, 2]; Jeffrey Park [1]; Michael Ritzwoller [1, 2] In the northwest Pacific Ocean, a sharp corner in the boundary between the [...]