An unfolded protein-induced conformational switch activates mammalian IRE1.

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization

Facilitators and Barriers to Prescribing PreExposure Prophylaxis (PrEP) for the Prevention of HIV

Background: What is PrEP and who gets it? PrEP is the use of medication by individuals to prevent HIV contraction, approved in 2012 after demonstrating safety and efficacy in the iPrEx study and Partners PrEP2 trials. HIV infection risk is 92% lower in patients using PrEP. Truvada®, a combination of tenofovir and emtricitabine taken orally daily, is the only approved PrEP regimen and is intended to compliment other prevention strategies such as condoms. HIV negative-individuals at risk for exposure to HIV have been identified as men who have sex with men (MSM), IV drug users, heterosexuals who have unprotected sex with partners of unknown HIV status, and those in serodiscordant relationships. Barriers to PrEP Implementation PrEP is effective when patients adhere; however, both the medical community and some high-risk populations have been slow to adopt it as an HIV prevention strategy. Surveys have shown clinicians perceived barriers to PrEP such as adverse side effects, viral drug resistance, increased high-risk behavior, cost, and training. HIV in Vermont New diagnoses of HIV among Vermont residents has remained relatively stable over the last twenty years. Vermont CARES, a non-profit, offers free and anonymous HIV tests and in-person risk-reduction counseling. Clients are increasingly asking about PrEP as a prevention strategy, but the response from the medical community is difficult to ascertain.https://scholarworks.uvm.edu/comphp_gallery/1235/thumbnail.jp

HST Imaging Polarimetry of the Gravitational Lens FSC10214+4724

We present imaging polarimetry of the extremely luminous, redshift 2.3 IRAS source FSC10214+4724. The observations were obtained with HST's Faint Object Camera in the F437M filter, which is free of strong emission lines. The 0.7 arcsec long arc is unresolved to 0.04 arcsec FWHM in the transverse direction, and has an integrated polarization of 28 +/- 3 percent, in good agreement with ground-based observations. The polarization position angle varies along the arc by up to 35 deg. The overall position angle is 62 +/- 3 deg east of north. No counterimage is detected to B = 27.5 mag ($3\sigma$), giving an observed arc to counterimage flux ratio greater than 250, considerably greater than the flux ratio of 100 measured previously in the I-band. This implies that the configuration of the object in the source plane at the B-band is different from that at I-band, and/or that the lensing galaxy is dusty.Comment: 17 pages, 3 figures. Accepted for publication in Astronomical Journal, February 199

MicroRNA-203 predicts human survival after resection of colorectal liver metastasis.

BackgroundResection of colorectal liver metastasis (CRLM) can be curative. Predicting which patients may benefit from resection, however, remains challenging. Some microRNAs (miRNAs) become deregulated in cancers and contribute to cancer progression. We hypothesized that miRNA expression can serve as a prognostic marker of survival after CRLM resection.ResultsMiR-203 was significantly overexpressed in tumors of short-term survivors compared to long-term survivors. R1/R2 margin status and high clinical risk score (CRS) were also significantly associated with short-term survival (both p = 0.001). After adjusting for these variables, higher miR-203 expression remained an independent predictor of shorter survival (p = 0.010). In the serum cohort, high CRS and KRAS mutation were significantly associated with short-term survival (p = 0.005 and p = 0.026, respectively). After adjusting for CRS and KRAS status, short-term survivors were found to have significantly higher miR-203 levels (p = 0.016 and p = 0.033, respectively).Materials and methodsWe employed next-generation sequencing of small-RNAs to profile miRNAs in solid tumors obtained from 38 patients who underwent hepatectomy for CRLM. To validate, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed on 91 tumor samples and 46 preoperative serum samples.ConclusionsAfter CRLM resection, short-term survivors exhibited significantly higher miR-203 levels relative to long-term survivors. MiR-203 may serve as a prognostic biomarker and its prognostic capacity warrants further investigation

Superpixel-based segmentation of muscle fibers in multi-channel microscopy

Background Confetti fluorescence and other multi-color genetic labelling strategies are useful for observing stem cell regeneration and for other problems of cell lineage tracing. One difficulty of such strategies is segmenting the cell boundaries, which is a very different problem from segmenting color images from the real world. This paper addresses the difficulties and presents a superpixel-based framework for segmentation of regenerated muscle fibers in mice. Results We propose to integrate an edge detector into a superpixel algorithm and customize the method for multi-channel images. The enhanced superpixel method outperforms the original and another advanced superpixel algorithm in terms of both boundary recall and under-segmentation error. Our framework was applied to cross-section and lateral section images of regenerated muscle fibers from confetti-fluorescent mice. Compared with “ground-truth” segmentations, our framework yielded median Dice similarity coefficients of 0.92 and higher. Conclusion Our segmentation framework is flexible and provides very good segmentations of multi-color muscle fibers. We anticipate our methods will be useful for segmenting a variety of tissues in confetti fluorecent mice and in mice with similar multi-color labels.National University of Singapore (Duke-NUS SRP Phase 2 Research Block Grant)Singapore. National Research Foundation (CREATE programme)Singapore-MIT Alliance for Research and Technology (SMART

Radio-frequency methods for Majorana-based quantum devices: fast charge sensing and phase diagram mapping

Radio-frequency (RF) reflectometry is implemented in hybrid semiconductor-superconductor nanowire systems designed to probe Majorana zero modes. Two approaches are presented. In the first, hybrid nanowire-based devices are part of a resonant circuit, allowing conductance to be measured as a function of several gate voltages ~40 times faster than using conventional low-frequency lock-in methods. In the second, nanowire devices are capacitively coupled to a nearby RF single-electron transistor made from a separate nanowire, allowing RF detection of charge, including charge-only measurement of the crossover from 2e inter-island charge transitions at zero magnetic field to 1e transitions at axial magnetic fields above 0.6 T, where a topological state is expected. Single-electron sensing yields signal-to-noise exceeding 3 and visibility 99.8% for a measurement time of 1 {\mu}s

An Efficient Implementation of Parallelization in the Domain Decomposition of TELEMAC

HydrodynamicsAbstrac