Negotiating scientific knowledge in the development of an eHealth MOOC

Interdisciplinary team communication in eHealth development is challenging because all disciplines have unique, intrinsic discursive practices, theories and artefacts. Due to these factors, members of interdisciplinary teams can experience problems in communication and collaboration. Through a centered focus, members can benefit individually, inspire one another, and ultimately reach a timely delivery of their common pedagogical goal(s). Using the lens of dialogism, this paper aims to identify the conceptual considerations that arose during the development of a Massive Open Online Course (MOOC) for higher education in eHealth. Methods included auto-ethnography and interdisciplinary dialogue supported by literacy artefacts, including visual material. Results yielded a visual tool for meta-assessment of team communication, and an organizing principle for topics in the MOOC. A major implication is that especially for eHealth, scientific communicative competence of experts—while establishing a common understanding—can lead to a unique and meaningful delivery of high pedagogical quality.publishedVersio

Inclusion of Host Quality Data Improves Predictions of Herbivore Phenology

Understanding the correspondence between ambient temperature and insect development is necessary to forecast insect phenology under novel environments. In the face of climate change, both conservation and pest control efforts require accurate phenological predictions. Here, we compare a suite of degree-day models to assess their ability to predict the phenology of a common, oligophagous butterfly, the silver-spotted skipper, Epargyreus clarus (Cramer) (Lepidoptera: Hesperiidae). To estimate model parameters, we used development time of eggs and larvae reared in the laboratory at six constant temperatures ranging from 8 to 38 °C and on two host plants of contrasting quality (kudzu and wisteria). We employed three approaches to determine the base temperature to calculate degree days: linear regression, modified reduced major axis regression, and application of a generic base temperature value of 10 °C, which is commonly used in the absence of laboratory data. To calculate the number of degree days required to complete a developmental stage, we used data from caterpillars feeding on high- and low-quality hosts, both in the field and in the laboratory. To test model accuracy, we predicted development time of seven generations of larvae reared in the field on the same host plants across 3 years (2014–2016). To compare performance among models, we regressed predicted vs. observed development time, and found that r2 values were significantly larger when accounting for host plant quality. The accuracy of development time predictions varied across the season, with estimates of the first two generations being more accurate than estimates of the third generation, when ambient temperatures dropped outside the range in which development rate and temperature have a linear relationship. Overall, we show that accounting for variation in host plant quality when calculating development time in the field is more important than the choice of the base temperature for calculating degree days

CMV-specific T-cell responses at older ages: broad responses with a large central memory component may be key to long-term survival

Cytomegalovirus (CMV) infection sometimes causes large expansions of CMV-specific T-cells, particularly in older people. This is believed to undermine immunity to other pathogens and to accelerate immunosenescence. While multiple different CMV proteins are recognized, most publications on age-related T-cell expansions have focused on dominant target proteins, UL83 or UL123, and the T-cell activation marker, IFN-γ. We were concerned that this narrow approach might have skewed our understanding of CMV-specific immunity at older ages. We have, therefore, widened the scope of analysis to include in vitro-induced T-cell responses to 19 frequently recognized CMV proteins in young and older healthy volunteers and a group of oldest old, long-term survivors (>85 years of age). Polychromatic flow-cytometry was used to analyze T-cell activation markers (CD107, CD154, IL-2, TNF, IFN-γ) and memory phenotype (CD27, CD45RA). The older had on average larger T-cell responses than the young, but, interestingly, response size differences were relatively smaller when all activation markers were considered rather than IFN-γ or TNF alone. The oldest old recognized more proteins on average than the other groups and had even bigger T-cell responses than the older with a significantly larger central memory CD4 T-cell component

Functional diversity of CMV-specific T-cells is maintained in older people and significantly associated with protein specificity and response size

Background: Parallel up-regulation of several T-cell effector functions (‘polyfunctionality’) is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of CMV-specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages. Methods: Polychromatic flow-cytometry was used to analyze the functional diversity (CD107, CD154, IL-2, TNF, IFN-) of CD4 and CD8 T-cell responses to 19 CMV proteins in a large group of young and older UK participants. A group of oldest old people (>85years) was included to explore these parameters in exceptional ‘survivors’. Polyfunctionality was assessed for each proteinspecific response subset by subset and in aggregate across all proteins using the novel polyfunctionality index (PI). Results: Polyfunctionality was not reduced in healthy older compared to young people. However, it was significantly related to target protein specificity. For each protein it increased with response size. In the oldest old overall T-cell polyfunctionality was significantly lower. Discussion: Our results give a new perspective on T-cell polyfunctionality and raise the question if maintaining polyfunctionality of CMV-specific T-cells at older ages is necessarily beneficial

Benny Benson's Hidden Unangax̂ Heritage

This paper is dedicated to Alaska seventh grade students who know there is no chance of winning a contest. And enter anyway.Friday, July 9, 2027, will be the 100-year anniversary of the raising of the Alaska flag designed by seventh grade student Benny Benson. Top 8% of US state flag designs. Only US state flag designed by a Native American. Youngest designer. Indentured #217. Orphan. Poorest. “Inmate.” Only US state flag designer alive when the flags were flown to the Moon. As we prepare for the 100-year anniversary, what do know about Benny - as opposed to assume? We assumed that Benny was age 13 when he won the Alaska flag contest in 1927; history books said so. We assumed that his date of birth was October 12, 1913, and that his mother’s maiden name was Tatiana Schebolein. His official State of Alaska birth certificate said so. Yet, while researching Benny’s family tree, we uncovered documents which indicated otherwise. We contacted a relative who said Benny’s birth certificate is incorrect. We contacted the State of Alaska’s Health Analytics and Vital Records Section (HAVRS) who contacted the Alaska State Museums. A panel of Alaska history experts reviewed our documents and agreed that Benny’s birthdate should be corrected. HAVRS said we needed a court order. We petitioned the Alaska Superior Court, and on February 28, 2022, Alaska Superior Court Judge Adolf Zeman issued a court order (containing Unangam Tunuu – Aleut language) to correct Benny Benson’s birth records. Benny was actually born on September 12, 1912 – over 13 months earlier than previously reported. Benny’s mother’s maiden name was not Tatiana Schebolein; it was Tatiana Ioannovna Dediukhina. We also assumed that Benny was Alutiiq. Many sources said so, and good sources too: Museums, libraries, Alaska Native organizations, and Alaska historical societies. In 1950, when Benny was age 38, he moved to Kodiak. Sadly, in 1972, at age 59, Benny passed away and is buried in Kodiak. Kodiak is Alutiiq territory, and this may explain why Benny is often identified as Alutiiq. Yet Alaska Native ancestry is not defined solely upon where we move to later in life or the geographical location where we are born or are buried. Alaska Native ancestry is defined by where our ancestors are born and lived. When one of our genealogy colleagues casually mentioned finding records that indicated Benny’s mother Tatiana was born in Unangax̂ territory, this launched a lengthy-, in-depth genealogical investigation of his family tree. With help from many others, we found birth and marriage records which demonstrate that Benny’s mother Tatiana and his grandparents were born in Unalaska – the heart of Unangax̂ territory. Thus, Benny was a member of the Qawalangin Tribe of Unalaska – the Qawax̂ or Sea Lion Tribe. His great grandparents were from Amlia Village; Benny was a descendant of the Native Village of Atka. Despite others claiming without evidence that Benny Benson was Alutiiq, the documents found during this research show that Benny was Unangax̂. This research is significant on several fronts. First, it spotlights Benny Benson who – despite all odds – won a contest by reaching for the stars. Over 95 years after he won the Alaska flag contest, Benny is still in the news in a heartwarming story during the depth of a gloomy global pandemic and conflict in Ukraine. Like most family tree stories, there are sad (even heart-wrenching) times, but overall, Benny’s story is uplifting. This paper illuminates the plight of Alaska orphans who sometimes do not know their date of birth, the names of their ancestors, or their cultural heritage. Orphans need good families and thorough family tree research. This paper also underscores the importance of questioning written history and the need for history detectives keen on forensically investigating Alaska family trees with patient persistence while seeking the truth – whatever the truth may be. The birth record correction is significant because it changes Alaska history and represents a larger effort towards truth, reconciliation, equity, and racial justice for North American indigenous peoples who were often given the short shrift in the 20th Century. The birth record correction is a victory for archivists, Russian Orthodox family record keepers, and genealogists who love a complex mystery that twists and turns over time. This paper spotlights the need for careful research before centenary celebrations. Finally, this paper spotlights the linguistic and artistic talents of the Unangax̂ people from whom so much has been taken during the past 300 years and who have given so much including the name Alaska itself and now we know the strong design of the unique Alaska flag.Institute of Museum and Library Services basic grants # NG-01- 19-0037-19 and # NAB-246356-OLS-20

The GALEX Arecibo SDSS survey: III. Evidence for the Inside-Out Formation of Galactic Disks

We analyze a sample of galaxies with stellar masses greater than $10^{10} M_{\odot}$ and with redshifts in the range $0.025<z<0.05$ for which HI mass measurements are available from the GALEX Arecibo SDSS Survey (GASS) or from the Arecibo Legacy Fast ALFA survey (ALFALFA). At a given value of $M_*$, our sample consists primarily of galaxies that are more HI-rich than average. We constructed a series of three control samples for comparison with these HI-rich galaxies. As expected, HI-rich galaxies differ strongly from galaxies of same stellar mass that are selected without regard to HI content. The majority of these differences are attributable to the fact that galaxies with more gas are bluer and more actively star-forming. In order to identify those galaxy properties that are causally connected with HI content, we compare results derived for the HI sample with those derived for galaxies matched in stellar mass, size and NUV-$r$ colour. The only photometric property that is clearly attributable to increasing HI content, is the colour gradient of the galaxy. Galaxies with larger HI fractions have bluer, more actively star-forming outer disks compared to the inner part of the galaxy. HI-rich galaxies also have larger $g$-band radii compared to $i$-band radii. Our results are consistent with the "inside-out" picture of disk galaxy formation, which has commonly served as a basis for semi-analytic models of the formation of disks in the context of Cold Dark Matter cosmologies. The lack of any intrinsic connection between HI fraction and galaxy asymmetry suggests that gas is accreted smoothly onto the outer disk.Comment: 18 pages, 20 figures. Accepted for publication in MNRAS. GASS publications and released data can be found at http://www.mpa-garching.mpg.de/GASS/index.ph

Structural Basis of Membrane Protein Chaperoning through the Mitochondrial Intermembrane Space

International audienceThe exchange of metabolites between the mitochon- drial matrix and the cytosol depends on b-barrel channels in the outer membrane and a-helical carrier proteins in the inner membrane. The essential trans- locase of the inner membrane (TIM) chaperones escort these proteins through the intermembrane space, but the structural and mechanistic details remain elusive. We have used an integrated struc- tural biology approach to reveal the functional princi- ple of TIM chaperones. Multiple clamp-like binding sites hold the mitochondrial membrane proteins in a translocation-competent elongated form, thus mimicking characteristics of co-translational mem- brane insertion. The bound preprotein undergoes conformational dynamics within the chaperone bind- ing clefts, pointing to a multitude of dynamic local binding events. Mutations in these binding sites cause cell death or growth defects associated with impairment of carrier and b-barrel protein biogen- esis. Our work reveals how a single mitochondrial ‘‘transfer-chaperone’’ system is able to guide a-heli- cal and b-barrel membrane proteins in a ‘‘nascent chain-like’’ conformation through a ribosome-free compartment

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2

The Wide-field Infrared Survey Explorer (WISE): Mission Description and Initial On-orbit Performance

The all sky surveys done by the Palomar Observatory Schmidt, the European Southern Observatory Schmidt, and the United Kingdom Schmidt, the InfraRed Astronomical Satellite and the 2 Micron All Sky Survey have proven to be extremely useful tools for astronomy with value that lasts for decades. The Wide-field Infrared Survey Explorer is mapping the whole sky following its launch on 14 December 2009. WISE began surveying the sky on 14 Jan 2010 and completed its first full coverage of the sky on July 17. The survey will continue to cover the sky a second time until the cryogen is exhausted (anticipated in November 2010). WISE is achieving 5 sigma point source sensitivities better than 0.08, 0.11, 1 and 6 mJy in unconfused regions on the ecliptic in bands centered at wavelengths of 3.4, 4.6, 12 and 22 microns. Sensitivity improves toward the ecliptic poles due to denser coverage and lower zodiacal background. The angular resolution is 6.1, 6.4, 6.5 and 12.0 arc-seconds at 3.4, 4.6, 12 and 22 microns, and the astrometric precision for high SNR sources is better than 0.15 arc-seconds.Comment: 22 pages with 19 included figures. Updated to better match the accepted version in the A

Strategy for tumor selective disruption of androgen receptor function in the spectrum of prostate cancer

Purpose: Testosterone suppression in prostate cancer (PC) is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for ARdependent growth in various hormone-dependent and castration resistant PC models. The amino terminal domain of AR docks at two sites on ELK1 to co-activate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of PC, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental design: Small molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of PC cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6h and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development