Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is caused by more than a hundred NOTCH3 mutations. Virtually all encoded mutant proteins contain an odd number of cysteines. As such, structural changes in NOTCH3 may be the primary molecular abnormality in CADASIL. Thus, we sought evidence for structurally altered NOTCH3 protein in CADASIL tissue. Four antibodies were raised in rabbits against two non-overlapping N-terminal NOTCH3 sequences. These reagents were used in immunohistochemical experiments to detect epitopes in post-mortem CADASIL brains (n=8), control brains, and cells overexpressing NOTCH3. To determine the biochemical nature of NOTCH3 epitopes, we used these antibodies to probe pure NOTCH3-Fc fusion proteins treated with acid, urea, guanidinium, ionic detergents, acrylamide, and thiol- and phosphorus-based reductants. All antibodies avidly stained arteries in 8 of 8 CADASIL brain samples. The most prominent staining was in degenerating media of leptomeningeal arteries and sclerotic penetrating vessels. Normal appearing vessels from control brains were not reactive. Antibodies did not react with cultured cells overexpressing NOTCH3 or with purified NOTCH3-Fc protein. Furthermore, treatment of pure protein with acid, chaotropic denaturants, alkylators, and detergents failed to unmask N-terminal NOTCH3 epitopes. Antibodies, however, recognized novel N-terminal epitopes in purified NOTCH3-Fc protein treated with three different reductants (DTT, beta-mercaptoethanol, and TCEP). We conclude that CADASIL arteries feature latent N-terminal NOTCH3 epitopes, suggesting the first evidence in vivo of NOTCH3 structural alterations

The Chemical Compositions of Very Metal-Poor Stars HD 122563 and HD 140283; A View From the Infrared

From high resolution (R = 45,000), high signal-to-noise (S/N > 400) spectra gathered with the Immersion Grating Infrared Spectrograph (IGRINS) in the H and K photometric bands, we have derived elemental abundances of two bright, well-known metal-poor halo stars: the red giant HD 122563 and the subgiant HD 140283. Since these stars have metallicities approaching [Fe/H] = -3, their absorption features are generally very weak. Neutral-species lines of Mg, Si, S and Ca are detectable, as well as those of the light odd-Z elements Na and Al. The derived IR-based abundances agree with those obtained from optical-wavelength spectra. For Mg and Si the abundances from the infrared transitions are improvements to those derived from shorter wavelength data. Many useful OH and CO lines can be detected in the IGRINS HD 122563 spectrum, from which derived O and C abundances are consistent to those obtained from the traditional [O I] and CH features. IGRINS high resolutions H- and K-band spectroscopy offers promising ways to determine more reliable abundances for additional metal-poor stars whose optical features are either not detectable, or too weak, or are based on lines with analytical difficulties.Comment: Accepted for publication in ApJ (28 pages, 4 tables, 6 figures

DASZL: Dynamic Action Signatures for Zero-shot Learning

There are many realistic applications of activity recognition where the set of potential activity descriptions is combinatorially large. This makes end-to-end supervised training of a recognition system impractical as no training set is practically able to encompass the entire label set. In this paper, we present an approach to fine-grained recognition that models activities as compositions of dynamic action signatures. This compositional approach allows us to reframe fine-grained recognition as zero-shot activity recognition, where a detector is composed "on the fly" from simple first-principles state machines supported by deep-learned components. We evaluate our method on the Olympic Sports and UCF101 datasets, where our model establishes a new state of the art under multiple experimental paradigms. We also extend this method to form a unique framework for zero-shot joint segmentation and classification of activities in video and demonstrate the first results in zero-shot decoding of complex action sequences on a widely-used surgical dataset. Lastly, we show that we can use off-the-shelf object detectors to recognize activities in completely de-novo settings with no additional training.Comment: 10 pages, 4 figures, 3 tables, AAAI2021 submissio

How do you define creativity? A qualitative study of undergraduate chemistry students’ perspectives.

As technology continues to become more sophisticated, human thought in a professional setting will become more dependent on creativity. Employers around Australia identify creativity as a highly sought after attribute of recent graduate. To better understand how universities can develop STEM students’ creativity, an open-ended questionnaire was administered to first, second and third year undergraduate chemistry students at Monash University in semester one of 2019. Over 900 students completed the questionnaire which was processed through via NVivo. When asked to define creativity, students commonly identified themes of “originality and innovation” which aligned with the existing literature. Additional themes uncommon to the literature, such as “expression” and “problem solving” were also expressed. Within their studies, students identified self-directed activities such as the laboratories, assignments, and “teamwork activities” where opinions and thoughts are discussed most developed their creativity. Finally, students most commonly associated creativity with performing or creative arts in their extracurricular activities and suggested that these activities helped develop their problem solving, team work and experimentation within a STEM context. Once this data is triangulated with educators and employer perspectives, we anticipate an undergraduate teaching intervention can be designed to improve STEM students’ learning outcomes in creativity

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-gamma production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases

Cross section for the H + H2O abstraction reaction: experiment and theory

The absolute value of the cross section for the abstraction reaction between fast H atoms and H2O has been determined experimentally at a mean collision energy of 2.46 eV. The OH population distribution at the same mean energy has also been determined. The new measurements are compared with state-ofthe- art quantum mechanical and quasiclassical scattering calculations on the most recently developed potential energy surface

CSO Bolocam 1.1 mm continuum mapping of the Braid Nebula star formation region in Cygnus OB7

We present a 1.1 mm map of the Braid Nebula star formation region in Cygnus OB7 taken using Bolocam on the Caltech Submillimeter Observatory. Within the 1 deg2 covered by the map, we have detected 55 cold dust clumps all of which are new detections. A number of these clumps are coincident with IRAS point sources although the majority are not. Some of the previously studied optical/near-IR sources are detected at 1.1 mm. We estimate total dust/gas masses for the 55 clumps together with peak visual extinctions. We conclude that over the whole region, approximately 20% of the clumps are associated with IRAS sources suggesting that these are protostellar objects. The remaining 80% are classed as starless clumps. In addition, both FU Orionis (FUor) like objects in the field, the Braid Star and HH 381 IRS, are associated with strong millimeter emission. This implies that FUor eruptions can occur at very early stages of pre-main-sequence life. Finally, we determine that the cumulative clump mass function for the region is very similar to that found in both the Perseus and Ï? Ophiuchus star-forming regions. © 2011. The American Astronomical Society. All rights reserved

The GALEX Ultraviolet Atlas of Nearby Galaxies

We present images, integrated photometry, and surface-brightness and color profiles for a total of 1034 nearby galaxies recently observed by the Galaxy Evolution Explorer (GALEX) satellite in its far-ultraviolet (FUV; λ_(eff) = 1516 Å) and near-ultraviolet (NUV; λ_(eff) = 2267 Å) bands. Our catalog of objects is derived primarily from the GALEX Nearby Galaxies Survey (NGS) supplemented by galaxies larger than 1' in diameter serendipitously found in these fields and in other GALEX exposures of similar of greater depth. The sample analyzed here adequately describes the distribution and full range of properties (luminosity, color, star formation rate [SFR]) of galaxies in the local universe. From the surface brightness profiles obtained we have computed asymptotic magnitudes, colors, and luminosities, along with the concentration indices C31 and C42. We have also morphologically classified the UV surface brightness profiles according to their shape. This data set has been complemented with archival optical, near-infrared, and far-infrared fluxes and colors. We find that the integrated (FUV − K) color provides robust discrimination between elliptical and spiral/irregular galaxies and also among spiral galaxies of different subtypes. Elliptical galaxies with brighter K-band luminosities (i.e., more massive) are redder in (NUV − K) color but bluer in (FUV − NUV) (a color sensitive to the presence of a strong UV upturn) than less massive ellipticals. In the case of the spiral/irregular galaxies our analysis shows the presence of a relatively tight correlation between the (FUV − NUV) color (or, equivalently, the slope of the UV spectrum, β) and the total infrared-to-UV ratio. The correlation found between (FUV − NUV) color and K-band luminosity (with lower luminosity objects being bluer than more luminous ones) can be explained as due to an increase in the dust content with galaxy luminosity. The images in this Atlas along with the profiles and integrated properties are publicly available through a dedicated Web page

Clinical and Microbiologic Investigation of an Expedited Peri-implantitis Dog Model: An Animal Study

Background: Animal studies are pivotal in allowing experimentation to identify efficacious treatment protocols for resolution of peri-implantitis. The purpose of this investigation was to characterize an expedited dog peri-implantitis model clinically, radiographically, and microbiologically. Methods: Eight hound dogs underwent extractions (week 0) and implant (3.3 × 8.5 mm) placement with simultaneous surgical defect creation and ligature placement for induction of peri-implantitis (week 10). Ligatures were replaced at 6 weeks (week 16) and removed after 9 weeks (week 19) when supporting bone loss involved approximately 50% of the peri-implant bone. Microbial samples from the defects and healthy control implant sites collected at week 19 were analyzed utilizing a microarray. Clinical measures of inflammation were obtained and radiographic bone loss was measured from periapical radiographs. Radiographic depth and width measurements of bony defect were repeated at weeks 10 (baseline), 16, and 19. Canonical analysis of principal coordinates was used to visualize overall differences in microbial abundance between peri-implantitis and healthy implants. Results: This accelerated disease protocol led to intrabony defect creation with a mean depth and width of 4.3 mm and 3.5 mm, respectively after 9 weeks of ligature placement. Microbial identification revealed 59 total bacteria in peri-implant sites, 21 of which were only present in peri-implant sites as compared to healthy controls. Overall microbial beta diversity (microbial between-sample compositional diversity) differed between peri-implantitis and healthy implants (p = 0.009). Conclusions: Within the limitations of this study, this protocol led to expedited generation of peri-implant defects with a microbial profile indicative of a shift to disease and defect patterns conducive to regenerative treatment. However, the possibility of potential spontaneous resolution of lesions due to the lack of a chronicity interval as compared to chronic disease models need to be further clarified and considered during preclinical peri-implantitis model selection