IgA as a potential candidate for enteric monoclonal antibody therapeutics with improved gastrointestinal stability

Mucosal surfaces of the gastrointestinal tract play an important role in immune homeostasis and defense and may be compromised by enteric disorders or infection. Therapeutic intervention using monoclonal antibody (mAb) offers the potential for treatment with minimal off-target effects as well as the possibility of limited systemic exposure when administered orally. Critically, to achieve efficacy at luminal surfaces, mAb must remain stable and functionally active in the gastrointestinal environment. To better understand the impact of isotype, class, and molecular structure on the intestinal stability of recombinant antibodies, we used an in vitro simulated intestinal fluid (SIF) assay to evaluate a panel of antibody candidates for enteric mAb-based therapeutics. Recombinant IgG1 was the least stable following SIF incubation, while the stability of IgA generally increased upon polymerization, with subtle differences between subclasses. Notably, patterns of variability within and between mAbs suggest that variable regions contribute to mAb stability and potentially mediate mAb susceptibility to proteases. Despite relatively rapid degradation in SIF, mAbs targeting Enterotoxigenic Escherichia coli (ETEC) displayed functional activity following SIF treatment, with SIgA1 showing improved function compared to SIgA2. The results of this study have implications for the design of enteric therapeutics and subsequent selection of lead candidates based upon in vitro intestinal stability assessments

Cloud Atlas: Weak Color Modulations Due to Rotation in the Planetary-mass Companion GU Psc b and 11 Other Brown Dwarfs

Among the greatest challenges in understanding ultracool brown dwarf and exoplanet atmospheres is the evolution of cloud structure as a function of temperature and gravity. In this study, we present the rotational modulations of GU Psc b—a rare mid-T spectral type planetary-mass companion at the end of the L/T spectral type transition. Based on the Hubble Space Telescope/WFC3 1.1–1.67 μm time-series spectra, we observe a quasi-sinusoidal light curve with a peak-to-trough flux variation of 2.7% and a minimum period of 8 h. The rotation-modulated spectral variations are weakly wavelength-dependent, or largely gray between 1.1 and 1.67 μm. The gray modulations indicate that heterogeneous clouds are present in the photosphere of this low-gravity mid-T dwarf. We place the color and brightness variations of GU Psc b in the context of rotational modulations reported for mid-L to late-T dwarfs. Based on these observations, we report a tentative trend: mid-to-late T dwarfs become slightly redder in J − H color with increasing J-band brightness, while L dwarfs become slightly bluer with increasing brightness. If this trend is verified with more T-dwarf samples, it suggests that in addition to the mostly gray modulations, there is a second-order spectral-type dependence on the nature of rotational modulations

Recent and Future Warm Extreme Events and High-mountain Slope Stability

The number of large slope failures in some high-mountain regions such as the European Alps has increased during the past two to three decades. There is concern that recent climate change is driving this increase in slope failures, thus possibly further exacerbating the hazard in the future. Although the effects of a gradual temperature rise on glaciers and permafrost have been extensively studied, the impacts of short-term, unusually warm temperature increases on slope stability in high mountains remain largely unexplored. We describe several large slope failures in rock and ice in recent years in Alaska, New Zealand and the European Alps, and analyse weather patterns in the days and weeks before the failures. Although we did not find one general temperature pattern, all the failures were preceded by unusually warm periods; some happened immediately after temperatures suddenly dropped to freezing. We assessed the frequency of warm extremes in the future by analysing eight regional climate models from the recently completed European Union programme ENSEMBLES for the central Swiss Alps. The models show an increase in the higher frequency of high-temperature events for the period 2001–2050 compared with a 1951–2000 reference period. Warm events lasting 5, 10 and 30 days are projected to increase by about 1.5–4 times by 2050 and in some models by up to 10 times. Warm extremes can trigger large landslides in temperature-sensitive high mountains by enhancing the production of water by melt of snow and ice, and by rapid thaw. Although these processes reduce slope strength, they must be considered within the local geological, glaciological and topographic context of a slope

The AllWISE Motion Survey, Part 2

We use the AllWISE Data Release to continue our search for WISE-detected motions. In this paper, we publish another 27,846 motion objects, bringing the total number to 48,000 when objects found during our original AllWISE motion survey are included. We use this list, along with the lists of confirmed WISE-based motion objects from the recent papers by Luhman and by Schneider et al. and candidate motion objects from the recent paper by Gagne et al. to search for widely separated, common-proper-motion systems. We identify 1,039 such candidate systems. All 48,000 objects are further analyzed using color-color and color-mag plots to provide possible characterizations prior to spectroscopic follow-up. We present spectra of 172 of these, supplemented with new spectra of 23 comparison objects from the literature, and provide classifications and physical interpretations of interesting sources. Highlights include: (1) the identification of three G/K dwarfs that can be used as standard candles to study clumpiness and grain size in nearby molecular clouds because these objects are currently moving behind the clouds, (2) the confirmation/discovery of several M, L, and T dwarfs and one white dwarf whose spectrophotometric distance estimates place them 5-20 pc from the Sun, (3) the suggestion that the Na 'D' line be used as a diagnostic tool for interpreting and classifying metal-poor late-M and L dwarfs, (4) the recognition of a triple system including a carbon dwarf and late-M subdwarf, for which model fits of the late-M subdwarf (giving [Fe/H] ~ -1.0) provide a measured metallicity for the carbon star, and (5) a possible 24-pc-distant K5 dwarf + peculiar red L5 system with an apparent physical separation of 0.1 pc.Comment: 62 pages with 80 figures, accepted for publication in The Astrophysical Journal Supplement Series, 23 Mar 2016; second version fixes a few small typos and corrects the footnotes for Table

WRAP: A Tool for Efficient Cross-Identification of Proper Motion Objects Spanning Multiple Surveys

We introduce the Wide-field Retrieval of Astrodata Program (WRAP), a tool created to aid astronomers in gathering photometric and astrometric data for point sources that may confuse simple cross-matching algorithms because of their faintness or motion. WRAP allows astronomers to correctly cross-identify objects with proper motion across multiple surveys by wedding the catalog data with its underlying images, thus providing visual confirmation of cross-associations in real time. Developed within the Backyard Worlds: Planet 9 citizen science project, WRAP aims to aid in the characterization of faint, high motion sources by this collaboration (and others).Comment: 4 pages, 1 figure, Github and DOI link to progra

Anti-CfaE nanobodies provide broad cross-protection against major pathogenic enterotoxigenic Escherichia coli strains, with implications for vaccine design

Enterotoxigenic Escherichia coli (ETEC) is estimated to cause approximately 380,000 deaths annually during sporadic or epidemic outbreaks worldwide. Development of vaccines against ETEC is very challenging due to the vast heterogeneity of the ETEC strains. An effective vaccines would have to be multicomponent to provide coverage of over ten ETEC strains with genetic variabilities. There is currently no vaccine licensed to prevent ETEC. Nanobodies are successful new biologics in treating mucosal infectious disease as they recognize conserved epitopes on hypervariable pathogens. Cocktails consisting of multiple nanobodies could provide even broader epitope coverage at a lower cost compared to monoclonal antibodies. Identification of conserved epitopes by nanobodies can also assist reverse engineering of an effective vaccine against ETEC. By screening nanobodies from immunized llamas and a naive yeast display library against adhesins of colonization factors, we identified single nanobodies that show cross-protective potency against eleven major pathogenic ETEC strains in vitro. Oral administration of nanobodies led to a significant reduction of bacterial colonization in animals. Moreover, nanobody-IgA fusion showed extended inhibitory activity in mouse colonization compared to commercial hyperimmune bovine colostrum product used for prevention of ETEC-induced diarrhea. Structural analysis revealed that nanobodies recognized a highly-conserved epitope within the putative receptor binding region of ETEC adhesins. Our findings support further rational design of a pan-ETEC vaccine to elicit robust immune responses targeting this conserved epitope

Y Dwarf Trigonometric Parallaxes from the Spitzer Space Telescope

Y dwarfs provide a unique opportunity to study free-floating objects with masses <30 M_(Jup) and atmospheric temperatures approaching those of known Jupiter-like exoplanets. Obtaining distances to these objects is an essential step toward characterizing their absolute physical properties. Using Spitzer's Infrared Array Camera (IRAC) [4.5] images taken over baselines of ~2–7 years, we measure astrometric distances for 22 late-T and early Y dwarfs, including updated parallaxes for 18 objects and new parallax measurements for 4 objects. These parallaxes will make it possible to explore the physical parameter space occupied by the coldest brown dwarfs. We also present the discovery of six new late-T dwarfs, updated spectra of two T dwarfs, and the reclassification of a new Y dwarf, WISE J033605.04−014351.0, based on Keck/NIRSPEC J-band spectroscopy. Assuming that effective temperatures are inversely proportional to absolute magnitude, we examine trends in the evolution of the spectral energy distributions of brown dwarfs with decreasing effective temperature. Surprisingly, the Y dwarf class encompasses a large range in absolute magnitude in the near- to mid-infrared photometric bandpasses, demonstrating a larger range of effective temperatures than previously assumed. This sample will be ideal for obtaining mid-infrared spectra with the James Webb Space Telescope because their known distances will make it easier to measure absolute physical properties

The hierarchy of coupled sleep oscillations reverses with aging in humans.

A well-orchestrated coupling hierarchy of slow waves and spindles during slow wave sleep supports memory consolidation. In old age, duration of slow wave sleep and number of coupling events decreases. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N=340, 237 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow wave frequency, and starts around midlife (∼age 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.Significance StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally and causally linked forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human lifespan and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human lifespan

An L Band Spectrum of the Coldest Brown Dwarf

The coldest brown dwarf, WISE 0855, is the closest known planetary-mass, free-floating object and has a temperature nearly as cold as the solar system gas giants. Like Jupiter, it is predicted to have an atmosphere rich in methane, water, and ammonia, with clouds of volatile ices. WISE 0855 is faint at near-infrared wavelengths and emits almost all its energy in the mid-infrared. Skemer et al. 2016 presented a spectrum of WISE 0855 from 4.5-5.1 micron (M band), revealing water vapor features. Here, we present a spectrum of WISE 0855 in L band, from 3.4-4.14 micron. We present a set of atmosphere models that include a range of compositions (metallicities and C/O ratios) and water ice clouds. Methane absorption is clearly present in the spectrum. The mid-infrared color can be better matched with a methane abundance that is depleted relative to solar abundance. We find that there is evidence for water ice clouds in the M band spectrum, and we find a lack of phosphine spectral features in both the L and M band spectra. We suggest that a deep continuum opacity source may be obscuring the near-infrared flux, possibly a deep phosphorous-bearing cloud, ammonium dihyrogen phosphate. Observations of WISE 0855 provide critical constraints for cold planetary atmospheres, bridging the temperature range between the long-studied solar system planets and accessible exoplanets. JWST will soon revolutionize our understanding of cold brown dwarfs with high-precision spectroscopy across the infrared, allowing us to study their compositions and cloud properties, and to infer their atmospheric dynamics and formation processes.Comment: 19 pages, 21 figures. Accepted for publication in Ap