Explore the vast range of titles available.

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved “checkpoint”-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor (FcγR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4–binding antibodies require an Fc domain for antitumor effect.

Direct numerical simulation and theoretical analysis of acoustic receptivity are performed for the boundary layer on a flat plate in Mach 6 flow at various angles of attack (AoA). Slow or fast acoustic wave passes through: a bow shock at AoA =-5∘, a weak shock induced by the viscous–inviscid interaction at AoA =0∘ or an expansion fan emanating from the plate leading edge at AoA =5∘. The study is focused on cases where the integral amplification of unstable mode S (or Mack second mode) is sufficiently large (N≈8.4) to be relevant to transition in low-disturbance environments. It is shown that excitation of dominant modes F and S occurs in a small vicinity of the plate leading edge. The initial disturbance propagates further downstream in accord with the two-mode approximation model accounting for the mean-flow nonparallel effects and the intermodal exchange mechanism. This computationally economical model can be useful for predictions of the second mode dominated transition onset using the physics-based amplitude method. Graphic abstract

Theoretical analysis of attachment-line instabilities is performed for supersonic swept flows using the compressible Hiemenz approximation for the mean flow and the successive approximation procedures for disturbances. The theoretical model captures the dominant attachment-line modes in wide ranges of the sweep Mach number ${M_e}$ and the wall temperature ratio. It is shown that these modes behave similar to the first and second Mack modes in the boundary layer flow. This similarity allows us to extrapolate the knowledge gained for Mack modes to the attachment-line instabilities. In particular, we find that at sufficiently large ${M_e}$, the dominant attachment-line instability is associated with the synchronisation of slow and fast modes of acoustic nature. Point-by-point comparisons of the theoretical predictions with the experiments of Gaillard et al. (Exp. Fluids, vol. 26, 1999, pp. 169–176) demonstrate that at ${M_e} > 4$, the theory captures a significant drop of the transition onset Reynolds number, which is below the contamination criterion of Poll $({R_\\mathrm{\\ast }} = 250)$ at ${M_e} > 6$. This contradicts the generally accepted assumption that the attachment-line flow is stable for ${R_\\mathrm{\\ast }} \\le 250$. The theoretical critical Reynolds numbers lie well below the experimental transition-onset Reynolds numbers. Stability computations using the Navier–Stokes mean flow and accounting for the leading-edge curvature effect do not eliminate this discrepancy. Most likely, in the experiments of Gaillard et al., we face with an unknown effect that does not fit to the concept of transition arising from linear instability.

Ice wedges are common features of the subsurface in permafrost regions. They develop by repeated frost cracking and ice vein growth over hundreds to thousands of years. Ice-wedge formation causes the archetypal polygonal patterns seen in tundra across the Arctic landscape. Here we use field and remote sensing observations to document polygon succession due to ice-wedge degradation and trough development in ten Arctic localities over sub-decadal timescales. Initial thaw drains polygon centres and forms disconnected troughs that hold isolated ponds. Continued ice-wedge melting leads to increased trough connectivity and an overall draining of the landscape. We find that melting at the tops of ice wedges over recent decades and subsequent decimetre-scale ground subsidence is a widespread Arctic phenomenon. Although permafrost temperatures have been increasing gradually, we find that ice-wedge degradation is occurring on sub-decadal timescales. Our hydrological model simulations show that advanced ice-wedge degradation can significantly alter the water balance of lowland tundra by reducing inundation and increasing runoff, in particular due to changes in snow distribution as troughs form. We predict that ice-wedge degradation and the hydrological changes associated with the resulting differential ground subsidence will expand and amplify in rapidly warming permafrost regions. The polygonal patterns in permafrost regions are caused by the formation of ice wedges. Observations of polygon evolution reveal that rapid ice-wedge melting has occurred across the Arctic since 1950, altering tundra hydrology.

Laminar–turbulent transition in the boundary layer at supersonic speeds can be initiated by small solid particles present in the free stream. Particulates interacting with the boundary-layer flow generate unstable wavepackets related to Tollmien–Schlichting (TS) waves. The latter grow downstream and ultimately break down to turbulent spots. This scenario of TS-dominated transition is modelled using the Mack amplitude method. A theoretical model describing the receptivity mechanism is developed to predict the initial spectrum of TS waves. With these initial conditions the downstream growth of TS instability is calculated using the linear stability theory. The transition onset is associated with the point where the disturbance amplitude reaches a threshold value. As an example, calculations are carried out for a 14° half-angle sharp wedge flying in the standard atmosphere at altitude 20 km, Mach number 4 and zero angle of attack. It is shown that spherical particles of radius from $10$ to $20~\\unicode[.5,0][STIXGeneral,Times]{x03BC} \\mathrm{m} $ and density ${\\geqslant }1~\\mathrm{g} ~{\\mathrm{cm} }^{- 3} $ can cause transition onset corresponding to the amplification factor $N= 9{\\unicode{x2013}} 10$ , which is in the empirical range of flight data. This indicates that atmospheric particulates may be a major source of TS-dominated transition on aerodynamically smooth surfaces at supersonic speeds. The receptivity model provides a foundation for further treatments of different cases associated with transition in dusty environments. It can also be used for predictions of particle-induced transition at subsonic and hypersonic speeds.

Spectroscopic detection of Dirac and Weyl fermions in real materials is vital for both, promising applications and fundamental bridge between high-energy and condensed-matter physics. While the presence of Dirac and noncentrosymmetric Weyl fermions is well established in many materials, the magnetic Weyl semimetals still escape direct experimental detection. In order to find a time-reversal symmetry breaking Weyl state we design two materials and present here experimental and theoretical evidence of realization of such a state in one of them, YbMnBi 2 . We model the time-reversal symmetry breaking observed by magnetization and magneto-optical microscopy measurements by canted antiferromagnetism and find a number of Weyl points. Using angle-resolved photoemission, we directly observe two pairs of Weyl points connected by the Fermi arcs. Our results not only provide a fundamental link between the two areas of physics, but also demonstrate the practical way to design novel materials with exotic properties. Candidate materials containing magnetic Weyl fermions remain rare. Here, the authors report evidence of a magnetic Weyl state and observe the surface Fermi arcs in YbMnBi 2 .

This study quantitatively evaluated how insulation by snow depth (SND) affected the soil thermal regime and permafrost degradation in the pan-Arctic area, and more generally defined the characteristics of soil temperature (T SOIL ) and SND from 1901 to 2009. This was achieved through experiments performed with the land surface model CHANGE to assess sensitivity to winter precipitation as well as air temperature. Simulated T SOIL , active layer thickness (ALT), SND, and snow density were generally comparable with in situ or satellite observations at large scales and over long periods. Northernmost regions had snow that remained relatively stable and in a thicker state during the past four decades, generating greater increases in T SOIL . Changes in snow cover have led to changes in the thermal state of the underlying soil, which is strongly dependent on both the magnitude and the timing of changes in snowfall. Simulations of the period 2001–2009 revealed significant differences in the extent of near-surface permafrost, reflecting differences in the model’s treatment of meteorology and the soil bottom boundary. Permafrost loss was greater when SND increased in autumn rather than in winter, due to insulation of the soil resulting from early cooling. Simulations revealed that T SOIL tended to increase over most of the pan-Arctic from 1901 to 2009, and that this increase was significant in northern regions, especially in northeastern Siberia where SND is responsible for 50 % or more of the changes in T SOIL at a depth of 3.6 m. In the same region, ALT also increased at a rate of approximately 2.3 cm per decade. The most sensitive response of ALT to changes in SND appeared in the southern boundary regions of permafrost, in contrast to permafrost temperatures within the 60°N–80°N region, which were more sensitive to changes in snow cover. Finally, our model suggests that snow cover contributes to the warming of permafrost in northern regions and could play a more important role under conditions of future Arctic warming.

One quarter of the Northern hemisphere is underlain by permanently frozen ground, referred to as permafrost. Due to climate warming, irreversibly thawing permafrost is releasing organic matter frozen for up to a million years, most of which decomposes into carbon dioxide and methane, further enhancing the greenhouse effect. Part of this organic matter also consists of revived cellular microbes (prokaryotes, unicellular eukaryotes) as well as viruses that have remained dormant since prehistorical times. While the literature abounds on descriptions of the rich and diverse prokaryotic microbiomes found in permafrost, no additional report about “live” viruses have been published since the two original studies describing pithovirus (in 2014) and mollivirus (in 2015). This wrongly suggests that such occurrences are rare and that “zombie viruses” are not a public health threat. To restore an appreciation closer to reality, we report the preliminary characterizations of 13 new viruses isolated from seven different ancient Siberian permafrost samples, one from the Lena river and one from Kamchatka cryosol. As expected from the host specificity imposed by our protocol, these viruses belong to five different clades infecting Acanthamoeba spp. but not previously revived from permafrost: Pandoravirus, Cedratvirus, Megavirus, and Pacmanvirus, in addition to a new Pithovirus strain.

Atmospheric particulates may be a major source of boundary-layer instabilities leading to laminar–turbulent transition on aerodynamically smooth bodies flying at supersonic speeds. Particulates penetrating into the boundary-layer flow can excite wavepackets of the first- and/or second-mode instability. The packets grow downstream, reach the threshold amplitude and ultimately break down to turbulent spots. A numerical model is developed to simulate excitation of unstable wavepackets by spherical solid particulates. As an example, computations are carried out for a $14^{\\circ }$ half-angle sharp wedge flying at an altitude of 20 km, Mach number 4 and zero angle of attack. The numerical results agree satisfactorily with the theory developed by Fedorov (J. Fluid Mech., vol. 737, 2013, pp. 105–131). The numerical model opens up an opportunity to investigate receptivity to particulates for practical supersonic and hypersonic configurations such as blunt bodies of revolution.

The linear stability analysis predicts that the Mack second mode propagating in the boundary layer on a sufficiently cold plate can radiate acoustic waves into the outer inviscid flow. This effect, which is called as a spontaneous radiation (or emission) of sound, is associated with synchronization of the second mode with slow acoustic waves of the continuous spectrum. The theoretical predictions are confirmed by direct numerical simulations of wave trains and wave packets propagating in the boundary layer on a flat plate at free-stream Mach number 6 and wall-to-edge temperature ratio $T_{w}/T_{e}=0.5$ . A non-uniform distribution of the wave packet components and the interference between the radiated acoustic waves result in an intricate pattern of the outer acoustic field. The spontaneous radiation of sound, in turn, strongly affects the wave packet in the boundary layer causing its elongation and modulation. This phenomenon may alter the downstream development of instability and delay the transition onset.