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Cyclops and Phoenix retire, ushering in a new era for the X-Men.

Most workers regard the Main Central Thrust (MCT) as one of the key high strain zones in the Himalaya because it accommodated at least 90 km of shortening, because that shortening exhumed and buried hanging wall and footwall rocks, and due to geometric and kinematic connections between the Main Central Thrust and the structurally overlying South Tibet Detachment. Geologists currently employ three unrelated definitions of the MCT: metamorphic-rheological, age of motion-structural, or protolith boundary-structural. These disparate definitions generate map and cross-section MCT positions that vary by up to 5 km of structural distance. The lack of consensus and consequent shifting locations impede advances in our understanding of the tectonic development of the orogen. Here, I review pros and cons of the three MCT definitions in current use. None of these definitions is flawless. The metamorphic-rheological and age of motion-structural definitions routinely fail throughout the orogen, whereas the protolith boundary-structural definition may fail only in rare cases, all limited to sectors of the eastern Himalaya. Accordingly, a definition based on high strain zone geometry and kinematics combined with identification of a protolith boundary is the best working definition of the MCT.

The Ediacaran biota were soft-bodied organisms, many with enigmatic phylogenetic placement and ecology, living in marine environments between 574 and 539 million years ago. Some studies hypothesize a metazoan affinity and aerobic metabolism for these taxa, whereas others propose a fundamentally separate taxonomic grouping and a reliance on chemoautotrophy. To distinguish between these hypotheses and test the redox-sensitivity of Ediacaran organisms, here we present a high-resolution local and global redox dataset from carbonates that contain in situ Ediacaran fossils from Siberia. Cerium anomalies are consistently >1, indicating that local environments, where a diverse Ediacaran assemblage is preserved in situ as nodules and carbonaceous compressions, were pervasively anoxic. Additionally, δ 238 U values match other terminal Ediacaran sections, indicating widespread marine euxinia. These data suggest that some Ediacaran biotas were tolerant of at least intermittent anoxia, and thus had the capacity for a facultatively anaerobic lifestyle. Alternatively, these soft-bodied Ediacara organisms may have colonized the seafloor during brief oxygenation events not recorded by redox proxy data. Broad temporal correlations between carbon, sulfur, and uranium isotopes further highlight the dynamic redox landscape of Ediacaran-Cambrian evolutionary events. Geochemical data from sedimentary rocks in Siberia indicate that members of the soft-bodied Ediacara biota (the earliest macroscopic life on Earth) were tolerant of low-oxygen conditions, suggesting they had the capacity for anaerobic metabolisms.

Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell-specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell-specific T-cell tolerance at the onset of clinical diabetes.

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19+ hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells. Alternatively, T cells from a healthy donor can be used to produce an allogeneic CAR T therapy, provided the cells are rendered incapable of eliciting graft versus host disease (GvHD). One approach to the production of these cells is gene editing to eliminate expression of the endogenous T cell receptor (TCR). Here we report a streamlined strategy for generating allogeneic CAR T cells by targeting the insertion of a CAR transgene directly into the native TCR locus using an engineered homing endonuclease and an AAV donor template. We demonstrate that anti-CD19 CAR T cells produced in this manner do not express the endogenous TCR, exhibit potent effector functions in vitro, and mediate clearance of CD19+ tumors in an in vivo mouse model. MacLeod and colleagues use a homing endonuclease and an AAV vector to insert an anti-CD19 CAR into the TRAC gene to create universal allogeneic CAR T cells. Targeted insertion of a CAR transgene may allow the generation of more homogeneous CAR T cell products with more predictable safety and efficacy profiles.

Microparticles coated with encephalitogenic peptides are effective at treating multiple sclerosis in a mouse model. Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide- co -glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.

This book examines young people's political engagement in the Anglo-American democracies. It is often alleged that young people are disengaged from politics on a number of levels. The commonly held view is that young people don't vote, they do not trust politicians and have low levels of political interest. But is this true, where is it true and to what extent? Examining voter turnout, political trust, political interest, electoral and non-electoral forms of participation and Internet use, this book provides a comprehensive account of young people's political engagement in the US, Britain, Canada and Australia. In doing so this book challenges the conventional wisdom on a number of fronts by showing young people's political engagement to be much more complicated than many of the stereotypes suggest (in both good and bad ways).In this way, this book provides a report card on young people's political engagement in the twenty-first century. Young People and Politics will be of interest to students and scholars of political science, comparative politics, public policy and sociology, particularly those with a focus on young people and politics, political participation and public opinion.

We investigate the role of landslide dams, spatial changes in lithology, and rock uplift on faults in the formation of knickzones on bedrock rivers. We focus our analysis in the southwestern Annapurna Range of the central Nepalese Himalaya where detailed geologic maps, topographic data, field observations, and aerial photographs are available. We identified knickzones in our study area from normalized river steepness indices (ksn values) extracted from river longitudinal profiles derived from a 25 m digital elevation model we interpolated from digitized topographic map contours. We compared the location of these knickzones with (1) lithologic contacts and faults from a detailed geologic map of the Modi Khola valley and (2) inferred ancient landslide dam features mapped from field observations and aerial photographs. The steepest location on the Modi Khola occurs near the same latitude as the steepest reach on the Mardi Khola located directly to the east, potentially highlighting a major topographic transition across the Annapurna. However, we find that landslide dams once blocked the flow of the Modi Khola, and damming followed by incision after landslide breaching can explain the location of these knickzones without the need for active faulting near the Main Central thrust. We also conclude that (1) knickzones do not correlate with any spatial changes in lithology and (2) knickzones generated by rock uplift on unmapped faults cannot be ruled out. We emphasize that disentangling the processes responsible for knickzone formation remains challenging even when high‐resolution geologic and topographic data are available. Key Points Landslide dams explain river knickzones without the need for active faulting We observe no correlation between river knickzones and lithologic contacts Out‐of‐sequence thrust faulting near the MCT may not be necessary

Thermobarometric estimates for Lesser and Greater Himalayan rocks combined with detailed structural mapping in the Modi Khola valley of central Nepal reveal that large displacement thrust-sense and normal-sense faults and ductile shear zones mostly control the spatial pattern of exposed metamorphic rocks. Individual shear zone- or fault-bounded domains contain rocks that record approximately the same peak metamorphic conditions and structurally higher thrust sheets carry higher grade rocks. This spatial pattern results from the kinematics of thrust-sense faults and shear zones, which usually place deeper, higher grade rocks on shallower, lower grade rocks. Lesser Himalayan rocks in the hanging wall of the Ramgarh thrust equilibrated at about 9 kbar and 580°C. There is a large increase in recorded pressures and temperatures across the Main Central thrust. Data presented here suggest the presence of a previously unrecognized normal fault entirely within Greater Himalayan strata, juxtaposing hanging wall rocks that equilibrated at about 11 kbar and 720°C against footwall rocks that equilibrated at about 15 kbar and 720°C. Normal faults occur at the structural top and within the Greater Himalayan series, as well as in Lesser Himalayan strata 175 and 1,900 m structurally below the base of the Greater Himalayan series. The major mineral assemblages in the samples collected from the Modi Khola valley record only one episode of metamorphism to the garnet zone or higher grades, although previously reported ca. 500 Ma concordant monazite inclusions in some Greater Himalayan garnets indicate pre-Cenozoic metamorphism.

We combine apatite fission track ages and track‐length measurements with apatite (U‐Th)/He ages to test the hypothesis that active near‐surface faulting is absent at the transition between the Higher and Lower Himalayan physiographic provinces in central Nepal. Fifteen samples define a 2.5‐km‐long, nearly constant‐elevation transect that crosses the largest knickzone on the Modi River in central Nepal. This knickzone could have resulted from modern faulting near the ancient Main Central thrust or from river incision following landslide dam breaching. Apatite fission track ages from the transect are generally ca. 1 Ma, and apatite He ages, selected by considering He concentrations, are 0.5–0.8 Ma. There is no discernable age difference between any of the samples outside 2σ uncertainty. Cooling rates are >100°C/Myr and are uniform across the sample transect. We calculate an average exhumation rate of ∼3 mm/yr across the region, with rates deduced from the fission track data equal to those extracted from the He ages. According to our new data, no fault in our study area has undergone a time‐averaged slip rate faster than 4 mm/yr during the past 1 Myr. Key Points There is no recent offset across a knickpoint in a major river valley Many people have suggested that such features are caused by active faults Low‐T thermochron suggests uniform cooling and exhumation in the valley