Recently, loss of beta-cell-specific traits has been proposed as an early cause of beta cell failure in diabetes. However, the molecular mechanisms that underlie the loss of beta cell features remain ...unclear. Here, we identify an Nkx6.1-controlled gene regulatory network as essential for maintaining the functional and molecular traits of mature beta cells. Conditional Nkx6.1 inactivation in adult mice caused rapid-onset diabetes and hypoinsulinemia. Genome-wide analysis of Nkx6.1-regulated genes and functional assays further revealed a critical role for Nkx6.1 in the control of insulin biosynthesis, insulin secretion, and beta cell proliferation. Over time, Nkx6.1-deficient beta cells acquired molecular characteristics of delta cells, revealing a molecular link between impaired beta cell functional properties and loss of cell identity. Given that Nkx6.1 levels are reduced in human type 2 diabetic beta cells, our study lends support to the concept that loss of beta cell features could contribute to the pathogenesis of diabetes.
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•Beta-cell-specific Nkx6.1 inactivation in adult mice causes diabetes•A gene network necessary for beta cell function is regulated by Nkx6.1•Nkx6.1 controls beta cell proliferation indirectly by regulating glucose import•Nkx6.1 deficiency results in gradual loss of beta cell identity with age
Type 2 diabetes is caused by impaired function of pancreatic beta cells. Beta cell failure in diabetes has been shown to coincide with reduced expression of beta-cell-enriched transcription factors, including Nkx6.1. Here, Sander and colleagues show that loss of Nkx6.1 causes diabetes due to reduced insulin production and secretion. By transcriptionally regulating genes controlling glycolytic flux, Nkx6.1 also maintains the proliferative capacity of beta cells. These results identify Nkx6.1 as an essential regulator of the functional beta cell state.
Discrimination continues to plague society, creating stark inequities between groups. While existing work has considered the role of prejudice in perpetuating discrimination, we draw on emerging ...research on privilege and inequity frames to offer an overlooked, complementary explanation: Objectively discriminatory decisions that are described as favoring, compared with disfavoring, are less likely to be recognized as discrimination. We further theorize this is because favoring decisions are perceived to be motivated by positive intentions. We find support for our hypotheses across eight studies. First, using both qualitative (Studies 1a-b) and experimental approaches (Studies 2-7), across a range of discrimination contexts including race, sex, nationality, and age, we find that inequity frames affect perceptions of discrimination. Further, we find that even human resource employees are less likely to recognize discrimination when described as favoring (Study 3), in turn affecting their reporting behaviors: They are less likely to report potentially discriminatory decisions for review. Next, sampling language from U.S. Supreme Court cases, we find that people support litigation less when discrimination uses a favoring frame, versus disfavoring frame (Study 4). Then, we find that this pattern is driven by inequity frames shaping perceived intentions, rather than perceived harm (Studies 5-6). Finally, we find some evidence that inequity frames regarding a discriminatory decision committed by an organization may affect candidates' job pursuit behaviors (Study 7). This work contributes to a nascent perspective that advantaging mechanisms are critical for creating group inequity: given individuals are less likely to recognize favoritism as discriminatory, favoritism may especially contribute to the persistence of inequity.
Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal ...lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1−/− mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1−/−tnfr1−/− mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.
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•Lethality in ripk1−/− mice is rescued by ablation of ripk3 with either casp8 or fadd•TNF induces apoptosis, and TRIF or IFN induce necroptosis in ripk1−/− cells•Ripk1−/−ripk3−/−tnfr1−/− mice reach adulthood•Lethality in ripk1−/− mice is delayed by deleting tnfr1 with either trif or ifnar
Genetic ablation of RIPK-1 causes postnatal lethality, which is prevented by deletion of RIPK3 together with caspase-8, FADD, or TNFR1. The role of RIPK3 in promoting lethality in ripk1−/− mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth, clarifying the complex roles for RIPK1 in postnatal life.
We prove a topological criterion for the existence of a zero-energy Majorana bound state on a disclination, a rotation symmetry breaking point defect, in fourfold symmetric topological crystalline ...superconductors (TCS) in two dimensions. We first establish a complete topological classification of TCS using the Chern invariant and three integral rotation invariants. By analytically and numerically studying disclinations, we algebraically deduce a Z2 index that identifies the parity of the number of Majorana zero modes at a disclination. Surprisingly, we also find weakly protected Majorana fermions bound at the corners of superconductors with trivial Chern and weak invariants.
Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine ...single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.
We classify discrete-rotation symmetric topological crystalline superconductors (TCS) in two dimensions and provide the criteria for a zero-energy Majorana bound state (MBS) to be present at ...composite defects made from magnetic flux, dislocations, and disclinations. In addition to the Chern number that encodes chirality, discrete rotation symmetry further divides TCS into distinct stable topological classes according to the rotation eigenspectrum of Bogoliubov-de Gennes quasiparticles. Conical crystalline defects are shown to be able to accommodate robust MBS when a certain combination of these bulk topological invariants is nontrivial as dictated by the index theorems proved within. The number parity of MBS is counted by a Z sub(2)-valued index that solely depends on the disclination and the topological class of the TCS. We also discuss the implications for cornerbound Majorana modes on the boundary of topological crystalline superconductors.
Mobile health (mHealth) customers shopping for applications (apps) should be aware of app privacy practices so they can make informed decisions about purchase and use. We sought to assess the ...availability, scope, and transparency of mHealth app privacy policies on iOS and Android. Over 35 000 mHealth apps are available for iOS and Android. Of the 600 most commonly used apps, only 183 (30.5%) had privacy policies. Average policy length was 1755 (SD 1301) words with a reading grade level of 16 (SD 2.9). Two thirds (66.1%) of privacy policies did not specifically address the app itself. Our findings show that currently mHealth developers often fail to provide app privacy policies. The privacy policies that are available do not make information privacy practices transparent to users, require college-level literacy, and are often not focused on the app itself. Further research is warranted to address why privacy policies are often absent, opaque, or irrelevant, and to find a remedy.
Racial inequity continues to plague America, yet many Whites still doubt the existence of racial advantages, limiting progress and cooperation. What happens when people are faced with evidence that ...their group benefits from privilege? We suggest such evidence will be threatening and that people will claim hardships to manage this threat. These claims of hardship allow individuals to deny that they personally benefit from privilege, while still accepting that group-level inequity exists. Experiments 1a and 1b show that Whites exposed to evidence of racial privilege claim to have suffered more personal life hardships than those not exposed to evidence of privilege. Experiment 2 shows that self-affirmation reverses the effect of exposure to evidence of privilege on hardship claims, implicating the motivated nature of hardship claims. Further, affirmed participants acknowledge more personal privilege, which is associated with increased support for inequity-reducing policies.
•We explore why and how Whites deny the existence of racial privilege•We introduce belief in personal privilege as important to psychology of privilege•When given privilege evidence, Whites claim more life hardships•Whites use hardship claims to deny personally benefitting from privilege•Self-affirmed Whites acknowledge personal privilege and support equality policies
Topological electronic materials, such as topological insulators, are distinct from trivial materials in the topology of their electronic band structures that lead to robust, unconventional ...topological states, which could bring revolutionary developments in electronics. This Perspective summarizes developments of topological insulators in various electronic applications including spintronics and magnetoelectronics. We group and analyse several important phenomena in spintronics using topological insulators, including spin-orbit torque, the magnetic proximity effect, interplay between antiferromagnetism and topology, and the formation of topological spin textures. We also outline recent developments in magnetoelectronics such as the axion insulator and the topological magnetoelectric effect observed using different topological insulators.