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FEATURE CONTENTS INTRODUCTION 570 I. AN OVERVIEW OF PRACTICE-BASED CONSTITUTIONAL THEORIES 577 A. Two Components of Constitutional Theories 579 B. Defining Practice-Based Constitutional Theories 582 1. Examples 584 2. The [...], This Feature provides the first full-length treatment of practice-based constitutional theories, which include some of the most important theories advanced in modern scholarship. Practice-based constitutional theories come in originalist and nonoriginalist--as well as conservative and progressive--varieties, and they assert that a constitutional theory should generally conform to our social practices about law. If, for example, it is part of our social practices for courts to apply a robust theory of stare decisis, then a constitutional theory that would require a less deferential theory of stare decisis is a less persuasive theory. Practice-based constitutional theorists would usually see it as a defect if a theory required a significant change in our social practices, such as overruling large swathes of landmark precedents. But why should we care whether a constitutional theory conforms to our social practices? That normative question requires a normative answer, yet there has been very little scholarship systematically analyzing the justifications often given by practice-based theorists for conforming constitutional theories to our social practices. This Feature identifies and examines the primary justifications offered for practice-based constitutional theories: legal positivism, reflective equilibrium, and the stability that comes from an overlapping consensus. In doing so, it also provides the most in-depth analysis of the nature of practice-based constitutional theories to date. The justifications usually offered by practice-based theorists reflect the influence of H.L.A. Hart and John Rawls on American constitutional theory. Although each justification is sophisticated, none can bear the normative weight that would justify conforming constitutional theories to our social practices. A constitutional theory cannot ignore our social practices, but it is the theory that can justify those practices, not the other way around.

INTRODUCTION 2 I. MORAL FRAMEWORKS IN CONSTITUTIONAL THEORY 10 A. Moral Arguments in Constitutional Theory 10 B. Selecting a Moral Framework 13 II. THE MORAL BASIS FOR POLITICAL AUTHORITY AND [...], One of the most enduring criticisms of originalism is that it lacks a sufficiently compelling moral justification. Scholars operating within the natural law tradition have been among the foremost critics of originalism's morality, yet originalists have yet to offer a sufficient defense of originalism from within the natural law tradition that demonstrates that these critics are mistaken. That task has become more urgent in recent years due to Adrian Vermeule's critique of originalism from within the natural law tradition, which has received greater attention than previous critiques. This Article is the first full-length response to the natural law critique of originalism as represented by Vermeule, presenting an affirmative argument for originalism from within the natural law tradition. Although other theorists have offered natural law justifications for originalism, they have not yet developed a theory of legitimate authority, which is essential both to the natural law tradition and to originalism. This Article fills that gap by grounding originalism in the legitimate authority of the people-as-sovereign. In doing so, it draws upon and adapts centuries-old natural law arguments in favor of popular sovereignty that have rarely been mentioned in American law reviews and have never been presented as the basis for originalism. By creating a novel synthesis between this natural law theory of popular sovereignty and originalism, the Article offers new responses to longstanding objections to popular-sovereignty-based originalist theories, such as the exclusion of women and enslaved Black people from the ratification process. Finally, having answered those criticisms, the Article shows that obeying the original meaning of the Constitution is necessary to preserve the legitimate authority of the people, which is essential to achieving the common good. This allows the Article to confront the core of the natural law critique: that originalism is incompatible with the natural law because it privileges the original meaning above the natural law when they are in conflict. The Article demonstrates that this critique overlooks the natural law limits on judicial authority that undergird the common good. By grounding originalism in a moral argument drawn from the natural law, this Article shows that, far from being a morally empty jurisprudence, originalism is justified by the moral authority of original meaning.

Background:Mailed outreach promoting colorectal cancer (CRC) screening with a stool blood test kit may increase participation, but magnitude and consistency of benefit of this intervention strategy is uncertain.Aim:Conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing mailed outreach offering stool tests to usual care, clinic-based screening offers on CRC screening uptake in the United States.Methods:We performed a systematic literature search of 5 databases for RCTs of mailed outreach January 1980 through June 2017. Primary outcome was screening completion, summarized using random-effects meta-analysis as pooled differences in proportion completing screening and relative risk of achieving screening compared to control. Subgroup analyses by test type offered--fecal immunochemical test (FIT) or guaiac fecal occult blood test (gFOBT)--, presence of telephone reminders, and presence of predominant underserved/minority population within study were performed. Quality of evidence was evaluated using the GRADE framework.Results:7 RCTs which enrolled 12,501 subjects were included (n=5,703 assigned mailed outreach and n=6,798 usual care). Mailed outreach resulted in a 28% absolute (95%CI: 25–30%; I2=47%), and a 2.8-fold relative (RR 2.65, 95%CI: 2.03–3.45; I2=92%) increase in screening completion compared to usual care, with a number needed to invite of 3.6. Similar outcomes were observed across subgroups. Overall body of evidence was moderate quality.Conclusions:Mailed outreach offering a gFOBT or FIT is associated with a large and consistent increase in CRC screening completion and should be considered for more widespread implementation for improving screening rates nationwide.DOI: 10.1007/s10620-019-05587-6

INTRODUCTION 1146 I. EMOTION IN THE INDIVIDUAL 1153 A. Appetite and Apprehension 1156 B. A clivation of the Appetites 1162 C. Reason, Emotion, and the Will 1164 D. Contra Aquinas [...], Although the role of emotion in law has become a major field of scholarship, there has been very little attention paid to the role of emotion in constitutional theory. This Article seeks to fill that gap by providing an integrated account of the role of emotion within the individual, how emotion affects constitutional culture, and how constitutional culture, properly understood, should affect our evaluation of major constitutional theories. The Article begins by reconstructing one of the most important and influential accounts of emotion in the philosophical literature: that of Thomas Aquinas. Because Aquinas's description of the nature of emotion accords with modern science and the insights of many law-and-emotion theorists, it provides a firm foundation for an analysis of emotion in constitutional theory. Having laid that foundation, the Article examines the role of emotion in constitutional culture, the subset of national culture concerned with a constitution. Constitutional culture combines a society's ideas about, and emotional attachments to, its constitution. Here, the Article develops a novel synthesis between Aquinas's model of emotion and Edmund Burke's sophisticated exploration of the importance of emotion in constitutional culture. Burke argues that theories of constitutional legitimacy shape constitutional culture and must accord with it. If a theory of legitimacy is at odds with a society's constitutional culture, the society risks the instability of the regime. This insight--which is consistent with Aquinas's model of emotion--is the primary basis for understanding the role of emotion in constitutional theory. Finally, the Article turns its attention to constitutional theory. Observing that popular sovereignty is the theory of legitimacy endorsed by our constitutional culture, the Article argues--based on the synthesis of the Thomistic and Burkean accounts--that emotion should play an important role in evaluating the contours and viability of theories of legitimacy. Theories of legitimacy that accord with popular sovereignty have a stronger argument in their favor because they reinforce the emotional attachments that lend stability to our Constitution. Theories of legitimacy that reject popular sovereignty, by contrast, must be modified or abandoned or, alternatively, must explain why attempts to change our constitutional culture will avoid the instability that the Thomistic and Burkean accounts would predict. The Article therefore has particular relevance to assessing radical constitutional theories--whether from the political right or the political left--that are critical of American constitutional culture. The Article concludes by exploring the implications of emotion for constitutional doctrine, focusing on stare decisis and the examples of"Roe v. Wade, 410U.S. 113(1973), and Miranda v. Arizona, 384 U.S. 436 (1966).

ObjectivesOffering financial incentives to promote or "nudge" participation in cancer screening programs, particularly among vulnerable populations who traditionally have lower rates of screening, has been suggested as a strategy to enhance screening uptake. However, effectiveness of such practices has not been established. Our aim was to determine whether offering small financial incentives would increase colorectal cancer (CRC) screening completion in a low-income, uninsured population.MethodsWe conducted a randomized, comparative effectiveness trial among primary care patients, aged 50-64 years, not up-to-date with CRC screening served by a large, safety net health system in Fort Worth, Texas. Patients were randomly assigned to mailed fecal immunochemical test (FIT) outreach (n=6,565), outreach plus a $5 incentive (n=1,000), or outreach plus a $10 incentive (n=1,000). Outreach included reminder phone calls and navigation to promote diagnostic colonoscopy completion for patients with abnormal FIT. Primary outcome was FIT completion within 1 year, assessed using an intent-to-screen analysis.ResultsFIT completion was 36.9% with vs. 36.2% without any financial incentive (P=0.60) and was also not statistically different for the $10 incentive (34.6%, P=0.32 vs. no incentive) or $5 incentive (39.2%, P=0.07 vs. no incentive) groups. Results did not differ substantially when stratified by age, sex, race/ethnicity, or neighborhood poverty rate. Median time to FIT return also did not differ across groups.ConclusionsFinancial incentives, in the amount of $5 or $10 offered in exchange for responding to mailed invitation to complete FIT, do not impact CRC screening completion.

ObjectiveTo examine behavioural intention to reduce soda consumption after exposure to the Choose Health LA 'Sugar Pack' campaign in Los Angeles County, California, USA.DesignA cross-sectional street-intercept survey was conducted to assess knowledge, attitudes, health behaviours and behavioural intentions after exposure to the 'Sugar Pack' campaign. A multivariable regression analysis was performed to examine the relationships between the amount of soda consumed and self-reported intention to reduce consumption of non-diet soda among adults who saw the campaign.SettingThree pre-selected Los Angeles County Metro bus shelters and/or rail stops with the highest number of 'Sugar Pack' campaign advertisement placements.SubjectsRiders of the region's Metro buses and railways who were the intended audience of the campaign advertisements.ResultsThe overall survey response rate was 56 % (resulting n 1041). Almost 60 % of respondents were exposed to the advertisements (619/1041). The multivariable logistic regression analysis suggested that the odds of reporting intention to reduce soda consumption among moderate consumers (1-6 sodas/week) were 1·95 times greater than among heavy consumers (≥1 soda/d), after controlling for clustering and covariates. Respondents with less than a high-school education and who perceived sugary beverage consumption as harmful also had higher odds; in contrast, respondents aged ≥65 years had lower odds.ConclusionsResults suggest that future campaigns should be tailored differently for moderate v. heavy consumers of soda. Similar tailoring strategies are likely needed for younger groups, for those with less educational attainment and for those who do not perceive consumption of soda as harmful.

Non-Abelian anyons promise to reveal spectacular features of quantum mechanics that could ultimately provide the foundation for a decoherence-free quantum computer. A key breakthrough in the pursuit of these exotic particles originated from Read and Green's observation that the Moore-Read quantum Hall state and a (relatively simple) two-dimensional p + ip superconductor both support so-called Ising non-Abelian anyons. Here, we establish a similar correspondence between the Z3 Read-Rezayi quantum Hall state and a novel two-dimensional superconductor in which charge-2e Cooper pairs are built from fractionalized quasiparticles. In particular, both phases harbor Fibonacci anyons that-unlike Ising anyons-allow for universal topological quantum computation solely through braiding. Using a variant of Teo and Kane's construction of non-Abelian phases from weakly coupled chains, we provide a blueprint for such a superconductor using Abelian quantum Hall states interlaced with an array of superconducting islands. Fibonacci anyons appear as neutral deconfined particles that lead to a twofold ground-state degeneracy on a torus. In contrast to a p + ip superconductor, vortices do not yield additional particle types, yet depending on nonuniversal energetics can serve as a trap for Fibonacci anyons. These results imply that one can, in principle, combine well-understood and widely available phases of matter to realize non-Abelian anyons with universal braid statistics. Numerous future directions are discussed, including speculations on alternative realizations with fewer experimental requirements.

Objective To assess whether crowdsourcing is a viable option for conducting surveillance of point of sale (POS) tobacco marketing practices. Methods We posted jobs to an online crowdsourcing platform to audit 194 Florida licensed tobacco retailers over a 3-week period. During the same period, trained data collectors conducted audits at the same retail locations. Data were collected on cigarette advertising, cigarette promotions and product availability (electronic cigarettes, snus and dissolvables). We compared data collected by crowdsourced workers and trained staff and computed frequencies, percent agreement and inter-rater reliability. Photographs of e-cigarettes and exterior cigarette advertisements submitted by crowdsourced workers were used to validate responses. Results Inter-rater reliability between crowdsourced and trained data collectors was moderate to high for coding exterior cigarette advertisements, product availability and some tobacco promotions, but poor to fair when coding presence of sales and interior cigarette advertisements. Photos submitted by crowdsourced workers confirmed e-cigarette availability that was missed by trained data collectors in three stores. Conclusions Crowdsourcing may be a promising form of data collection for some POS tobacco measures. Future studies should examine the cost-effectiveness of crowdsourcing compared with traditional trained data collectors and assess which POS measures are most amenable to crowdsourcing. [ABSTRACT FROM AUTHOR]

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, is associated with cognitive impairment and tau accumulation. In this study, we explored tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify the tau seeding activity present in brain homogenates by detecting the conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Pathogenic tau assemblies exhibit seeding barriers, where a specific assembly structure cannot serve as a template for a native monomer if the amino acid sequences are incompatible. We recently leveraged this species barrier to define tauopathies systematically by substituting alanine (Ala) into the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. This Ala scan precisely classified the conformation of tau seeds from various tauopathies. In this study, we analyzed 18 ET patient brains with tau pathology, detecting robust tau seeding activity in 9 (50%) of the cases, predominantly localized to the temporal pole and temporal cortex. We further examined 8 of these ET cases using the Ala scan and found that the amino acid requirements for tau monomer incorporation into aggregates seeded from ET brain homogenates were identical to those of Alzheimer's disease (AD) and primary age-related tauopathy (PART), and distinct from other tauopathies, such as corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP). These findings indicate that in a pathologically confined subset of ET cases with significant tau pathology, tau assembly cores are identical to those seen in AD and PART. This could facilitate more precise diagnosis and targeted therapies for ET patients presenting with cognitive impairment., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process., Methods: We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5 h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and pharmacological manipulations of VCP., Results: VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on seeding in HEK293T tau biosensor cells and human neurons: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors only functioned when administered within 8 h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding., Conclusions: Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: The authors give consent for publication. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disease that, in some cases, is associated with cognitive impairment and tau accumulation. Consequently, we explored the tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify tau prion seeding activity present in brain homogenates based on conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Prions exhibit seeding barriers, whereby a specific assembly structure cannot serve as a template for a native monomer if the amino acids are not compatible. We recently exploited the tau prion species barrier to define tauopathies by systematically substituting alanine (Ala) in the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. The Ala scan precisely classified the conformation of tau seeds from diverse tauopathies. We next studied 18 ET patient brains with tau pathology. Only one case had concurrent high amyloid-β plaque pathology consistent with Alzheimer's disease (AD). We detected robust tau seeding activity in 9 (50%) of the patients. This predominantly localized to the temporal pole and temporal cortex. We examined 8 ET cases with the Ala scan and determined that the amino acid requirements for tau monomer incorporation into aggregates seeded from these ET brain homogenates were identical to those of AD and primary age-related tauopathy (PART), and completely distinct from other tauopathies such as corticobasal degeneration, chronic traumatic encephalopathy, and progressive supranuclear palsy. Based on these studies, tau assembly cores in a pathologically confined subset of ET cases with high tau pathology are identical to AD and PART. This could facilitate more precise diagnosis and therapy for ET patients with cognitive impairment., Competing Interests: Competing interests: All authors declare they have no competing interests.

Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids., (© 2024. The Author(s).)

Magic-angle twisted trilayer graphene (MATTG) exhibits a range of strongly correlated electronic phases that spontaneously break its underlying symmetries 1,2 . Here we investigate the correlated phases of MATTG using scanning tunnelling microscopy and identify marked signatures of interaction-driven spatial symmetry breaking. In low-strain samples, over a filling range of about two to three electrons or holes per moiré unit cell, we observe atomic-scale reconstruction of the graphene lattice that accompanies a correlated gap in the tunnelling spectrum. This short-scale restructuring appears as a Kekulé supercell-implying spontaneous inter-valley coherence between electrons-and persists in a wide range of magnetic fields and temperatures that coincide with the development of the gap. Large-scale maps covering several moiré unit cells further reveal a slow evolution of the Kekulé pattern, indicating that atomic-scale reconstruction coexists with translation symmetry breaking at a much longer moiré scale. We use auto-correlation and Fourier analyses to extract the intrinsic periodicity of these phases and find that they are consistent with the theoretically proposed incommensurate Kekulé spiral order 3,4 . Moreover, we find that the wavelength characterizing moiré-scale modulations monotonically decreases with hole doping away from half-filling of the bands and depends weakly on the magnetic field. Our results provide essential insights into the nature of the correlated phases of MATTG in the presence of strain and indicate that superconductivity can emerge from an inter-valley coherent parent state., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Recent experiments on Bernal bilayer graphene (BLG) deposited on monolayer WSe_{2} revealed robust, ultraclean superconductivity coexisting with sizable induced spin-orbit coupling. Here, we propose BLG/WSe_{2} as a platform to engineer gate-defined planar topological Josephson junctions, where the normal and superconducting regions descend from a common material. More precisely, we show that if superconductivity in BLG/WSe_{2} is gapped and emerges from a parent state with intervalley coherence, then Majorana zero-energy modes can form in the barrier region upon applying weak in-plane magnetic fields. Our results spotlight a potential pathway for "internally engineered" topological superconductivity that minimizes detrimental disorder and orbital-magnetic-field effects.

Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306 VQIVYK 311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations., (© 2023. The Author(s).)

Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We evaluate our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures., (© 2023. The Author(s).)

In the presence of a large perpendicular electric field, Bernal-stacked bilayer graphene (BLG) features several broken-symmetry metallic phases 1-3 as well as magnetic-field-induced superconductivity 1 . The superconducting state is quite fragile, however, appearing only in a narrow window of density and with a maximum critical temperature T c  ≈ 30 mK. Here we show that placing monolayer tungsten diselenide (WSe 2 ) on BLG promotes Cooper pairing to an extraordinary degree: superconductivity appears at zero magnetic field, exhibits an order of magnitude enhancement in T c and occurs over a density range that is wider by a factor of eight. By mapping quantum oscillations in BLG-WSe 2 as a function of electric field and doping, we establish that superconductivity emerges throughout a region for which the normal state is polarized, with two out of four spin-valley flavours predominantly populated. In-plane magnetic field measurements further reveal that superconductivity in BLG-WSe 2 can exhibit striking dependence of the critical field on doping, with the Chandrasekhar-Clogston (Pauli) limit roughly obeyed on one end of the superconducting dome, yet sharply violated on the other. Moreover, the superconductivity arises only for perpendicular electric fields that push BLG hole wavefunctions towards WSe 2 , indicating that proximity-induced (Ising) spin-orbit coupling plays a key role in stabilizing the pairing. Our results pave the way for engineering robust, highly tunable and ultra-clean graphene-based superconductors., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Graphene moiré superlattices show an abundance of correlated insulating, topological, and superconducting phases. Whereas the origins of strong correlations and nontrivial topology can be directly linked to flat bands, the nature of superconductivity remains enigmatic. We demonstrate that magic-angle devices made of twisted tri-, quadri-, and pentalayer graphene placed on monolayer tungsten diselenide exhibit flavor polarization and superconductivity. We also observe insulating states in the tril- and quadrilayer arising at finite electric displacement fields. As the number of layers increases, superconductivity emerges over an enhanced filling-factor range, and in the pentalayer it extends well beyond the filling of four electrons per moiré unit cell. Our results highlight the role of the interplay between flat and more dispersive bands in extending superconducting regions in graphene moiré superlattices.

Relativistic Mott insulators known as "Kitaev materials" potentially realize spin liquids hosting non-Abelian anyons. Motivated by fault-tolerant quantum-computing applications in this setting, we introduce a dynamical anyon-generation protocol that exploits universal edge physics. The setup features holes in the spin liquid, which define energetically cheap locations for non-Abelian anyons, connected by a narrow bridge that can be tuned between spin liquid and topologically trivial phases. We show that modulating the bridge from trivial to spin liquid over intermediate time scales-quantified by analytics and extensive simulations-deposits non-Abelian anyons into the holes with O(1) probability. The required bridge manipulations can be implemented by integrating the Kitaev material into magnetic tunnel junction arrays that engender locally tunable exchange fields. Combined with existing readout strategies, our protocol reveals a path to topological qubit experiments in Kitaev materials at zero applied magnetic field.

Magic-angle twisted trilayer graphene (MATTG) has emerged as a moiré material that exhibits strong electronic correlations and unconventional superconductivity 1,2 . However, local spectroscopic studies of this system are still lacking. Here we perform high-resolution scanning tunnelling microscopy and spectroscopy of MATTG that reveal extensive regions of atomic reconstruction favouring mirror-symmetric stacking. In these regions, we observe symmetry-breaking electronic transitions and doping-dependent band-structure deformations similar to those in magic-angle bilayers, as expected theoretically given the commonality of flat bands 3,4 . Most notably in a density window spanning two to three holes per moiré unit cell, the spectroscopic signatures of superconductivity are manifest as pronounced dips in the tunnelling conductance at the Fermi level accompanied by coherence peaks that become gradually suppressed at elevated temperatures and magnetic fields. The observed evolution of the conductance with doping is consistent with a gate-tunable transition from a gapped superconductor to a nodal superconductor, which is theoretically compatible with a sharp transition from a Bardeen-Cooper-Schrieffer superconductor to a Bose-Einstein-condensation superconductor with a nodal order parameter. Within this doping window, we also detect peak-dip-hump structures that suggest that superconductivity is driven by strong coupling to bosonic modes of MATTG. Our results will enable further understanding of superconductivity and correlated states in graphene-based moiré structures beyond twisted bilayers 5 ., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43., Methods: We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice., Results: One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons., Conclusion: Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP's surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP., (© 2022. The Author(s).)

An IQ consortium working group (WG) conducted a survey across multiple biopharmaceutical companies to gain information about the level of blinding commonly utilized for early clinical development trials. The main objectives were: (1) to understand blinding practices between healthy volunteer (HV) and early explorative patient trials in all therapeutic areas except oncology where early clinical trials are commonly open-label; (2) to understand the rationale for blinding/unblinding practices; (3) to understand the groups and personnel involved in unblinding; and (4) strategic considerations around blinding/unblinding options in early clinical development trials-risk of bias vs. potential for acceleration. A survey containing 31 main questions with additional sub-clarifying questions was conducted. Sixteen large and mid-size pharmaceutical companies responded. Responses were aligned across functions within each participating company. Additional information was gathered at an American Association of Pharmaceutical Scientists (AAPS) webinar with polling options to roughly 550 registered attendees to evaluate the reason for the unblinding decisions. The results revealed divergence across companies in the blinding approaches most commonly applied but with some study types, there were clearly favored options. Based on these results, the WG developed strategic considerations for first-in-human HV trials and nonpivotal explorative trials in patients. This paper should facilitate discussions among various clinical development functions, such as Clinical Pharmacology, Statistics, Clinical, Bioanalytics, and Regulatory Functions. Such discussions on study design and operations are warranted to allow implementation of more flexible blinding approaches to accelerate data driven decisions in drug development and allow earlier access of patients to needful medicines., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Tauopathies consist of over 25 different neurodegenerative diseases that include argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Tauopathies are defined by brain accumulation of microtubule-associated protein tau in fibrillar aggregates, whose prevalence strongly correlates with dementia. Dominant mutations in tau cause neurodegenerative diseases, and most increase its aggregation propensity. Pathogenesis of tauopathies may involve pathological tau conformers that serve as templates to recruit native protein into growing assemblies and also move between brain cells to cause disease progression, similar to prions. Prions adopt pathological conformations, termed "strains," that stably propagate in living systems, and create unique patterns of neuropathology. Data from multiple laboratories now suggest that tau acts as a prion. It propagates unique strains indefinitely in cultured cells, and when these are inoculated into mouse models, they create defined neuropathological patterns, which establish a direct link between conformation and disease. In humans, distinct fibril structures are associated with different diseases, but causality has not been established as in mice. Cryo-EM structures of tau fibrils isolated from tauopathy brains reveal distinct fibril cores across disease. Interestingly, the conformation of the tau monomer unit within different fibril subtypes from the same patient appears relatively preserved. This is consistent with data that the tau monomer samples an ensemble of conformations that act as distinct pathologic templates in the formation of restricted numbers of strains. The propensity of a tau monomer to adopt distinct conformations appears to be linked to defined local motifs that expose different patterns of amyloidogenic amino acid sequences. The prion hypothesis, which predicts that protein structure dictates resultant disease, has proved particularly useful to understand the diversity of human tauopathies. The challenge now is to develop methods to rapidly classify patients according to the structure of the underlying pathological protein assemblies to achieve more accurate diagnosis and effective therapy.