Electrically Tunable, Rapid Spin-Orbit Torque Induced Modulation of Colossal Magnetoresistance in Mn3Si2Te6 Nanoflakes.

As a quasi-layered ferrimagnetic material, Mn3Si2Te6 nanoflakes exhibit magnetoresistance behavior that is fundamentally different from their bulk crystal counterparts. They offer three key properties crucial for spintronics. First, at least 106 times faster response compared to that exhibited by bulk crystals has been observed in current-controlled resistance and magnetoresistance. Second, ultralow current density is required for resistance modulation (∼5 A/cm2). Third, electrically gate-tunable magnetoresistance has been realized. Theoretical calculations reveal that the unique magnetoresistance behavior in the Mn3Si2Te6 nanoflakes arises from a magnetic field induced band gap shift across the Fermi level. The rapid current induced resistance variation is attributed to spin-orbit torque, an intrinsically ultrafast process (∼nanoseconds). This study suggests promising avenues for spintronic applications. In addition, it highlights Mn3Si2Te6 nanoflakes as a suitable platform for investigating the intriguing physics underlying chiral orbital moments, magnetic field induced band variation, and spin torque.

The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series.

Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed.

GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

Room-Temperature Magnetic Phase Transition in an Electrically Tuned van der Waals Ferromagnet.

Finding tunable van der Waals (vdW) ferromagnets that operate at above room temperature is an important research focus in physics and materials science. Most vdW magnets are only intrinsically magnetic far below room temperature and magnetism with square-shaped hysteresis at room temperature has yet to be observed. Here, we report magnetism in a quasi-2D magnet Cr_{1.2}Te_{2} observed at room temperature (290 K). This magnetism was tuned via a protonic gate with an electron doping concentration up to 3.8×10^{21} cm^{-3}. We observed nonmonotonic evolutions in both coercivity and anomalous Hall resistivity. Under increased electron doping, the coercivities and anomalous Hall effects (AHEs) vanished, indicating a doping-induced magnetic phase transition. This occurred up to room temperature. DFT calculations showed the formation of an antiferromagnetic (AFM) phase caused by the intercalation of protons which induced significant electron doping in the Cr_{1.2}Te_{2}. The tunability of the magnetic properties and phase in room temperature magnetic vdW Cr_{1.2}Te_{2} is a significant step towards practical spintronic devices.

Electric Control of Exchange Bias Effect in FePS3-Fe5GeTe2 van der Waals Heterostructures.

Manipulating the exchange bias (EB) effect using an electronic gate is a significant goal in spintronics. The emergence of van der Waals (vdW) magnetic heterostructures has provided improved means to study interlayer magnetic coupling, but to date, these heterostructures have not exhibited electrical gate-controlled EB effects. Here, we report electrically controllable EB effects in a vdW heterostructure, FePS3-Fe5GeTe2. By applying a solid protonic gate, the EB effects were repeatably electrically tuned. The EB field reaches up to 23% of the coercivity and the blocking temperature ranges from 30 to 60 K under various gate-voltages. The proton intercalations not only tune the average magnetic exchange coupling but also change the antiferromagnetic configurations in the FePS3 layer. These result in a dramatic modulation of the total interface exchange coupling and the resultant EB effects. The study is a significant step toward vdW heterostructure-based magnetic logic for future low-energy electronics.

Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism.

While structural symmetry is a prevailing feature of homo-oligomeric proteins, asymmetry provides unique mechanistic opportunities. We present the crystal structure of full-length TRAP1, the mitochondrial Hsp90 molecular chaperone, in a catalytically active closed state. The TRAP1 homodimer adopts a distinct, asymmetric conformation, where one protomer is reconfigured via a helix swap at the middle:C-terminal domain (MD:CTD) interface. This interface plays a critical role in client binding. Solution methods validate the asymmetry and show extension to Hsp90 homologs. Point mutations that disrupt unique contacts at each MD:CTD interface reduce catalytic activity and substrate binding and demonstrate that each protomer needs access to both conformations. Crystallographic data on a dimeric NTD:MD fragment suggests that asymmetry arises from strain induced by simultaneous NTD and CTD dimerization. The observed asymmetry provides the potential for an additional step in the ATPase cycle, allowing sequential ATP hydrolysis steps to drive both client remodeling and client release.

Spin-Momentum Locking Induced Anisotropic Magnetoresistance in Monolayer WTe2.

Monolayer WTe2 is predicted to be a quantum spin Hall insulator (QSHI), and its quantized edge transport has recently been demonstrated. However, one of the essential properties of a QSHI, spin-momentum locking of the helical edge states, has yet to be experimentally validated. Here, we measure and observe gate-controlled anisotropic magnetoresistance (AMR) in monolayer WTe2 devices. Electrically tuning the Fermi energy into the band gap, a large in-plane AMR is observed and the minimum of the in-plane AMR occurs when the applied magnetic field is perpendicular to the current direction. In line with the experimental observations, the theoretical predictions based on the band structure of monolayer WTe2 demonstrate that the AMR effect originates from spin-momentum locking in the helical edge states of monolayer WTe2. Our findings reveal that the spin quantization axis of the helical edge states in monolayer WTe2 can be precisely determined from AMR measurements.

Gate-Controlled Magnetic Phase Transition in a van der Waals Magnet Fe5GeTe2.

Magnetic van der Waals (vdW) materials are poised to enable all-electrical control of magnetism in the two-dimensional limit. However, tuning the magnetic ground state in vdW itinerant ferromagnets by voltage-induced charge doping remains a significant challenge, due to the extremely large carrier densities in these materials. Here, by cleaving the vdW itinerant ferromagnet Fe5GeTe2 (F5GT) into 5.4 nm (around two unit cells), we find that the ferromagnetism (FM) in F5GT can be substantially tuned by the thickness. Moreover, by utilizing a solid protonic gate, an electron doping concentration of above 1021 cm-3 has been exhibited in F5GT nanosheets. Such a high carrier accumulation exceeds that possible in widely used electric double-layer transistors (EDLTs) and surpasses the intrinsic carrier density of F5GT. Importantly, it is accompanied by a magnetic phase transition from FM to antiferromagnetism (AFM). The realization of an antiferromagnetic phase in nanosheet F5GT suggests the promise of applications in high-temperature antiferromagnetic vdW devices and heterostructures.

Gate-Tuned Interlayer Coupling in van der Waals Ferromagnet Fe_{3}GeTe_{2} Nanoflakes.

The weak interlayer coupling in van der Waals (vdW) magnets has confined their application to two dimensional (2D) spintronic devices. Here, we demonstrate that the interlayer coupling in a vdW magnet Fe_{3}GeTe_{2} (FGT) can be largely modulated by a protonic gate. With the increase of the protons intercalated among vdW layers, interlayer magnetic coupling increases. Because of the existence of antiferromagnetic layers in FGT nanoflakes, the increasing interlayer magnetic coupling induces exchange bias in protonated FGT nanoflakes. Most strikingly, a rarely seen zero-field cooled (ZFC) exchange bias with very large values (maximally up to 1.2 kOe) has been observed when higher positive voltages (V_{g}≥4.36 V) are applied to the protonic gate, which clearly demonstrates that a strong interlayer coupling is realized by proton intercalation. Such strong interlayer coupling will enable a wider range of applications for vdW magnets.

Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition.

Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the ∼10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity.

Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.

Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.

Electrically controlled superconductor-to-failed insulator transition and giant anomalous Hall effect in kagome metal CsV3Sb5 nanoflakes.

The electronic correlations (e.g. unconventional superconductivity (SC), chiral charge order and nematic order) and giant anomalous Hall effect (AHE) in topological kagome metals AV3Sb5 (A = K, Rb, and Cs) have attracted great interest. Electrical control of those correlated electronic states and AHE allows us to resolve their own nature and origin and to discover new quantum phenomena. Here, we show that electrically controlled proton intercalation has significant impacts on striking quantum phenomena in CsV3Sb5 nanodevices mainly through inducing disorders in thinner nanoflakes and carrier density modulation in thicker ones. Specifically, in disordered thin nanoflakes (below 25 nm), we achieve a quantum phase transition from a superconductor to a "failed insulator" with a large saturated sheet resistance for T → 0 K. Meanwhile, the carrier density modulation in thicker nanoflakes shifts the Fermi level across the charge density wave (CDW) gap and gives rise to an extrinsic-intrinsic transition of AHE. With the first-principles calculations, the extrinsic skew scattering of holes in the nearly flat bands with finite Berry curvature by multiple impurities would account for the giant AHE. Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition (SIT), outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV3Sb5 family.

Psycho-social reflections on craniofacial morphogenesis.

Psychologists are now increasingly involved in understanding the challenges faced by people who experience facial disfigurements from many causes (congenital, traumatic, oncological, iatrogenic, neurological, ophthalmological or dermatological). This article describes how the author has combined the lessons of his personal recovery after severe facial burns with the rigorous science of psychological research to enable improved psycho-social support and interventions to be developed, through a UK not-for-profit (Changing Faces) and in formal health care services. It suggests that against the background of a culture that is less-than-positive about disfigurement, anyone who experiences it needs access to a range of support, advice, counselling and social skills training to enable them to live full, confident lives.

A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities.

E3 ubiquitin ligases catalyze the final step of ubiquitin conjugation and regulate numerous cellular processes. The HECT class of E3 ubiquitin (Ub) ligases directly transfers Ub from bound E2 enzyme to a myriad of substrates. The catalytic domain of HECT Ub ligases has a bilobal architecture that separates the E2 binding region and catalytic site. An important question regarding HECT domain function is the control of ligase activity and specificity. Here we present a functional analysis of the HECT domain of the E3 ligase HUWE1 based on crystal structures and show that a single N-terminal helix significantly stabilizes the HECT domain. We observe that this element modulates HECT domain activity, as measured by self-ubiquitination induced in the absence of this helix, as distinct from its effects on Ub conjugation of substrate Mcl-1. Such subtle changes to the protein may be at the heart of the vast spectrum of substrate specificities displayed by HECT domain E3 ligases.

A small molecule that preferentially binds the closed conformation of Hsp90.

Described is the synthesis of three different fluorescein-tagged derivatives of a macrocycle, and their binding affinity to heat shock protein 90 (Hsp90). Using fluorescence polarization anisotropy, we report the binding affinity of these fluorescein-labeled compounds to Hsp90 in its open state and ATP-dependent closed state. We show that the compounds demonstrate a conformation-dependent preference for binding to the closed state.

Antisymmetric magnetoresistance in van der Waals Fe3GeTe2/graphite/Fe3GeTe2 trilayer heterostructures.

With no requirements for lattice matching, van der Waals (vdW) ferromagnetic materials are rapidly establishing themselves as effective building blocks for next-generation spintronic devices. We report a hitherto rarely seen antisymmetric magnetoresistance (MR) effect in vdW heterostructured Fe3GeTe2 (FGT)/graphite/FGT devices. Unlike conventional giant MR (GMR), which is characterized by two resistance states, the MR in these vdW heterostructures features distinct high-, intermediate-, and low-resistance states. This unique characteristic is suggestive of underlying physical mechanisms that differ from those observed before. After theoretical calculations, the three-resistance behavior was attributed to a spin momentum locking induced spin-polarized current at the graphite/FGT interface. Our work reveals that ferromagnetic heterostructures assembled from vdW materials can exhibit substantially different properties to those exhibited by similar heterostructures grown in vacuum. Hence, it highlights the potential for new physics and new spintronic applications to be discovered using vdW heterostructures.

Structures of human plasma ß-factor XIIa cocrystallized with potent inhibitors.

Activated factor XIIa (FXIIa) is a serine protease that has received a great deal of interest in recent years as a potential target for the development of new antithrombotics. Despite the strong interest in obtaining structural information, only the structure of the FXIIa catalytic domain in its zymogen conformation is available. In this work, reproducible experimental conditions found for the crystallization of human plasma ß-FXIIa and crystal growth optimization have led to determination of the first structure of the active form of the enzyme. Two crystal structures of human plasma ß-FXIIa complexed with small molecule inhibitors are presented herein. The first is the noncovalent inhibitor benzamidine. The second is an aminoisoquinoline containing a boronic acid-reactive group that targets the catalytic serine. Both benzamidine and the aminoisoquinoline bind in a canonical fashion typical of synthetic serine protease inhibitors, and the protease domain adopts a typical chymotrypsin-like serine protease active conformation. This novel structural data explains the basis of the FXII activation, provides insights into the enzymatic properties of ß-FXIIa, and is a great aid toward the further design of protease inhibitors for human FXIIa.

Hard magnetic properties in nanoflake van der Waals Fe3GeTe2.

Two-dimensional van der Waals materials have demonstrated fascinating optical and electrical characteristics. However, reports on magnetic properties and spintronic applications of van der Waals materials are scarce by comparison. Here, we report anomalous Hall effect measurements on single crystalline metallic Fe3GeTe2 nanoflakes with different thicknesses. These nanoflakes exhibit a single hard magnetic phase with a near square-shaped magnetic loop, large coercivity (up to 550 mT at 2 K), a Curie temperature near 200 K and strong perpendicular magnetic anisotropy. Using criticality analysis, the coupling length between van der Waals atomic layers in Fe3GeTe2 is estimated to be ~5 van der Waals layers. Furthermore, the hard magnetic behaviour of Fe3GeTe2 can be well described by a proposed model. The magnetic properties of Fe3GeTe2 highlight its potential for integration into van der Waals magnetic heterostructures, paving the way for spintronic research and applications based on these devices.

Synthesis of Spirooxindoles via the tert-Amino Effect.

A new method is developed for the synthesis of spirooxindoles from amines and isatins via C-H functionalization. The reaction leverages the tert-amino effect to form an enolate-iminium intermediate via [1,5]-hydride shift followed by cyclization. Interestingly the hydride migrates to the N atom of a C═N, which is atypical for hydride additions to imines.

Structure-Guided Design of Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors.

A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, 2, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor 29, with an IC50 of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.