Non-volatile magnon transport in a single domain multiferroic.

Antiferromagnets have attracted significant attention in the field of magnonics, as promising candidates for ultralow-energy carriers for information transfer for future computing. The role of crystalline orientation distribution on magnon transport has received very little attention. In multiferroics such as BiFeO3 the coupling between antiferromagnetic and polar order imposes yet another boundary condition on spin transport. Thus, understanding the fundamentals of spin transport in such systems requires a single domain, a single crystal. We show that through Lanthanum (La) substitution, a single ferroelectric domain can be engineered with a stable, single-variant spin cycloid, controllable by an electric field. The spin transport in such a single domain displays a strong anisotropy, arising from the underlying spin cycloid lattice. Our work shows a pathway to understanding the fundamental origins of magnon transport in such a single domain multiferroic.

Designed Spin-Texture-Lattice to Control Anisotropic Magnon Transport in Antiferromagnets.

Spin waves in magnetic materials are promising information carriers for future computing technologies due to their ultra-low energy dissipation and long coherence length. Antiferromagnets are strong candidate materials due, in part, to their stability to external fields and larger group velocities. Multiferroic antiferromagnets, such as BiFeO3 (BFO), have an additional degree of freedom stemming from magnetoelectric coupling, allowing for control of the magnetic structure, and thus spin waves, with the electric field. Unfortunately, spin-wave propagation in BFO is not well understood due to the complexity of the magnetic structure. In this work, long-range spin transport is explored within an epitaxially engineered, electrically tunable, 1D magnonic crystal. A striking anisotropy is discovered in the spin transport parallel and perpendicular to the 1D crystal axis. Multiscale theory and simulation suggest that this preferential magnon conduction emerges from a combination of a population imbalance in its dispersion, as well as anisotropic structural scattering. This work provides a pathway to electrically reconfigurable magnonic crystals in antiferromagnets.

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.

Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.

Clamping enables enhanced electromechanical responses in antiferroelectric thin films.

Thin-film materials with large electromechanical responses are fundamental enablers of next-generation micro-/nano-electromechanical applications. Conventional electromechanical materials (for example, ferroelectrics and relaxors), however, exhibit severely degraded responses when scaled down to submicrometre-thick films due to substrate constraints (clamping). This limitation is overcome, and substantial electromechanical responses in antiferroelectric thin films are achieved through an unconventional coupling of the field-induced antiferroelectric-to-ferroelectric phase transition and the substrate constraints. A detilting of the oxygen octahedra and lattice-volume expansion in all dimensions are observed commensurate with the phase transition using operando electron microscopy, such that the in-plane clamping further enhances the out-of-plane expansion, as rationalized using first-principles calculations. In turn, a non-traditional thickness scaling is realized wherein an electromechanical strain (1.7%) is produced from a model antiferroelectric PbZrO3 film that is just 100 nm thick. The high performance and understanding of the mechanism provide a promising pathway to develop high-performance micro-/nano-electromechanical systems.

Heterogeneous integration of spin-photon interfaces with a CMOS platform.

Colour centres in diamond have emerged as a leading solid-state platform for advancing quantum technologies, satisfying the DiVincenzo criteria1 and recently achieving quantum advantage in secret key distribution2. Blueprint studies3-5 indicate that general-purpose quantum computing using local quantum communication networks will require millions of physical qubits to encode thousands of logical qubits, presenting an open scalability challenge. Here we introduce a modular quantum system-on-chip (QSoC) architecture that integrates thousands of individually addressable tin-vacancy spin qubits in two-dimensional arrays of quantum microchiplets into an application-specific integrated circuit designed for cryogenic control. We demonstrate crucial fabrication steps and architectural subcomponents, including QSoC transfer by means of a 'lock-and-release' method for large-scale heterogeneous integration, high-throughput spin-qubit calibration and spectral tuning, and efficient spin state preparation and measurement. This QSoC architecture supports full connectivity for quantum memory arrays by spectral tuning across spin-photon frequency channels. Design studies building on these measurements indicate further scaling potential by means of increased qubit density, larger QSoC active regions and optical networking across QSoC modules.

Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy.

The nonphysiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels affect therapeutic response by performing drug screening in human plasma-like medium. We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that recently failed in phase III clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response and how incorporation of human-specific physiological nutrient medium might help identify compounds whose efficacy could be influenced in humans.

Manipulating chiral spin transport with ferroelectric polarization.

A magnon is a collective excitation of the spin structure in a magnetic insulator and can transmit spin angular momentum with negligible dissipation. This quantum of a spin wave has always been manipulated through magnetic dipoles (that is, by breaking time-reversal symmetry). Here we report the experimental observation of chiral spin transport in multiferroic BiFeO3 and its control by reversing the ferroelectric polarization (that is, by breaking spatial inversion symmetry). The ferroelectrically controlled magnons show up to 18% modulation at room temperature. The spin torque that the magnons in BiFeO3 carry can be used to efficiently switch the magnetization of adjacent magnets, with a spin-torque efficiency comparable to the spin Hall effect in heavy metals. Utilizing such controllable magnon generation and transmission in BiFeO3, an all-oxide, energy-scalable logic is demonstrated composed of spin-orbit injection, detection and magnetoelectric control. Our observations open a new chapter of multiferroic magnons and pave another path towards low-dissipation nanoelectronics.

Secondary Repair of Jersey Finger: A Novel Method of Tendon Length Estimation via Measurement of Adjacent Landmarks.

Jersey finger describes the rupture of the flexor digitorum profundus (FDP) tendon at its insertion into the distal phalanx. In the absence of an evidence-based approach to tensioning during secondary repair, we aimed to devise a novel method to determine the required tendon length pre/intraoperatively. We measured anatomical landmarks, associated with the FDP tendon, on dissected cadavers, to assess whether these can be used to estimate tendon segment lengths. Eight cadaveric hands were dissected. Three measurements from the distal lumbrical origin to (1) FDP insertion, (2) the distal end of A1 (Annular 1 pulley), and (3) the proximal end of A1 were recorded for digits II-V. Relative ratios for measurement 1 were consistent for all digits, compared to digit III. Linear regression analysis confirmed a strong correlation for measurement 1 between digit II (R2 =0.97) and digit IV(R2 =0.97) compared to digit III across all specimens. Digit III distal lumbrical origin to FDP insertion measurements could facilitate the estimation of the required graft length for digit II or IV during secondary repair. This is a level IV study, providing proof of concept for a novel method of tendon tensioning.

Low-temperature grapho-epitaxial La-substituted BiFeO3 on metallic perovskite.

Bismuth ferrite has garnered considerable attention as a promising candidate for magnetoelectric spin-orbit coupled logic-in-memory. As model systems, epitaxial BiFeO3 thin films have typically been deposited at relatively high temperatures (650-800 °C), higher than allowed for direct integration with silicon-CMOS platforms. Here, we circumvent this problem by growing lanthanum-substituted BiFeO3 at 450 °C (which is reasonably compatible with silicon-CMOS integration) on epitaxial BaPb0.75Bi0.25O3 electrodes. Notwithstanding the large lattice mismatch between the La-BiFeO3, BaPb0.75Bi0.25O3, and SrTiO3 (001) substrates, all the layers in the heterostructures are well ordered with a [001] texture. Polarization mapping using atomic resolution STEM imaging and vector mapping established the short-range polarization ordering in the low temperature grown La-BiFeO3. Current-voltage, pulsed-switching, fatigue, and retention measurements follow the characteristic behavior of high-temperature grown La-BiFeO3, where SrRuO3 typically serves as the metallic electrode. These results provide a possible route for realizing epitaxial multiferroics on complex-oxide buffer layers at low temperatures and opens the door for potential silicon-CMOS integration.

Regulation of antioxidants in cancer.

Scientists in this field often joke, "If you don't have a mechanism, say it's ROS." Seemingly connected to every biological process ever described, reactive oxygen species (ROS) have numerous pleiotropic roles in physiology and disease. In some contexts, ROS act as secondary messengers, controlling a variety of signaling cascades. In other scenarios, they initiate damage to macromolecules. Finally, in their worst form, ROS are deadly to cells and surrounding tissues. A set of molecules with detoxifying abilities, termed antioxidants, is the direct counterpart to ROS. Notably, antioxidants exist in the public domain, touted as a "cure-all" for diseases. Research has disproved many of these claims and, in some cases, shown the opposite. Of all the diseases, cancer stands out in its paradoxical relationship with antioxidants. Although the field has made numerous strides in understanding the roles of antioxidants in cancer, many questions remain.

Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation.

IMPORTANCE: Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.

Lysosomal cystine: an unexpected alarm bell for cysteine scarcity.

Cells respond to amino acid depletion by activating stress responses. A recent study by Swanda et al. reveals that a decrease in lysosomal cystine triggers a novel stress response that transcriptionally activates ATF4 and protects cells from ferroptosis. A synthetic mRNA, CysRx, can prevent ATF4 activation and enhance antitumor effects.

Reconnecting to Internal Sensations and Experiences (RISE): An online, multi-session intervention improves interoceptive sensibility for military personnel.

OBJECTIVE: This preregistered randomized controlled trial tested the effects of a four-session, online interoceptive awareness intervention relative to an active comparator, matched for time and attention on interoception and suicidal ideation. METHOD: Participants (N = 195; 69% male; mean age = 37) were active duty service members (62%) and veterans (38%) who completed measures of interoceptive sensibility, interoceptive accuracy, and suicidal ideation at baseline. They were randomized to either the interoceptive awareness intervention, Reconnecting to Internal Sensations and Experiences (RISE), or the comparator, Healthy Habits. Participants completed the assessment battery again at posttest as well as a 1 and 3-month follow-up. RESULTS: RISE was rated as acceptable and demonstrated excellent feasibility per completion rates (85% completed all four modules). RISE improved the majority of interoceptive sensibility domains assessed (noticing body sensations, not worrying about sensations of pain or discomfort, emotional awareness, self-regulation, body listening, and body trust), and most of these gains remained at 1 and 3-month follow-ups. There were no differences between conditions on suicidal ideation, perhaps due to the low levels of ideation reported, or interoceptive accuracy. CONCLUSIONS: RISE is a disseminable, cost-effective, and transdiagnostic intervention that improves interoceptive sensibility up to 3 months.

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy.

The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism waste product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. Structural modelling studies suggest that uric acid interacts with the tubulin-rigosertib complex and may act as an uncompetitive inhibitor of rigosertib. These results offer a possible explanation for the failure of rigosertib in clinical trials and demonstrate the utility of physiological media to achieve in vitro results that better represent human therapeutic responses.

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.

Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation.

Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38's inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.

Glutathione supports lipid abundance in vivo.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Photonic Indistinguishability of the Tin-Vacancy Center in Nanostructured Diamond.

Tin-vacancy centers in diamond are promising spin-photon interfaces owing to their high quantum efficiency, large Debye-Waller factor, and compatibility with photonic nanostructuring. Benchmarking their single-photon indistinguishability is a key challenge for future applications. Here, we report the generation of single photons with 99.7_{-2.5}^{+0.3}% purity and 63(9)% indistinguishability from a resonantly excited tin-vacancy center in a single-mode waveguide. We obtain quantum control of the optical transition with 1.71(1)-ns-long π pulses of 77.1(8)% fidelity and show it is spectrally stable over 100 ms. A modest Purcell enhancement factor of 12 would enhance the indistinguishability to 95%.