A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers.

Background: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted. Methods: SB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101. Results: Participants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines. Conclusion: SON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients. Clinical trial registration: https://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.

Oxytocin-receptor-expressing neurons in the lateral parabrachial nucleus activate widespread brain regions predominantly involved in fluid satiation.

Fluid satiation is an important signal and aspect of body fluid homeostasis. Oxytocin-receptor-expressing neurons (OxtrPBN) in the dorsolateral subdivision of the lateral parabrachial nucleus (dl LPBN) are key neurons which regulate fluid satiation. In the present study, we investigated brain regions activated by stimulation of OxtrPBN neurons in order to better characterise the fluid satiation neurocircuitry in mice. Chemogenetic activation of OxtrPBN neurons increased Fos expression (a proxy marker for neuronal activation) in known fluid-regulating brain nuclei, as well as other regions that have unclear links to fluid regulation and which are likely involved in regulating other functions such as arousal and stress relief. In addition, we analysed and compared Fos expression patterns between chemogenetically-activated fluid satiation and physiological-induced fluid satiation. Both models of fluid satiation activated similar brain regions, suggesting that the chemogenetic model of stimulating OxtrPBN neurons is a relevant model of physiological fluid satiation. A deeper understanding of this neural circuit may lead to novel molecular targets and creation of therapeutic agents to treat fluid-related disorders.

Extraordinary Magnetic Response of an Anisotropic 2D Antiferromagnet via Site Dilution.

A prominent characteristic of 2D magnetic systems is the enhanced spin fluctuations, which reduce the ordering temperature. We report that a magnetic field of only 1000th of the Heisenberg superexchange interaction can induce a crossover, which for practical purposes is the effective ordering transition, at temperatures about 6 times the Néel transition in a site-diluted two-dimensional anisotropic quantum antiferromagnet. Such a strong magnetic response is enabled because the system directly enters the antiferromagnetically ordered state from the isotropic disordered state, skipping the intermediate anisotropic stage. The underlying mechanism is achieved on a pseudospin-half square lattice realized in the [(SrIrO3)1/(SrTiO3)2] superlattice thin film that is designed to linearly couple the staggered magnetization to external magnetic fields by virtue of the rotational symmetry-preserving Dzyaloshinskii-Moriya interaction. Our model analysis shows that the skipping of the anisotropic regime despite finite anisotropy is due to the enhanced isotropic fluctuations under moderate dilution.

Strain-switchable field-induced superconductivity.

Field-induced superconductivity is a rare phenomenon where an applied magnetic field enhances or induces superconductivity. Here, we use applied stress as a control switch between a field-tunable superconducting state and a robust non-field-tunable state. This marks the first demonstration of a strain-tunable superconducting spin valve with infinite magnetoresistance. We combine tunable uniaxial stress and applied magnetic field on the ferromagnetic superconductor Eu(Fe0.88Co0.12)2As2 to shift the field-induced zero-resistance temperature between 4 K and a record-high value of 10 K. We use x-ray diffraction and spectroscopy measurements under stress and field to reveal that strain tuning of the nematic order and field tuning of the ferromagnetism act as independent control parameters of the superconductivity. Combining comprehensive measurements with DFT calculations, we propose that field-induced superconductivity arises from a novel mechanism, namely, the uniquely dominant effect of the Eu dipolar field when the exchange field splitting is nearly zero.

Discovery of Charge Order in the Transition Metal Dichalcogenide Fe_{x}NbS_{2}.

The Fe intercalated transition metal dichalcogenide (TMD), Fe_{1/3}NbS_{2}, exhibits remarkable resistance switching properties and highly tunable spin ordering phases due to magnetic defects. We conduct synchrotron x-ray scattering measurements on both underintercalated (x=0.32) and overintercalated (x=0.35) samples. We discover a new charge order phase in the overintercalated sample, where the excess Fe atoms lead to a zigzag antiferromagnetic order. The agreement between the charge and magnetic ordering temperatures, as well as their intensity relationship, suggests a strong magnetoelastic coupling as the mechanism for the charge ordering. Our results reveal the first example of a charge order phase among the intercalated TMD family and demonstrate the ability to stabilize charge modulation by introducing electronic correlations, where the charge order is absent in bulk 2H-NbS_{2} compared to other pristine TMDs.

Feeding signals inhibit fluid-satiation signals in the mouse lateral parabrachial nucleus to increase intake of highly palatable, caloric solutions.

Chemogenetic activation of oxytocin receptor-expressing neurons in the parabrachial nucleus (OxtrPBN neurons) acts as a satiation signal for water. In this research, we investigated the effect of activating OxtrPBN neurons on satiation for different types of fluids. Chemogenetic activation of OxtrPBN neurons in male and female transgenic OxtrCre mice robustly suppressed the rapid, initial (15-min) intake of several solutions after dehydration: water, sucrose, ethanol and saccharin, but only slightly decreased intake of Ensure®, a highly caloric solution (1 kcal/mL; containing 3.72 g protein, 3.27 g fat, 13.42 g carbohydrates, and 1.01 g dietary fibre per 100 mL). OxtrPBN neuron activation also suppressed cumulative, longer-term (2-h) intake of lower caloric, less palatable solutions, but not highly caloric, palatable solutions. These results suggest that OxtrPBN neurons predominantly control initial fluid-satiation responses after rehydration, but not longer-term intake of highly caloric, palatable solutions. The suppression of fluid intake was not because of anxiogenesis, but because OxtrPBN neuron activation decreased anxiety-like behaviour. To investigate the role of different PBN subdivisions on the intake of different solutions, we examined FOS as a proxy marker of PBN neuron activation. Different PBN subdivisions were activated by different solutions: the dorsolateral PBN similarly by all fluids; the external lateral PBN by caloric but not non-caloric solutions; and the central lateral PBN primarily by highly palatable solutions, suggesting PBN subdivisions regulate different aspects of fluid intake. To explore the possible mechanisms underlying the minimal suppression of Ensure® after OxtrPBN neuron activation, we demonstrated in in vitro slice recordings that the feeding-associated agouti-related peptide (AgRP) inhibited OxtrPBN neuron firing in a concentration-related manner, suggesting possible inhibition by feeding-related neurocircuitry of fluid satiation neurocircuitry. Overall, this research suggests that although palatable beverages like sucrose- and ethanol-containing beverages activate fluid satiation signals encoded by OxtrPBN neurons, these neurons can be inhibited by hunger-related signals (agouti-related peptide, AgRP), which may explain why these fluids are often consumed in excess of what is required for fluid satiation.

Symmetry Control of Unconventional Spin-Orbit Torques in IrO2.

Spin-orbit torques generated by a spin current are key to magnetic switching in spintronic applications. The polarization of the spin current dictates the direction of switching required for energy-efficient devices. Conventionally, the polarizations of these spin currents are restricted to be along a certain direction due to the symmetry of the material allowing only for efficient in-plane magnetic switching. Unconventional spin-orbit torques arising from novel spin current polarizations, however, have the potential to switch other magnetization orientations such as perpendicular magnetic anisotropy, which is desired for higher density spintronic-based memory devices. Here, it is demonstrated that low crystalline symmetry is not required for unconventional spin-orbit torques and can be generated in a nonmagnetic high symmetry material, iridium dioxide (IrO2 ), using epitaxial design. It is shown that by reducing the relative crystalline symmetry with respect to the growth direction large unconventional spin currents can be generated and hence spin-orbit torques. Furthermore, the spin polarizations detected in (001), (110), and (111) oriented IrO2 thin films are compared to show which crystal symmetries restrict unconventional spin transport. Understanding and tuning unconventional spin transport generation in high symmetry materials can provide a new route towards energy-efficient magnetic switching in spintronic devices.

Spontaneous orbital polarization in the nematic phase of FeSe.

The origin of nematicity in FeSe remains a critical outstanding question towards understanding unconventional superconductivity in proximity to nematic order. To understand what drives the nematicity, it is essential to determine which electronic degree of freedom admits a spontaneous order parameter independent from the structural distortion. Here we use X-ray linear dichroism at the Fe K pre-edge to measure the anisotropy of the 3d orbital occupation as a function of in situ applied stress and temperature across the nematic transition. Along with using X-ray diffraction to precisely quantify the strain state, we reveal a lattice-independent, spontaneously ordered orbital polarization within the nematic phase, as well as an orbital polarizability that diverges as the transition is approached from above. These results provide strong evidence that spontaneous orbital polarization serves as the primary order parameter of the nematic phase.

Portable Diffuse Reflectance Spectroscopy of Potato Leaves for Pre-Symptomatic Detection of Late Blight Disease.

We report on the use of leaf diffuse reflectance spectroscopy for plant disease detection. A smartphone-operated, compact diffused reflectance spectrophotometer is used for field collection of leaf diffuse reflectance spectra to enable pre-symptomatic detection of the progression of potato late blight disease post inoculation with oomycete pathogen Phytophthora infestans. Neural-network-based analysis predicts infection with >96% accuracy, only 24 h after inoculation with the pathogen, and nine days before visual late blight symptoms appear. Our study demonstrates the potential of using portable optical spectroscopy in tandem with machine learning analysis for early diagnosis of plant diseases.

Reconciling Monolayer and Bilayer J_{eff}=1/2 Square Lattices in Hybrid Oxide Superlattice.

The number of atomic layers confined in a two-dimensional structure is crucial for the electronic and magnetic properties. Single-layer and bilayer J_{eff}=1/2 square lattices are well-known examples where the presence of the extra layer turns the XY anisotropy to the c-axis anisotropy. We report on experimental realization of a hybrid SrIrO_{3}/SrTiO_{3} superlattice that integrates monolayer and bilayer square lattices in one layered structure. By synchrotron x-ray diffraction, resonant x-ray magnetic scattering, magnetization, and resistivity measurements, we found that the hybrid superlattice exhibits properties that are distinct from both the single-layer and bilayer systems and cannot be explained by a simple addition of them. In particular, the entire hybrid superlattice orders simultaneously through a single antiferromagnetic transition at temperatures similar to the bilayer system but with all the J_{eff}=1/2 moments mainly pointing in the ab plane similar to the single-layer system. The results show that bringing monolayer and bilayer with orthogonal properties in proximity to each other in a hybrid superlattice structure is a powerful way to stabilize a unique state not obtainable in a uniform structure.

Controllable Emergent Spatial Spin Modulation in Sr_{2}IrO_{4} by In Situ Shear Strain.

Symmetric anisotropic interaction can be ferromagnetic and antiferromagnetic at the same time but for different crystallographic axes. We show that the competition of anisotropic interactions of orthogonal irreducible representations can be a general route to obtain new exotic magnetic states. We demonstrate it here by observing the emergence of a continuously tunable 12-layer spatial spin modulation when distorting the square-lattice planes in the quasi-two-dimensional antiferromagnetic Sr_{2}IrO_{4} under in situ shear strain. This translation-symmetry-breaking phase is a result of an unusual strain-activated anisotropic interaction which is at the fourth order and competing with the inherent quadratic anisotropic interaction. Such a mechanism of competing anisotropy is distinct from that among the ferromagnetic, antiferromagnetic, and/or the Dzyaloshinskii-Moriya interactions, and it could be widely applicable and highly controllable in low-dimensional magnets.

Template Engineering of Metal-to-Insulator Transitions in Epitaxial Bilayer Nickelate Thin Films.

Understanding metal-to-insulator phase transitions in solids has been a keystone not only for discovering novel physical phenomena in condensed matter physics but also for achieving scientific breakthroughs in materials science. In this work, we demonstrate that the transport properties (i.e., resistivity and transition temperature) in the metal-to-insulator transitions of perovskite nickelates are tunable via the epitaxial heterojunctions of LaNiO3 and NdNiO3 thin films. A mismatch in the oxygen coordination environment and interfacial octahedral coupling at the oxide heterointerface allows us to realize an exotic phase that is unattainable in the parent compound. With oxygen vacancy formation for strain accommodation, the topmost LaNiO3 layer in LaNiO3/NdNiO3 bilayer thin films is structurally engineered and it electrically undergoes a metal-to-insulator transition that does not appear in metallic LaNiO3. Modification of the NdNiO3 template layer thickness provides an additional knob for tailoring the tilting angles of corner-connected NiO6 octahedra and the linked transport characteristics further. Our approaches can be harnessed to tune physical properties in complex oxides and to realize exotic physical phenomena through oxide thin-film heterostructuring.

The transport-structural correspondence across the nematic phase transition probed by elasto X-ray diffraction.

Electronic nematicity in iron pnictide materials is coupled to both the lattice and the conducting electrons, which allows both structural and transport observables to probe nematic fluctuations and the order parameter. Here we combine simultaneous transport and X-ray diffraction measurements with in-situ tunable strain (elasto X-ray diffraction) to measure the temperature dependence of the shear modulus and elastoresistivity above the nematic transition and the spontaneous orthorhombicity and resistivity anisotropy below the nematic transition, all within a single sample of Ba(Fe0.96Co0.04)2As2. The ratio of transport to structural quantities is nearly temperature independent over a 74 K range and agrees between the ordered and disordered phases. These results show that elasto X-ray diffraction is a powerful technique to probe the nemato-elastic and nemato-transport couplings, which have important implications to the nearby superconductivity. It also enables the measurement in the large strain limit, where the breakdown of the mean-field description reveals the intertwined nature of nematicity.

The median preoptic nucleus: A major regulator of fluid, temperature, sleep, and cardiovascular homeostasis.

Located in the midline lamina terminalis of the anterior wall of the third ventricle, the median preoptic nucleus is a thin elongated nucleus stretching around the rostral border of the anterior commissure. Its neuronal elements, composed of various types of excitatory glutamatergic and inhibitory GABAergic neurons, receive afferent neural signals from (1) neighboring subfornical organ and organum vasculosum of the lamina terminalis related to plasma osmolality and hormone concentrations, e.g., angiotensin II; (2) from peripheral sensors such as arterial baroreceptors and cutaneous thermosensors. Different sets of these MnPO glutamatergic and GABAergic neurons relay output signals to hypothalamic, midbrain, and medullary regions that drive homeostatic effector responses. Included in the effector responses are (1) thirst, antidiuretic hormone secretion and renal sodium excretion that subserve osmoregulation and body fluid homeostasis; (2) vasoconstriction or dilatation of skin blood vessels, and shivering and brown adipose tissue thermogenesis for core temperature homeostasis; (3) inhibition of hypothalamic and midbrain nuclei that stimulate wakefulness and arousal, thereby promoting both REM and non-REM sleep; and (4) activation of sympathetic pathways that drive vasoconstriction and heart rate to maintain arterial pressure and the perfusion of vital organs. The small size of MnPO belies its massive homeostatic significance.

Colossal Magnetoresistance without Mixed Valence in a Layered Phosphide Crystal.

Materials with strong magnetoresistive responses are the backbone of spintronic technology, magnetic sensors, and hard drives. Among them, manganese oxides with a mixed valence and a cubic perovskite structure stand out due to their colossal magnetoresistance (CMR). A double exchange interaction underlies the CMR in manganates, whereby charge transport is enhanced when the spins on neighboring Mn3+ and Mn4+ ions are parallel. Prior efforts to find different materials or mechanisms for CMR resulted in a much smaller effect. Here an enormous CMR at low temperatures in EuCd2 P2 without manganese, oxygen, mixed valence, or cubic perovskite structure is shown. EuCd2 P2 has a layered trigonal lattice and exhibits antiferromagnetic ordering at 11 K. The magnitude of CMR (104 %) in as-grown crystals of EuCd2 P2 rivals the magnitude in optimized thin films of manganates. The magnetization, transport, and synchrotron X-ray data suggest that strong magnetic fluctuations are responsible for this phenomenon. The realization of CMR at low temperatures without heterovalency leads to a new regime for materials and technologies related to antiferromagnetic spintronics.

Magnetic Weyl Semimetallic Phase in Thin Films of Eu_{2}Ir_{2}O_{7}.

The interplay between electronic interactions and strong spin-orbit coupling is expected to create a plethora of fascinating correlated topological states of quantum matter. Of particular interest are magnetic Weyl semimetals originally proposed in the pyrochlore iridates, which are only expected to reveal their topological nature in thin film form. To date, however, direct experimental demonstrations of these exotic phases remain elusive, due to the lack of usable single crystals and the insufficient quality of available films. Here, we report on the discovery of signatures for the long-sought magnetic Weyl semimetallic phase in (111)-oriented Eu_{2}Ir_{2}O_{7} high-quality epitaxial thin films. We observed an intrinsic anomalous Hall effect with colossal coercivity but vanishing net magnetization, which emerges right below the onset of a peculiar magnetic phase with all-in-all-out (AIAO) antiferromagnetic ordering. The anomalous Hall conductivity obtained experimentally is consistent with the theoretical prediction, likely arising from the nonzero Berry curvature emanated by Weyl node pairs near the Fermi level that act as sources and sinks of Berry flux, activated by broken cubic crystal symmetry at the top and bottom terminations of the thin film.

Self-Assembled Periodic Nanostructures Using Martensitic Phase Transformations.

We describe a novel approach for the rational design and synthesis of self-assembled periodic nanostructures using martensitic phase transformations. We demonstrate this approach in a thin film of perovskite SrSnO3 with reconfigurable periodic nanostructures consisting of regularly spaced regions of sharply contrasted dielectric properties. The films can be designed to have different periodicities and relative phase fractions via chemical doping or strain engineering. The dielectric contrast within a single film can be tuned using temperature and laser wavelength, effectively creating a variable photonic crystal. Our results show the realistic possibility of designing large-area self-assembled periodic structures using martensitic phase transformations with the potential of implementing "built-to-order" nanostructures for tailored optoelectronic functionalities.

Superconductivity in undoped BaFe2As2 by tetrahedral geometry design.

Fe-based superconductors exhibit a diverse interplay between charge, orbital, and magnetic ordering. Variations in atomic geometry affect electron hopping between Fe atoms and the Fermi surface topology, influencing magnetic frustration and the pairing strength through changes of orbital overlap and occupancies. Here, we experimentally demonstrate a systematic approach to realize superconductivity without chemical doping in BaFe2As2, employing geometric design within an epitaxial heterostructure. We control both tetragonality and orthorhombicity in BaFe2As2 through superlattice engineering, which we experimentally find to induce superconductivity when the As-Fe-As bond angle approaches that in a regular tetrahedron. This approach to superlattice design could lead to insights into low-dimensional superconductivity in Fe-based superconductors.

Comprehensive Electrical Control of Metamagnetic Transition of a Quasi-2D Antiferromagnet by In Situ Anisotropic Strain.

Effective nonmagnetic control of the spin structure is at the forefront of the study for functional quantum materials. This study demonstrates that, by applying an anisotropic strain up to only 0.05%, the metamagnetic transition field of spin-orbit-coupled Mott insulator Sr2 IrO4 can be in situ modulated by almost 300%. Simultaneous measurements of resonant X-ray scattering and transport reveal that this drastic response originates from the complete strain-tuning of the transition between the spin-flop and spin-flip limits, and is always accompanied by large elastoconductance and magnetoconductance. This enables electrically controllable and electronically detectable metamagnetic switching, despite the antiferromagnetic insulating state. The obtained strain-magnetic field phase diagram reveals that C4 -symmetry-breaking anisotropy is introduced by strain via pseudospin-lattice coupling, directly demonstrating the pseudo-Jahn-Teller effect of spin-orbit-coupled complex oxides. The extracted coupling strength is much weaker than the superexchange interactions, yet crucial for the spontaneous symmetry-breaking, affording the remarkably efficient strain-control.

Regional brain responses associated with using imagination to evoke and satiate thirst.

In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.