General Mechanism Research Articles

Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.

γ-Secretase plays a crucial role in producing disease-related amyloid-β proteins by cleaving the amyloid precursor protein (APP). The enzyme employs its catalytic dyad containing two aspartates (Asp257 and Asp385) to hydrolyze the substrate by a general acid-base catalytic mechanism, necessitating monoprotonation of the two aspartates for efficient hydrolysis. However, the precise protonation states of the aspartates remain uncertain. In this study, we employed a multiscale computational approach to investigate the dependence of the catalytic efficiency of γ-secretase on the protonation states of its catalytic dyad. Over 200 ms unbiased atomistic simulations of the substrate-enzyme complex reveal diverse orientations of the scissile bond of the bound substrate and accessible structural ensembles of the catalytic dyad with Asp257-Asp385 distances fluctuating between 4 and 10 Å. With a quantum mechanics/molecular mechanics (QM/MM) approach accelerated by enhanced sampling techniques, we find that the first step of the hydrolysis reaction, i.e., the formation of a gem-diol intermediate, experiences a higher reaction barrier by ∼2 kcal/mol when Asp385 is protonated. Furthermore, we find that Arg269 of the enzyme is most likely responsible for this preference of the protonation state: its basic side chain is spatially close to that of Asp257 and specifically stabilizes the transition state electrostatically when Asp257 is protonated. Collectively, our study suggests that Asp257 is likely the favored protonation site for APP cleavage by γ-secretase.

Microscopic mechanism of water-assisted diffusional phase transitions in inorganic metal halide perovskites.

The stability of perovskite materials is profoundly influenced by the presence of moisture in the surrounding environment. While it is well-established that water triggers and accelerates the black-yellow phase transition, leading to the degradation of the photovoltaic properties of perovskites, the underlying microscopic mechanism remains elusive. In this study, we employ classical molecular dynamics simulations to examine the role of water molecules in the yellow-black phase transition in a typical inorganic metal halide perovskite, CsPbI3. We have demonstrated, through interfacial energy calculations and classical nucleation theory, that the phase transition necessitates a crystal-amorphous-crystal two-step pathway rather than the conventional crystal-crystal mechanism. Simulations for CsPbI3 nanowires show that water molecules in the air can enter the amorphous interface between the black and yellow regions. The phase transition rate markedly increases with the influx of interfacial water molecules, which enhance ion diffusivity by reducing the diffusion barrier, thereby expediting the yellow-black phase transition in CsPbI3. We propose a general mechanism through which solvent molecules can greatly facilitate phase transitions that otherwise have prohibitively high transition energies.

Real-time correction of gain nonlinearity in electrostatic actuation for whole-angle micro-shell resonator gyroscope

MEMS gyroscopes are well known for their outstanding advantages in Cost Size Weight and Power (CSWaP), which have inspired great research attention in recent years. A higher signal-to-noise ratio (SNR) for MEMS gyroscopes operating at larger vibrating amplitudes provides improved measuring resolution and ARW performance. However, the increment of amplitude causes strong nonlinear effects of MEMS gyroscopes due to their micron size, which has negative influences on the performance. This paper carries out detailed research on a general nonlinear mechanism on the sensors using parallel-plate capacitive transducers, which is called the gain nonlinearity in electrostatic actuation. The theoretical model established in this paper demonstrates the actuation gain nonlinearity causes the control-force coupling and brings extra angle-dependent bias with the 4th component for the whole-angle gyroscopes, which are verified by the experiments carried out on a micro-shell resonator gyroscope (MSRG). Furthermore, a real-time correction method is proposed to restore a linear response of the electrostatic actuation, which is realized by the gain modification with an online parameter estimation based on the harmonic-component relationship of capacitive detection. This real-time correction method could reduce the 4th component of the angle-dependent bias by over 95% from 0.003°/s to less than 0.0001°/s even under different temperatures. After the correction of actuation gain nonlinearity, the bias instability (BI) of whole-angle MSRG is improved by about 3.5 times from 0.101°/h to 0.029°/h and the scale factor nonlinearity (SFN) is reduced by almost one order of magnitude from 2.02 ppm to 0.21 ppm.

FREE FATTY ACIDS INHIBIT AN ION-COUPLED MEMBRANE TRANSPORTER BY DISSIPATING THE ION GRADIENT

Glutamate is the main excitatory transmitter in the mammalian central nervous system; glutamate transporters keep the synaptic glutamate concentrations at bay for normal brain function. Arachidonic acid (AA), docosahexaenoic acid (DHA), and other unsaturated fatty acids modulate glutamate transporters in cell- and tissue slices-based studies. Here, we investigated their effect and mechanism using a purified archaeal glutamate transporter homolog reconstituted into the lipid membranes. AA, DHA, and related fatty acids irreversibly inhibited the sodium-dependent concentrative substrate uptake into lipid vesicles within the physiologically relevant concentration range. In contrast, AA did not inhibit amino acid exchange across the membrane. The length and unsaturation of the aliphatic tail affect inhibition, and the free carboxylic headgroup is necessary. The inhibition potency did not correlate with the fatty acid effects on the bilayer deformation energies. AA does not affect the conformational dynamics of the protein, suggesting it does not inhibit structural transitions necessary for transport. Single-transporter and membrane voltage assays showed that AA and related fatty acids mediate cation leak, dissipating the driving sodium gradient. Thus, such fatty acids can act as cation ionophores, suggesting a general modulatory mechanism of membrane channels and ion-coupled transporters.

Splenic filtration of red blood cells in physiology, malaria and sickle cell disease.

The human spleen clears the blood from circulating microorganisms and red blood cells (RBCs) displaying alterations. This review analyzes how generic mechanisms by which the spleen senses RBC, such pitting, trapping and erythrophagocytosis, impact the pathogenesis of two major spleen-related diseases, malaria and sickle cell disease (SCD). Scintigraphy, functional histology, comparison of circulating and splenic RBC, ex-vivo perfusion of human spleens and in-silico modeling enable relevant exploration of how the spleen retains and processes RBC in health and disease. Iterative cross-validations between medical observations, in-vitro experiments and in-silico modeling point to mechanical sensing of RBC as a central event in both conditions. Spleen congestion is a common pathogenic process explaining anemia and splenomegaly, the latter carrying a risk of severe complications such as acute splenic sequestration crisis and hypersplenism in SCD. Sickling of hemoglobin S-containing RBC may contribute to these complications without necessarily being the trigger. Ongoing progress in the exploration and understanding of spleen-related complications in malaria and SCD open the way to optimized prognosis evaluation and therapeutic applications.

Periodic dynamics in viscous fingering

The displacement of a viscous liquid by air inside a Hele-Shaw channel is an archetype for nonlinear pattern-forming systems. Typically, bubbles or fingers of air propagate steadily at low values of the capillary number Ca = μ U * / σ , where μ is the viscosity of the liquid, U * is the speed of the bubble or finger and σ is the surface tension at the air–liquid interface. However, as the capillary number increases, the advancing interface can exhibit disordered pattern-forming dynamics. We demonstrate experimentally that a sustained, remote perturbation of the bubble tip can drive time-periodic dynamics. We exploit the propensity of a group of bubbles to propagate in steady spatial arrangements inside a Hele-Shaw channel with a centralized depth-reduction to apply a sustained pressure perturbation ahead of the bubble as it propagates. The oscillation cycle is initiated by the splitting of the bubble tip, via the Saffman–Taylor instability, which is promoted by the local flow-field conditions. The restoral of the bubble tip follows naturally because the system is driven by a fixed flow rate and the perturbed bubble is attracted to the weakly unstable, steadily propagating state that is set by the ratio of imposed viscous and capillary forces. The splitting and restoral mechanisms do not rely on the specific perturbation used in this study, suggesting a generic mechanism for periodic dynamics of propagating curved fronts subject to steady flow-field perturbations.

Structural variation of types IV-A1- and IV-A3-mediated CRISPR interference

CRISPR-Cas mediated DNA-interference typically relies on sequence-specific binding and nucleolytic degradation of foreign genetic material. Type IV-A CRISPR-Cas systems diverge from this general mechanism, using a nuclease-independent interference pathway to suppress gene expression for gene regulation and plasmid competition. To understand how the type IV-A system associated effector complex achieves this interference, we determine cryo-EM structures of two evolutionarily distinct type IV-A complexes (types IV-A1 and IV-A3) bound to cognate DNA-targets in the presence and absence of the type IV-A signature DinG effector helicase. The structures reveal how the effector complexes recognize the protospacer adjacent motif and target-strand DNA to form an R-loop structure. Additionally, we reveal differences between types IV-A1 and IV-A3 in DNA interactions and structural motifs that allow for in trans recruitment of DinG. Our study provides a detailed view of type IV-A mediated DNA-interference and presents a structural foundation for engineering type IV-A-based genome editing tools.

Auditory competition and stimulus selection across spatial locations from midbrain to forebrain in barn owls

Barn owls enable investigation of neural mechanisms underlying stimulus selection of concurrent stimuli. The audio-visual space map in the optic tectum (OT), avian homologue of the superior colliculus, encodes relative strength of concurrent auditory stimuli through spike response rate and interneuronal spike train synchrony (STS). Open questions remain regarding stimulus selection in downstream forebrain regions lacking topographic coding of auditory space, including the functional consequences of interneuronal STS on interregional signaling. To this end, we presented concurrent stimuli at different locations and manipulated relative strength while simultaneously recording neural responses from OT and its downstream thalamic target, nucleus rotundus (nRt), in awake barn owls of both sexes. Results demonstrated that broadly spatially tuned nRt units exhibit different spike response patterns to competition depending on spatial tuning preferences. Modeling suggests nRt units integrate convergent inputs from distant locations across midbrain map regions. Additionally, STS within nRt reflects the temporal properties of the strongest stimulus. Furthermore, interregional STS between OT and nRt was strongest when spatial tuning overlap between units across regions was large and when the strongest stimulus location during competition was favorable for units in both regions. Additionally, though gamma oscillations synthesized within OT are weakly propagated within nRt, average gamma power across regions correlates with strength of interregional STS. Overall, we demonstrate that nRt integrates inputs across distant areas of OT, retains spatial information through differences in strength of inputs from various locations of the midbrain map across neurons, and prioritizes coding of identity features to the strongest sound.Significance StatementThe brain strategically selects and preferentially processes salient stimuli. A critical function to this process involves transferring salient information across regions that may exhibit drastic transformations in coding schemes. Our study in barn owls investigates bottom-up signaling between the midbrain space map and its downstream thalamic target, which lacks spatial topography as also observed in mammalian auditory forebrain regions to elucidate general mechanisms underlying how spatial location information and other properties of the strongest sound are relayed between regions. Results show that the thalamus integrates neural responses widely across the midbrain map, retains coding of spatial location through varying strength of inputs of the map across neurons, and prioritizes further coding of identity features only to the strongest sound.

Interleukin-22 inhibits right ventricular remodelling by a unique mechanism in a pulmonary artery constriction model

Abstract Background Fibrosis and remodeling of right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) is performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band: 25–40 mmHg at 1 week after surgery by echo Doppler) were included in the study protocol. Four weeks after PAB, RV function was measured by echocardiography and real-time PCR analysis was performed to measure Col1a1, Col3a1, BNP, and transcriptome analysis was performed. Survival confirmation of mice with moderate pulmonary artery stenosis was also performed up to 56 days. Results IL-22 KO mice had significantly higher 56-day mortality rate compared with WT mice after PAC (p<0.01). Four weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 4 weeks after PAB. (IL-22 KO mice vs wild type mice; RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, TAPSE: 10.8±1.8mm vs 9.5±1.7mm, P=0.04, FAC: 35.2±7.8% vs 23±6.0%, P<0.001). The expressions of Col1a1 and Col3a1 were no difference between in IL22-KO mice and Wild mice. However, BNP, a cardioprotective marker, tended to be lower in IL-22KO mice. The transcriptome analysis also showed that the group of fibrosis-related genes that are elevated in PAC in WT mice were less elevated in IL-22 KO mice. Conclusion These results suggest that IL-22 is involved in RV remodelling during RV pressure loading without a general mechanism.

Does Peer Socialization Within Cohorts Foster Political Attitudes? A Longitudinal Study of Elite Business Students

AbstractThe association between higher education and political attitudes is well-recognized, and research suggests that socialization amongst peers is one of the most probable mechanisms explaining a possible attitudinal change. However, identifying a socialization effect is difficult due to self-selection mechanisms and limitations in data availability. This article empirically investigates the underlying peer socialization by employing a longitudinal network study of undergraduate students in Swedish and Finnish top-ranked business schools (N = 2651). The study tests the hypotheses that (1) attitudes within a cohort converge over time, and (2) socially embedded students experience more attitudinal change during their studies than students who do not engage with their peers. The paper leverages the Covid-19 pandemic as an exogenous shock that severely affected the networking dynamics of specific cohorts since it moved their education off campus. It is thereby among the first studies to directly test the relationship between socializing behaviors within higher education and political attitudes using both subjective and objective measurements. Contrary to previous conjectures, the findings challenge a general socialization mechanism to foster political attitudes. Instead, they point toward the importance of self-selection mechanisms in studies of higher education and for the specific student composition.

The Cumulation of Debris Clouds around a Fast-rotating Asteroid

Abstract The rotational mass loss has been realized to be a prevalent mechanism to produce low-speed debris near the asteroid, and the size composition of the asteroid’s surface regolith has been closely measured by in situ explorations. However, the full-scale evolution of the shedding debris has not been examined using the observed particle sizes, which may hold vital clues to the initial growth of an asteroid moonlet and help us to understand the general mechanisms that dominate the formation of asteroid systems. This paper presents our study on the cumulative evolution of the debris cloud formed by a rotationally unstable asteroid. A semianalytical model is developed to characterize the spatiotemporal evolution of the debris cloud posterior to a shedding event. Large-scale discrete element method (DEM) simulations are performed to quantify the clustering behavior of the debris particles in the mechanical environment near the asteroid. As a result, we found that the cumulation of a steady debris cloud is dominated by large pieces of debris, and the shedding particles follow a common migration trend, which fundamentally determines the mass distribution of the debris cloud. For the accretion analysis, we sketched the life cycle of a debris cluster and showed its dependency on particle size. The DEM simulations adopt physical parameters estimated from observations and asteroid missions. The results confirm that porous fluffy cluster structures can form shortly after a shedding event with magnitudes the same as the observed shedding activities. Measurements of these structures show that they themselves possess a certain strength and have the capacity to collisions to absorb dissociative particles that collide with them.

A simple action reduces high fat diet intake and obesity in mice.

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

Scaling behaviour of rotating convection in a spherical shell with different Prandtl numbers

Rayleigh–Bénard convection in a rotating spherical shell provides a simplified model for convective dynamics of planetary and stellar interiors. Over the past decades, the problem has been studied extensively via numerical simulations, but most previous simulations set the Prandtl number $Pr$ to unity. In this study we build more than 200 numerical models of rotating convection in a spherical shell over a wide range of $Pr$ ( $10^{-2}\le Pr \le 10^2$ ). By increasing the Rayleigh number $Ra$ , we characterise four different flow regimes, starting from the linear onset to multiple modes, then transitioning to the geostrophic turbulence and eventually approaching the weakly rotating regime. In the multiple modes regime, we show evidence of triadic resonances in numerical models with different $Pr$ , which may provide a generic mechanism for the transition from laminar to turbulence in rotating convection. We analyse scaling behaviours of the heat transfer and convective flow speeds in numerical simulations, paying particular attention to the $Pr$ dependence. We find that the so-called diffusion-free scaling for the heat transfer cannot reconcile all numerical models with different $Pr$ in the geostrophic turbulence regime. However, the characteristic flow speeds at different $Pr$ roughly follow a unified scaling that can be described by visco-Archimedean–Coriolis force balances, though the scaling tends to approach the Coriolis-inertial-Archimedean force balance at low $Pr$ . We also show that transition behaviours from rotating to non-rotating convection depend on $Pr$ . The transition criteria based on heat transfer and flow morphology would be rather different when $Pr>1$ , but the two criteria are consistent for cases with $Pr\le 1$ . Both scaling behaviours and transition behaviours suggest that the heat transfer is controlled by the boundary layers while the convective flow speeds are mainly determined by the force balance in the bulk for cases with $Pr>1$ , which is in line with recent experimental results with moderate to high $Pr$ . For cases with $Pr \le 1$ , both the heat transfer and convective velocities are approaching the inviscid dynamics in the bulk. We also briefly analysed the magnitude and scaling of zonal flows at different $Pr$ , showing that the zonal flow amplitude rapidly increases as $Pr$ decreases.

Microscopic Structure of Neat Linear Alkylamine Liquids: An X-Ray Scattering and Computer Simulation Study.

Linear amines, from propylamine to nonylamine, are studied under ambient conditions by X-ray scattering and molecular dynamics simulations of various force field models. The major finding is that the prepeak in alkylamines is about 1 order of magnitude weaker than that in alkanols, hence suggesting much weaker hydrogen bonding-induced clustering of the amine groups than for the hydroxyl groups. Computer simulation studies reveal that the OPLS-UA model reproduces the prepeak, but with larger amplitudes, while the GROMOS-UA and CHARMM-AA force fields show almost no prepeak. Simulations of all models show the existence of hydrogen-bonded clusters, equally confirmed by the prominent prepeak of the structure factor between the nitrogen atoms. The hydrogen bond strength, as modeled by the Coulomb association in classical force field models, is about the same order of magnitude for both systems. Then, one may ask what is the origin of the weaker prepeak in alkylamines? Simulation data reveal that the existence of the prepeak is controlled through the cancellation of the positive contributions from the charged group correlations by the negative contributions from the cross charged-uncharged correlations. The C2v symmetry of the amine headgroup hinders clustering, which favors cross correlations with the tail atoms. This is opposite to alkanols where the symmetry of the hydroxyl headgroup favors clustering and hinders cross correlations with the alkyl tail. This competition between charged and uncharged atomic groups appears as a general mechanism to explain the existence of scattering prepeaks, including their position and amplitude.

The Residual Activity of Fatty Acyl-CoA Reductase Underlies Thermo-Sensitive Genic Male Sterility in Rice.

Photoperiod/thermo-sensitive genic male sterility (P/TGMS) is critical for rice two-line hybrid system. Previous studies showed that slow development of pollen is a general mechanism for sterility-to-fertility conversion of TGMS in Arabidopsis. However, whether this mechanism still exists in rice is unknown. Here, we identified a novel rice TGMS line, ostms16, which exhibits abnormal pollen exine under high temperature and fertility restoration under low temperature. In mutant, a single base mutation of OsTMS16, a fatty acyl-CoA reductase (FAR), reduced its enzyme activity, leading to defective pollen wall. Under high temperature, the mOsTMS16M549I couldn't provide sufficient protection for the microspores. Under low temperature, the enzyme activity of mOsTMS16M549I is closer to that of OsTMS16, so that the imperfect exine could still protect microspore development. These results indicated whether the residual enzyme activity in mutant could meet the requirement in different temperature is a determinant factor for fertility conversion of P/TGMS lines. Additionally, we previously found that res2, the mutant of a polygalacturonase for tetrad pectin wall degradation, restored multiple TGMS lines in Arabidopsis. In this study, we proved that the osres2 in rice restored the fertility of ostms16, indicating the slow development is also suitable for the fertility restoration in rice.

Navigating patient journeys across healthcare borders: hot potatoes, medical professionalism and a negotiated order

PurposeThis study explores the dynamics of patient transfers within the Polish healthcare system during the COVID-19 pandemic, focusing on the roles of negotiation, boundary work and systemic flexibility. Despite extensive literature on patient transfers, gaps remain in understanding the general mechanisms that complicate these processes, especially under crisis conditions.Design/methodology/approachBy interviewing 18 specialists across various medical fields, our research provides empirical evidence from Poland, highlighting the experiences of medical practitioners who navigated the complex landscape of patient transfers during the pandemic.FindingsBy integrating negotiation and boundary work theories, we reveal how healthcare professionals manage patient flows and the challenges they face. Our findings show that during the unique situation caused by the uncertainties and lack of preparedness for the pandemic, while standardization and rationalization tools have limited effectiveness, proactive involvement and strategic negotiation are crucial for successful patient management.Research limitations/implicationsThe study's primary limitation is its focus solely on the Polish healthcare system during the COVID-19 pandemic, which may not fully represent other contexts or healthcare systems.Originality/valueThe study underscores the importance of communication and interpersonal skills in facilitating patient transfers. We also argue that the previous experiences with negotiating orders, dealing with limited resources and making constant compromises had, in a way, built resilience in Polish medical experts and prepared them for the uncertainties encountered while treating COVID-19 patients. These insights contribute to academic theories and offer practical recommendations for enhancing healthcare system resilience and adaptability in future crises. Ultimately, the study emphasizes that flexibility and strategic negotiation are key to managing patient transfers in a fragmented and complex healthcare environment.

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

Strain energy density maximization principle for material design and the reflection in trans-scale continuum theory

Traditional efforts in the design of damage-tolerant structural materials were largely exercises in optimizing the combination of strength and ductility. However, the simultaneous consideration of these two conflicting mechanical indices, improving one inevitably sacrifices the other, makes the design extremely complex and difficult, due to the dilemma of choosing between them. Here, physically guided by the energy variational expression in trans-scale continuum mechanics theory, we propose a general mechanics principle for material design that involving only one index: towards strong and tough material the strain energy density limit (w) should be maximized, i.e., strain energy density maximization principle, referred to as wmax principle. It aims to guide the attainment of exceptional comprehensive mechanical properties, while circumventing the dual-index dilemma by employing a singular index w. Extensive experimental data analyses prove that (i) the maximum wmax always exists, at a critical dimension of characteristic microstructure dc,micro, and (ii) w can effectively index strength-ductility synergy and the wmax is conjugated with both high strength and high ductility, verifying the validity of wmax principle. The universality, practicality and downward compatibility are also examined. The dc,micro approaches twice the span of strain gradient region around internal boundary, suggesting that the microstructure state with wmax is the critical state with strongest strain gradient. Importantly, the w improvement as a function of the characteristic size of either microstructure or deformation field can be well captured by strain gradient theory, confirming the consistence between the wmax principle, experimental results and trans-scale continuum theories. This principle opens up a new design concept for advanced structural materials from the perspective of microstructure-w-mechanical properties relationship.

Localizing Transitions via Interaction-Induced Flat Bands.

This Letter presents a theory of interaction-induced band-flattening in strongly correlated electron systems. We begin by illustrating an inherent connection between flat bands and index theorems, and presenting a generic prescription for constructing flat bands by periodically repeating local Hamiltonians with topological zero modes. Specifically, we demonstrate that a Dirac particle in an external, spatially periodic magnetic field can be cast in this form. We derive a condition on the field to produce perfectly flat bands and provide an exact analytical solution for the flat band wave functions. Furthermore, we explore an interacting model of Dirac fermions in a spatially inhomogeneous field. We show that certain Hubbard-Stratonovich configurations exist that "rectify" the field configuration, inducing band flattening. We present an explicit model where this localization scenario is energetically favorable-specifically in Dirac systems with nearly flat bands, where the energy cost of rectifying textures is quadratic in the order parameter, whereas the energy gain from flattening is linear. In conclusion, we discuss alternative symmetry-breaking channels, especially superconductivity, and propose that these interaction-induced band-flattening scenarios represent a generic nonperturbative mechanism for spontaneous symmetry breaking, pertinent to many strongly correlated electron systems.

Developmental spike timing-dependent long-term depression requires astrocyte D-serine at L2/3-L2/3 synapses of the mouse somatosensory cortex.

Spike timing-dependent plasticity (STDP) is a learning rule important for synaptic refinement and for learning and memory during development. While different forms of presynaptic t-LTD have been deeply investigated, little is known about the mechanisms of somatosensory cortex postsynaptic t-LTD. In the present work, we investigated the requirements and mechanisms for induction of developmental spike timing-dependent long-term depression (t-LTD) at L2/3-L2/3 synapses in the juvenile mouse somatosensory cortex. We found that P13-21 mice of either sex show t-LTD at L2/3-L2/3 synapses induced by pairing single presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz) is expressed postsynaptically, and requires the activation of ionotropic postsynaptic NMDA-type glutamate receptors containing GluN2B subunits. In addition, it requires postsynaptic Ca2+, Ca2+ release from internal stores, calcineurin, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signalling to release the gliotransmitter d-serine to activate postsynaptic NMDARs to induce t-LTD. These results show direct evidence of the mechanism involved in developmental postsynaptic t-LTD at L2/3-L2/3 synapses, revealing a central role of astrocytes and their release of D-serine in its induction.Significance statement We show here the mechanisms and role of astrocytes and gliotransmitters in a postsynaptic spike timing dependent long-term depression (t-LTD) form defined at layer (L)2/3-L2/3 synapses of the somatosensory cortex. We have discovered that this form of plasticity involves N-methyl D-aspartate receptors (NMDAR) containing the GluN2B subunit and requires astrocytes and the gliotransmitter D-serine to co-activate (together with glutamate) postsynaptic NMDAR to mediate LTD. This can be a general mechanism in the brain to define different forms of plasticity. Defining the mechanisms of synaptic plasticity may have important implications for brain repair, sensorial recovery, the treatment of neurodevelopmental disorders and even, for educational policy.