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Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress

Personalized functional topography–based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression

Major depressive disorder (MDD) is associated with widespread alterations in functional brain networks across the lifespan. However, heterogeneity in atypical brain development among patients with MDD remains largely uncharacterized. Using a multisite resting-state functional MRI dataset consisting of 1,105 MDD patients and 1,065 healthy controls, we constructed a harmonized multicenter brain age prediction model based on individualized functional topography and identified two patient subgroups with positive or negative brain age gaps (BAGs). In patients with a positive BAG (BAG+), expansion of the salience network (SAL) into the dorsolateral prefrontal and ventrolateral prefrontal cortices, in addition to contraction of the sensorimotor and dorsal attention networks (DAN), contributes to accelerated brain aging. Conversely, in the negative BAG (BAG−) group, SAL expansion into the orbitofrontal cortex (OFC) and contraction of the visual and sensorimotor networks (SMN) were linked to delayed brain development. These subgroups also exhibited distinct neurodevelopmental trajectories. Clinically, BAG+ patients showed stronger associations between higher-order network topography and mood symptoms, whereas BAG− patients exhibited links between visual/default mode network topography and insomnia. At the molecular level, both groups showed enrichment of genes related to synaptic signaling but displayed distinct expression patterns and divergent expression trajectories in key neurodevelopmental gene sets. Notably, antidepressant treatment modulated the brain in ways that were specific to each subgroup. These findings reveal heterogeneous neurodevelopmental profiles in MDD with distinct biological and clinical signatures, offering insights into personalized precision medicine for this disorder.

Design of electric and remote operating vehicles battery carrier by using small aluminum closed-cell foam blocks shielded by aluminum tubes

Abstract Aluminum closed-cell foam blocks (ACCFBs) are small blocks of foam shielded with small aluminum (Al) tubes developed to enhance the energy absorption of Al foam in limited volumes, such as one cubic inch. It is designed to overcome the problems of the high cost of production, maintenance, and heat insulation properties of foam sheets. Al blocks ideas quoted from human and animal bone parts, and it is designed to absorb energy laterally. This work presents the designs of remote operating vehicles (ROVs) and electric vehicles (EVs) battery carriers, constructed from a cube block of ACCFBs and two Al sheets. The carrier design is based on the properties of Al foam blocks. It is designed to withstand temperatures up to 120 °C. The carrier idea relies on replacing large sheets of Al foam with small, distributed blocks. It has good energy absorption, and at the same time, it helps solve the problems of harness design for crossing wires in narrow areas, such as in ROVs. The results show that the ROVs battery carrier made from the Al sandwich panel (AFS) needs 900 s to transfer 120 °C from the upper sheet to the lower sheet, while the carrier made from ACCFBs with the same volume needs 40 s only. It can also bear a load of up to 0.8 kN and has a working strength δ working : 1.093 MPa. The EVs battery carrier can bear a load of 117 kN (about 25 times the battery weight) at yield strength (0.45 MPa), and it has a δ working : 0.516 MPa. The calculated total time of cooling for the conduction and forced convection for both the ROVs and EVs carriers at a cooling temperature of 25 °C and at air velocity 1 m/s were 4:31 min and 32:25 min, and at 2 m/s were 3:15 min and 20:41 min, respectively, at a summer working temperature of 40 °C.

Polar chromosomes are rescued from missegregation by spindle elongation-driven microtubule pivoting

Viral mimicry may help explain immunogenic cell death

Viral mimicry may be an underappreciated contributor to chemotherapeutic potency in animal models and patients. This hypothesis is based on studies of a bis-Au(I)-NHC complex that was found to generate a strong anti-tumor immune response in vivo in two different challenge studies using an iKAP colorectal cancer mouse model. RNA profiling of treated cells revealed the stimulation of genes that overlap with those upregulated during a viral infection. The bis-Au(I)-NHC complex generates reactive oxygen species (ROS) through the simultaneous redox cycling of the naphthoquinone moiety and inhibition of thioredoxin reductase with Au(I). This ROS increase causes endoplasmic reticulum stress, activation of the unfolded protein response pathway and upregulation of Ifih1, a gene that encodes for the viral dsRNA sensor MDA5. Activation of MDA5 triggers a strong type I interferon response and expression of chemokine ligand 10 that can recruit immune cells to the treated tumor in a manner analogous to immune responses during viral infection. This proposed mechanism bridges the gap between cytotoxicity and the innate and adaptive immune responses. We suggest viral mimicry may be a key driver of chemotherapy potency in animals and an important determinant of positive outcomes in cancer patients.

Real-world use of rivaroxaban for primary thromboprophylaxis and cardiac thrombosis treatment in congenital and acquired heart disease: a prospective cohort study

Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice

Correction for Jaen Maisonet et al., Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)

Phonon frequency comb close to an isolated Einstein mode in $$\hbox {InSiTe}_{3}$$

Abstract The emergence of phonon frequency combs exemplifies a rare and intriguing phenomenon in quantum solids. Materials with distinctive phonon band structures are especially promising for hosting such states, as their vibrational dispersion landscape across the Brillouin zone can facilitate the formation of long-lived, collective lattice excitations. In the layered Van der Waals compound $$\textrm{InSi}\textrm{Te}_{3}$$ , polarization-resolved Raman spectroscopy reveals a pronounced anharmonicity in symmetry-predicted modes and the formation of a self-organized frequency domain structure (coherent-like state), in the range of a localized high-energy $$A_{1g}$$ phonon mode near 500 cm −1 . This strong phonon-phonon coupling manifests itself as an anomalous temperature dependence around 200 K, coinciding with the appearance of higher-order excitations within the phonon density of states gap. These findings position $$\textrm{InSi}\textrm{Te}_{3}$$ as an unconventional platform where intrinsic highly structured phonon spectral correlations and unusually strong anharmonic effects coexist, opening new avenues for exploring emergent vibrational phenomena in low-dimensional materials.

Reliable uncertainty estimates in deep learning with efficient Metropolis-Hastings algorithms

Abstract Approaching problems with data-driven models often requires reliable uncertainty estimates. Bayesian neural networks can offer these for deep learning models. Without the knowledge to set informative prior distributions, sampling methods such as Hamiltonian Monte Carlo are a robust choice. However, these come with prohibitive computational costs. We study two ways to incorporate computationally light-weight Metropolis-Hastings acceptance steps into deep neural networks and stochastic gradient Hamiltonian Monte Carlo. The first method proposes noisy acceptance steps computed on batched training samples rather than the entire set during the simulation of the stochastic dynamics accepting a small minima preserving bias. The second method sacrifices bias-free sampling of Hamiltonian Monte Carlo in favor of stochastic gradient driven trajectories. While the first is analytically plausible, the second is inspired by the Hamiltonian ensemble concept. Prediction accuracy is improved by up to 5.8% over deterministic and by up to 4.3% over Bayesian approaches while still guaranteeing calibration of the predictions. We observe that sampling methods facilitate model predictions with merely a third of the ensemble while maintaining prediction accuracy. In conclusion, the methods combine efficiency and regularization of stochastic gradients, showing strong performance despite the sampling bias.

Gut microbiome–produced bile acid metabolite lengthens the circadian period in host intestinal cells

Host circadian signaling, feeding, and the gut microbiome are tightly interconnected. Changes in the gut microbial community can affect the expression of core clock genes, but the specific metabolites and molecular mechanisms that mediate this relationship remain largely unknown. Here, we sought to identify gut microbial metabolites that impact circadian signaling. Through a phenotypic screen of a focused library of gut microbial metabolites, we identified a bile acid metabolite, lithocholic acid (LCA), as a circadian modulator. LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells. We found evidence that LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback loop and stabilizes core clock protein cryptochrome 2 (CRY2). Furthermore, we showed that LCA feeding alters circadian transcription in mouse distal ileum and colon. Taken together, our work identifies LCA as a molecular link between host circadian biology and the microbiome. Because bile acids are secreted in response to feeding, our work provides potential mechanistic insight into the molecular nature of the food-entrainable oscillator (FEO) by which peripheral clocks adapt to the timing of food intake. Given the association between circadian rhythm, feeding, and metabolic disease, our insights may offer an avenue for modulating host health.

Biostimulant-driven improvement in yield, seed quality, and soil health of peanut (Arachis hypogaea L.) cultivated in arid sandy environment

Global record-shattering breadbasket droughts emerge from moderately extreme regional events

Abstract Simultaneous droughts across multiple maize-producing regions can strike record-shattering portions of the global maize agricultural area, threatening global food security as the system is poorly adapted to large shocks. Yet the future probability of such global droughts remains unknown. Here, we close this gap by analyzing surface soil moisture data from large ensemble climate models under future emission scenarios. During 2026-2099, the chance of at least one such event is 52% (32–80%, range across models) under an intermediate emission scenario and 60% (32–100%) under high emissions, about seven to eleven times higher than expected if there were no long-term trends in soil moisture. These elevated probabilities are primarily driven by long-term drying in Brazil, Europe, and the USA. Interestingly, global record-shattering droughts do not emerge from simultaneous regional record-shattering events, but they mostly occur when several regions simultaneously face moderately extreme droughts relative to the new climate. These results demonstrate a high potential for an upcoming global record-shattering drought in crop-producing areas, an under-recognized risk for food security.

BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance

Extrachromosomal circular DNA (ecDNA) is frequently generated within the nucleus, contributing to genome dynamics and heterogeneity, thereby promoting cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here, using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes as key drivers of ecDNA production. Following DNA segmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively mediates ecDNA production by joining the free ends of the DNA fragments. Furthermore, ecDNA from patient tumors harbors junction sites with a LIG4 signature. Notably, disruption of either LIG4 or the BRCA1-A complex in cancer cells impairs ecDNA-mediated adaptation, hindering the development of resistance to both chemotherapy and targeted therapies. Together, our study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers therapeutic targets to block ecDNA-mediated adaptation for cancer treatment.

Obesity is linked to impaired sensorimotor synchronization during walking but not tapping

Spatial transcriptomics uncovers vasculature-centered cellular interactions driving Japanese encephalitis progression in a mouse model

Directed differentiation of bovine trophoblast stem cells: A useful in vitro model for placenta development

Cattle have a synepitheliochorial type of placenta characterized by placental cotyledons and maternal endometrial caruncles forming placentomes that are essential for fetal development to term. As the elongated conceptus begins implantation, binucleated trophoblast giant cells (TGC) begin to appear in the chorion. The TGC are hypothesized to arise from progenitor UNC through endoreplication and express unique placenta-specific genes, including placental lactogen (CSH2), pregnancy-associated glycoproteins (PAGs), and prolactin like proteins (PRPs). Despite their essential role in placental cotyledon development and placental function, the cellular and molecular mechanisms regulating trophoblast differentiation in the bovine placenta remain undefined. Here, a differentiation protocol was developed that enabled bovine trophoblast stem cells (TSCs) to generate TGC. The morphologically distinct TGCs were binucleated with a cytoplasm containing abundant secretory granules. Expression of TGC marker genes (CSH2, PAGs, PRPs) was increased in differentiated TSCs. Single-cell transcriptome analysis revealed distinct developmental programs underlying TGC lineage specification. To interrogate regulatory mechanisms governing TGC differentiation, bovine TSCs were engineered to enable inducible GCM1 (glial cells missing 1) expression. Induction of GCM1 during TSC differentiation increased TGC number and TGC-specific gene expression. This robust and tractable in vitro TSC differentiation system is useful to explore trophoblast differentiation and provide fundamental insights into the cellular and molecular mechanisms regulating placenta development in cattle.

Transformation method of Φ-OTDR optical fiber strain and tunnel liner strain and its application in tunnel safety monitoring

Abstract A distributed optical fiber stress and strain monitoring system (DSS) is developed based on Φ-OTDR sensing in this study. To apply the system to tunnel monitoring, dynamic and static tests of concrete beams are proposed to calibrate the relationship between Φ-OTDR strain and structural strain. The development trend of Φ-OTDR strain accumulation over time under the influence of the external environment is ε fiber, t =(0.023 ± 0.001)· t +(0.1425 ± 1.1795) through static tests. Combined with dynamic tests, the transformation relationship between Φ-OTDR strain and structural strain is ε struc  = 1.263· ε fiber - 0.029· t  + 0.708. The accuracy of the transformation method and the feasibility of Φ-OTDR fiber in structural strain monitoring are verified by tunnel field monitoring test. Finally, a tunnel safety warning platform is established based on Φ-OTDR technology. The calculation program and safety threshold library of monitoring indexes are implanted into the platform, making the system automatically judge and alarm the tunnel safety, thus ensuring the tunnel construction safety intelligently.

Global patterns and drivers of soil microbial nitrogen and phosphorus use efficiency

Abstract While nutrient use efficiency of soil microorganisms, the proportion of assimilated nutrients allocated into biosynthesis rather than invested in mineralization, is a critical microbial functional trait, its global patterns remain poorly quantified. Here, we estimate microbial nitrogen use efficiency (NUE, n  = 2012) and phosphorus use efficiency (PUE, n  = 3419) across terrestrial ecosystems using the ecoenzymatic stoichiometric approach. Globally, NUE (mean 0.60) is nearly twice as high as PUE (0.35). Soil organic carbon (SOC) is the strongest predictor of both, with higher SOC associated with greater nutrient use efficiency. Spatial upscaling shows that tundra and boreal forest soils have markedly lower NUE than other regions, suggesting high nitrogen investments in nutrient acquisition in cold ecosystems, whereas PUE is similar across biomes, implying pervasively low phosphorus acquisition capacity. Our study identifies potential nutrient cycling hotspots worldwide and offers critical parameters to refine large-scale predictions of soil carbon and nutrient dynamics.

Locus coeruleus–amygdala circuit disrupts prefrontal control to impair fear extinction

Stress undermines extinction learning and hinders exposure-based clinical therapies for a variety of neuropsychiatric disorders. In both animals and humans, dysfunction in the ventromedial prefrontal cortex (vmPFC) contributes to stress-impaired extinction, but the neural circuit by which stress modulates vmPFC function is not known. We hypothesize that locus coeruleus (LC) norepinephrine undermines extinction learning by recruiting projections from the basolateral amygdala (BLA) to vmPFC. Using a combination of circuit-specific chemogenetics and calcium imaging, we find that activation of LC noradrenergic neurons mimics a behavioral stressor (footshock), induces freezing behavior, reduces spontaneous neuronal activity in the vmPFC, impairs extinction learning, and alters the population dynamics of vmPFC ensembles. Activation of LC also increases shock-induced responses in BLA neurons that project to vmPFC. Selective chemogenetic activation of LC→BLA projections impairs extinction; propranolol infusions into the BLA mitigate the effects of LC activation. Together, these results indicate that the BLA serves as a critical interface between the LC and mPFC to mediate stress-induced extinction impairments.