Superfine Nanodomain Engineering Unleashing Ferroelectricity in Incipient Ferroelectrics.

Incipient ferroelectrics have emerged as an attractive class of functional materials owing to their potential to be engineered for exotic ferroelectric behavior, holding great promise for expanding the ferroelectric family. However, thus far, their artificially engineered ferroelectricity has fallen far short of rivaling classic ferroelectrics. In this study, we address this challenge by developing a superfine nanodomain engineering strategy. By applying this approach to representative incipient ferroelectric of SrTiO3-based films, we achieve unprecedentedly strong ferroelectricity, not only surpassing previous records for incipient ferroelectrics but also being comparable to classic ferroelectrics. The remanent polarization of the thin film reaches up to 17.0 µC cm-2 with an ultrahigh Curie temperature of 973 K. Atomic-scale investigations elucidate the origin of this robust ferroelectricity in the emergent high-density superfine nanodomains spanning merely 3-10 unit cells. Combining experimental results with theoretical assessments, we unveil the underlying mechanism, where the intentionally introduced diluted foreign Fe element creates a deeper Landau energy well and promotes a short-range ordering of polarization. Our developed strategy significantly streamlines the design of unconventional ferroelectrics, providing a versatile pathway for exploring new and superior ferroelectric materials.

Discovering novel Cathepsin L inhibitors from natural products using artificial intelligence.

Cathepsin L (CTSL) is a promising therapeutic target for metabolic disorders. Current pharmacological interventions targeting CTSL have demonstrated potential in reducing body weight gain, serum insulin levels, and improving glucose tolerance. However, the clinical application of CTSL inhibitors remains limited. In this study, we used a combination of artificial intelligence and experimental methods to identify new CTSL inhibitors from natural products. Through a robust deep learning model and molecular docking, we screened 150 molecules from natural products for experimental validation. At a concentration of 100 µM, we found that 36 of them exhibited more than 50 % inhibition of CTSL. Notably, 13 molecules displayed over 90 % inhibition and exhibiting concentration-dependent effects. The molecular dynamics simulation on the two most potent inhibitors, Plumbagin and Beta-Lapachone, demonstrated stable interaction at the CTSL active site. Enzyme kinetics studies have shown that these inhibitors exert an uncompetitive inhibitory effect on CTSL. In conclusion, our research identifies Plumbagin and Beta-Lapachone as potential CTSL inhibitors, offering promising candidates for the treatment of metabolic disorders and illustrating the effectiveness of artificial intelligence in drug discovery.

Syntropic spin alignment at the interface between ferromagnetic and superconducting nitrides.

The magnetic correlations at the superconductor/ferromagnet (S/F) interfaces play a crucial role in realizing dissipation-less spin-based logic and memory technologies, such as triplet-supercurrent spin-valves and 'π' Josephson junctions. Here we report the observation of an induced large magnetic moment at high-quality nitride S/F interfaces. Using polarized neutron reflectometry and DC SQUID measurements, we quantitatively determined the magnetization profile of the S/F bilayer and confirmed that the induced magnetic moment in the adjacent superconductor only exists below T C. Interestingly, the direction of the induced moment in the superconductors was unexpectedly parallel to that in the ferromagnet, which contrasts with earlier findings in S/F heterostructures based on metals or oxides. First-principles calculations verified that the unusual interfacial spin texture observed in our study was caused by the Heisenberg direct exchange coupling with constant J∼4.28 meV through d-orbital overlapping and severe charge transfer across the interfaces. Our work establishes an incisive experimental probe for understanding the magnetic proximity behavior at S/F interfaces and provides a prototype epitaxial 'building block' for superconducting spintronics.

The origin of the large T c variation in FeSe thin films probed by dual-beam pulsed laser deposition.

FeSe is one of the most enigmatic superconductors. Among the family of iron-based compounds, it has the simplest chemical makeup and structure, and yet it displays superconducting transition temperature ( T c ) spanning 0 to 15 K for thin films, while it is typically 8 K for single crystals. This large variation of T c within one family underscores a key challenge associated with understanding superconductivity in iron chalcogenides. Here, using a dual-beam pulsed laser deposition (PLD) approach, we have fabricated a unique lattice-constant gradient thin film of FeSe which has revealed a clear relationship between the atomic structure and the superconducting transition temperature for the first time. The dual-beam PLD that generates laser fluence gradient inside the plasma plume has resulted in a continuous variation in distribution of edge dislocations within a single film, and a precise correlation between the lattice constant and T c has been observed here, namely, T c ∝ c - c 0 , where c is the c-axis lattice constant (and c 0 is a constant). This explicit relation in conjunction with a theoretical investigation indicates that it is the shifting of the d xy orbital of Fe which plays a governing role in the interplay between nematicity and superconductivity in FeSe. Supplementary Information: The online version contains supplementary material available at 10.1007/s44214-024-00058-0.

Heterogeneous metabolic changes of brown and white adipose tissues are associated with metabolic adaptations in periparturient mice.

Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analysis revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT, but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maxicum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation, and facilitate the development of the prevention and treatment of metabolic diseases.

The impact of hyperkalemia on ICU admission and mortality: a retrospective study of Chinese emergency department data.

OBJECTIVE: This study assesses the influence of hyperkalemia on both disease severity and the risk of mortality among patients admitted to the emergency room. METHODS: This retrospective observational study utilized data from the Chinese Emergency Triage Assessment and Treatment database (CETAT, version 2.0), which was designed to evaluate and optimize management strategies for emergency room (ER) patients. Patients were systematically categorized based on serum potassium levels. Relationships between serum potassium levels, risk of mortality, and the severity of illness were then analyzed using multifactorial logistic regression and through Receiver Operating Characteristic (ROC) analysis. The effectiveness of various treatments at lowering potassium levels was also investigated. RESULTS: 12,799 emergency patients were enrolled, of whom 20.1% (n = 2,577) were hypokalemic and 2.98% (n = 381) were hyperkalemic. Among hyperkalemic patients, the leading reasons for visiting the ER were altered consciousness 23.88% (n = 91), cardiovascular symptoms 22.31% (n = 85), and gastrointestinal symptoms 20.47% (n = 78). Comparative analysis with patients exhibiting normal potassium levels revealed hyperkalemia as an independent factor associated with mortality in the ER. Mortality risk appears to positively correlate with increasing potassium levels, reaching peaks when blood potassium levels ranged between 6.5 and 7.0. Hyperkalemia emerged as a strong predictor of death in the ER, with an Area Under the Curve (AUC) of 0.89. The most frequently prescribed treatment for hyperkalemia patients was diuretics (57.32%, n = 188), followed by intravenous sodium bicarbonate (50.91%, n = 167), IV calcium (37.2%, n = 122), insulin combined with high glucose (27.74%, n = 91), and Continuous Renal Replacement Therapy (CRRT) for 19.82% (n = 65). Among these, CRRT appeared to be the most efficacious at reducing potassium levels. Diuretics appeared relatively ineffective, while high-glucose insulin, sodium bicarbonate, and calcium preparations having no significant effect on the rate of potassium decline. CONCLUSION: Hyperkalemia is common in emergency situations, especially among patients with altered consciousness. There is a strong positive correlation between the severity of hyperkalemia and mortality risk. CRRT appears to be the most effective potassium reducting strategy, while the use of diuretics should be approached with caution.

Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Uncovering the characteristics of the gut microbiota in patients with ischemic stroke and hemorrhagic stroke.

This study aimed to explore the gut microbiota characteristics of ischemic and hemorrhagic stroke patients. A case-control study was conducted, and high-throughput sequencing of the V4-V5 region of 16S rRNA was used to analyze the differences in gut microbiota. The results showed that Proteobacteria was significantly increased in the ischemic stroke group compared with the healthy control group, while Fusobacteria was significantly increased in the hemorrhagic stroke group. In the ischemic stroke group, Butyricimonas, Alloprevotella, and Escherichia were significantly more abundant than in the healthy control group. In the hemorrhagic stroke group, Atopobium, Hungatella, Eisenbergiella, Butyricimonas, Odonbacter, Lachnociostridium, Alistipes, Parabacteroides, and Fusobacterium were significantly more abundant than in the healthy control group. Additionally, Alloprevotella, Ruminococcus, and Prevotella were significantly more abundant in the ischemic stroke group than in the hemorrhagic stroke group. The gut microbiota of ischemic and hemorrhagic stroke patients has significant diversity characteristics. These results provide new theoretical basis for exploring the prevention and treatment of different types of stroke through gut microbiota research.

Synthesis, Characterization, and Catalytic Behaviors in Isoprene Polymerization of Pyridine-Oxazoline-Ligated Cobalt Complexes.

A family of pyridine-oxazoline-ligated cobalt complexes L2CoCl23a-h were synthesized and characterized. Determined via single-crystal X-ray diffraction, complexes 3a and 3d, ligated by two ligands, displayed a distorted tetrahedral coordination of a cobalt center. The X-ray structure indicated the pyridine-oxazoline ligands acted as unusual mono-dentate ligands by coordinating only to Noxazoline. Upon activation with AlEt2Cl (diethylaluminum chloride), these cobalt complexes all exhibited high catalytic activity (up to 2.5 × 106 g·molCo-1·h-1), affording cis-1,4-co-3,4-polyisoprene with molecular weights of 4.4-176 kg mol-1 and a narrow Ð of 1.79-3.42, suggesting a single-site nature of the active sites. The structure of cobalt catalysts and reaction parameters, especially co-catalysts and the reaction temperature, all have significant influence on the polymerization activity but not on the microstructure of polyisoprene.

High-performance terahertz modulators induced by substrate field in Te-based all-2D heterojunctions.

High-performance active terahertz modulators as the indispensable core components are of great importance for the next generation communication technology. However, they currently suffer from the tradeoff between modulation depth and speed. Here, we introduce two-dimensional (2D) tellurium (Te) nanofilms with the unique structure as a new class of optically controlled terahertz modulators and demonstrate their integrated heterojunctions can successfully improve the device performances to the optimal and applicable levels among the existing all-2D broadband modulators. Further photoresponse measurements confirm the significant impact of the stacking order. We first clarify the direction of the substrate-induced electric field through first-principles calculations and uncover the unusual interaction mechanism in the photoexcited carrier dynamics associated with the charge transfer and interlayer exciton recombination. This advances the fundamental and applicative research of Te nanomaterials in high-performance terahertz optoelectronics.

Dynamical interplay between superconductivity and pseudogap in cuprates as revealed by terahertz third-harmonic generation spectroscopy.

We report on nonlinear terahertz third-harmonic generation (THG) measurements on YBa2Cu3O6+x thin films. Different from conventional superconductors, the THG signal starts to appear in the normal state, which is consistent with the crossover temperature T* of pseudogap over broad doping levels. Upon lowering the temperature, the THG signal shows an anomaly just below Tc in the optimally doped sample. Notably, we observe a beat pattern directly in the measured real-time waveform of the THG signal. We elaborate that the Higgs mode, which develops below Tc, couples to the mode already developed below T*, resulting in an energy level splitting. However, this coupling effect is not evident in underdoped samples. We explore different potential explanations for the observed phenomena. Our research offers valuable insight into the interplay between superconductivity and pseudogap.

Inference of Gene Regulatory Networks Based on Multi-view Hierarchical Hypergraphs.

Since gene regulation is a complex process in which multiple genes act simultaneously, accurately inferring gene regulatory networks (GRNs) is a long-standing challenge in systems biology. Although graph neural networks can formally describe intricate gene expression mechanisms, current GRN inference methods based on graph learning regard only transcription factor (TF)-target gene interactions as pairwise relationships, and cannot model the many-to-many high-order regulatory patterns that prevail among genes. Moreover, these methods often rely on limited prior regulatory knowledge, ignoring the structural information of GRNs in gene expression profiles. Therefore, we propose a multi-view hierarchical hypergraphs GRN (MHHGRN) inference model. Specifically, multiple heterogeneous biological information is integrated to construct multi-view hierarchical hypergraphs of TFs and target genes, using hypergraph convolution networks to model higher order complex regulatory relationships. Meanwhile, the coupled information diffusion mechanism and the cross-domain messaging mechanism facilitate the information sharing between genes to optimise gene embedding representations. Finally, a unique channel attention mechanism is used to adaptively learn feature representations from multiple views for GRN inference. Experimental results show that MHHGRN achieves better results than the baseline methods on the E. coli and S. cerevisiae benchmark datasets of the DREAM5 challenge, and it has excellent cross-species generalization, achieving comparable or better performance on scRNA-seq datasets from five mouse and two human cell lines.

KCNH6 channel promotes insulin exocytosis via interaction with Munc18-1 independent of electrophysiological processes.

Glucose-stimulated insulin secretion (GSIS) in pancreatic islet ß-cells primarily relies on electrophysiological processes. Previous research highlighted the regulatory role of KCNH6, a member of the Kv channel family, in governing GSIS through its influence on ß-cell electrophysiology. In this study, we unveil a novel facet of KCNH6's function concerning insulin granule exocytosis, independent of its conventional electrical role. Young mice with ß-cell-specific KCNH6 knockout (ßKO) exhibited impaired glucose tolerance and reduced insulin secretion, a phenomenon not explained by electrophysiological processes alone. Consistently, islets from KCNH6-ßKO mice exhibited reduced insulin secretion, conversely, the overexpression of KCNH6 in murine pancreatic islets significantly enhanced insulin release. Moreover, insulin granules lacking KCNH6 demonstrated compromised docking capabilities and a reduced fusion response upon glucose stimulation. Crucially, our investigation unveiled a significant interaction between KCNH6 and the SNARE protein regulator, Munc18-1, a key mediator of insulin granule exocytosis. These findings underscore the critical role of KCNH6 in the regulation of insulin secretion through its interaction with Munc18-1, providing a promising and novel avenue for enhancing our understanding of the Kv channel in diabetes mechanisms.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic ß cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic ß-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 ß-cell-specific knockout (ßKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of ßKO mice, which contributed to ER stress and ER stress-induced apoptosis in ß cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic ß cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in ßKO mice, restored ER Ca2+ overload and attenuated ER stress in ß cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect ß cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

All-potassium channel CRISPR screening reveals a lysine-specific pathway of insulin secretion.

OBJECTIVE: Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known that glucose stimulates insulin secretion from pancreatic ß-cells, mainly via the KATP depolarization channel, but whether other nutrients directly regulate the repolarization K+ channel to promote insulin secretion is unknown. METHODS: We used a system involving CRISPR-Cas9-mediated knockout of all 83 K+ channels and scRNA-seq in a pancreatic ß cell line to identify genes associated with insulin secretion. RESULTS: The expression levels of insulin genes were significantly increased after all-K+ channel knockout. Furthermore, Kcnb1 and Kcnh6 were the two most important repolarization K+ channels for the increase in high-glucose-dependent insulin secretion that occurred upon application of specific inhibitors of the channels. Kcnh6 currents, but not Kcnb1 currents, were reduced by one of the amino acids, lysine, in both transfected cells, primary cells and mice with ß-cell-specific deletion of Kcnh6. CONCLUSIONS: Our function-related CRISPR screen with scRNA-seq identifies Kcnh6 as a lysine-specific channel.

Effectiveness and safety of probiotics on patients with severe acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to assess the efficacy and safety of probiotics in conjunction with early enteral nutrition for the treatment of severe acute pancreatitis (SAP). This study focused on multiple clinical endpoints, including mortality rate, risk of organ failure, and duration of hospital stay. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The study adhered to the Patient, Intervention, Comparison, Outcome framework and utilized randomized controlled trials to examine the impact of probiotics on patients with SAP. Data extraction and quality assessment were conducted independently by 2 evaluators, with discrepancies resolved collaboratively, or by a third adjudicator. Statistical analyses were performed using chi-square statistics, I2 metrics, and both fixed- and random-effects models, as dictated by heterogeneity levels. RESULTS: The meta-analysis covered 6 randomized controlled trials. Compared to control groups (placebo or standard care without probiotics), probiotics did not significantly reduce mortality rates or organ failure risk. However, they notably shortened hospital stays by a weighted mean difference of -5.49 days (95% confidence interval: -10.40 to -0.58; P = .010). The overall bias risk was low to moderate. CONCLUSIONS: Probiotics combined with early enteral nutrition did not significantly improve mortality rates or reduce the risk of organ failure in patients with SAP, but shortened hospital stays. Further studies are required to corroborate these findings.

Erratum: Upper limit of the transition temperature of superconducting materials.

[This corrects the article DOI: 10.1016/j.patter.2022.100609.].

Modeling the XBB strain of SARS-CoV-2: Competition between variants and impact of reinfection.

XBB, an Omicron subvariant of SARS-CoV-2 that began to circulate in late 2022, has been dominant in the US since early 2023. To quantify the impact of XBB on the progression of COVID-19, we propose a new mathematical model which describes the interplay between XBB and other SARS-CoV-2 variants at the population level and which incorporates the effects of reinfection. We apply the model to COVID-19 data in the US that include surveillance data on the cases and variant proportions from the New York City, the State of New York, and the State of Washington. Our fitting and simulation results show that the transmission rate of XBB is significantly higher than that of other variants and the reinfection from XBB may play an important role in shaping the pandemic/epidemic pattern in the US.

Xuebijing injection protects sepsis induced myocardial injury by mediating TLR4/NF-κB/IKKα and JAK2/STAT3 signaling pathways.

OBJECTIVE: Compelling evidence has demonstrated that Xuebijing (XBJ) exerted protective effects against SIMI. The aims of this study were to investigate whether TLR4/IKKα-mediated NF-κB and JAK2/STAT3 pathways were involved in XBJ's cardio-protection during sepsis and the mechanisms. METHODS: In this study, rats were randomly assigned to three groups: Sham group; CLP group; XBJ group. Rats were treated with XBJ or sanitary saline after CLP. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6 and TNF-α in serum were measured using ELISA kits. Cardiomyocyte apoptosis were tested by TUNEL staining. The protein levels of Bax, Bcl-2, Bcl-xl, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3 in the myocardium were assayed by western blotting. And finally, immunofluorescence was used to assess the level of p-JAK2 and p-STAT3 in heart tissue. RESULTS: The results of echocardiography, myocardial enzyme and HE test showed that XBJ could significantly improve SIMI. The IL-1ß, IL-6 and TNF-α levels in the serum were markedly lower in the XBJ group than in the CLP group (p<0.05). TUNEL staining's results showed that XBJ ameliorated CLP-induced cardiomyocyte apoptosis. Meanwhile, XBJ downregulated the protein levels of Bax, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3, as well as upregulated the protein levels of Bcl-2, Bcl-xl (p <0.05). CONCLUSIONS: In here, we observed that XBJ's cardioprotective advantages may be attributable to its ability to suppress inflammation and apoptosis via inhibiting the TLR4/ IKKα-mediated NF-κB and JAK2/STAT3 pathways during sepsis.

Black Phosphorus/Ferroelectric P(VDF-TrFE) Field-Effect Transistors with High Mobility for Energy-Efficient Artificial Synapse in High-Accuracy Neuromorphic Computing.

The neuromorphic system is an attractive platform for next-generation computing with low power and fast speed to emulate knowledge-based learning. Here, we design ferroelectric-tuned synaptic transistors by integrating 2D black phosphorus (BP) with a flexible ferroelectric copolymer poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)). Through nonvolatile ferroelectric polarization, the P(VDF-TrFE)/BP synaptic transistors show a high mobility value of 900 cm2 V-1 s-1 with a 103 on/off current ratio and can operate with low energy consumption down to the femtojoule level (∼40 fJ). Reliable and programmable synaptic behaviors have been demonstrated, including paired-pulse facilitation, long-term depression, and potentiation. The biological memory consolidation process is emulated through ferroelectric gate-sensitive neuromorphic behaviors. Inspiringly, the artificial neural network is simulated for handwritten digit recognition, achieving a high recognition accuracy of 93.6%. These findings highlight the prospects of 2D ferroelectric field-effect transistors as ideal building blocks for high-performance neuromorphic networks.