Ultrasensitive Wearable Pressure Sensors with Stress-Concentrated Tip-Array Design for Long-Term Bimodal Identification.

The great challenges for existing wearable pressure sensors are the degradation of sensing performance and weak interfacial adhesion owing to the low mechanical transfer efficiency and interfacial differences at the skin-sensor interface. Here, an ultrasensitive wearable pressure sensor is reported by introducing a stress-concentrated tip-array design and self-adhesive interface for improving the detection limit. A bipyramidal microstructure with various Young's moduli is designed to improve mechanical transfer efficiency from 72.6% to 98.4%. By increasing the difference in modulus, it also mechanically amplifies the sensitivity to 8.5 V kPa-1 with a detection limit of 0.14 Pa. The self-adhesive hydrogel is developed to strengthen the sensor-skin interface, which allows stable signals for long-term and real-time monitoring. It enables generating high signal-to-noise ratios and multifeatures when wirelessly monitoring weak pulse signals and eye muscle movements. Finally, combined with a deep learning bimodal fused network, the accuracy of fatigued driving identification is significantly increased to 95.6%.

Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor.

The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G's conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 µM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.

Streamlining Computational Fragment-Based Drug Discovery through Evolutionary Optimization Informed by Ligand-Based Virtual Prescreening.

Recent advances in computational methods provide the promise of dramatically accelerating drug discovery. While mathematical modeling and machine learning have become vital in predicting drug-target interactions and properties, there is untapped potential in computational drug discovery due to the vast and complex chemical space. This paper builds on our recently published computational fragment-based drug discovery (FBDD) method called fragment databases from screened ligand drug discovery (FDSL-DD). FDSL-DD uses in silico screening to identify ligands from a vast library, fragmenting them while attaching specific attributes based on predicted binding affinity and interaction with the target subdomain. In this paper, we further propose a two-stage optimization method that utilizes the information from prescreening to optimize computational ligand synthesis. We hypothesize that using prescreening information for optimization shrinks the search space and focuses on promising regions, thereby improving the optimization for candidate ligands. The first optimization stage assembles these fragments into larger compounds using genetic algorithms, followed by a second stage of iterative refinement to produce compounds with enhanced bioactivity. To demonstrate broad applicability, the methodology is demonstrated on three diverse protein targets found in human solid cancers, bacterial antimicrobial resistance, and the SARS-CoV-2 virus. Combined, the proposed FDSL-DD and a two-stage optimization approach yield high-affinity ligand candidates more efficiently than other state-of-the-art computational FBDD methods. We further show that a multiobjective optimization method accounting for drug-likeness can still produce potential candidate ligands with a high binding affinity. Overall, the results demonstrate that integrating detailed chemical information with a constrained search framework can markedly optimize the initial drug discovery process, offering a more precise and efficient route to developing new therapeutics.

Self-Assembly Behavior, Aggregation Structure, and the Charge Carrier Transport Properties of S-Heterocyclic Annulated Perylene Diimide Derivatives.

The construction of high-performance n-type semiconductors is crucial for the advancement of organic electronics. As an attractive n-type semiconductor, molecular systems based on perylene diimide derivatives (PDIs) have been extensively investigated over recent years. Owing to the fascinating aggregated structure and high performance, S-heterocyclic annulated PDIs (SPDIs) are receiving increasing attention. However, the relationship between the structure and the electrical properties of SPDIs has not been deeply revealed, restricting the progress of PDI-based organic electronics. Here, we developed two novel SPDIs with linear and dendronized substituents in the imide position, named linear SPDI and dendronized SPDI, respectively. A series of structural and property characterizations indicated that linear SPDI formed a long-range-ordered crystalline structure based on helical supramolecular columns, while dendronized SPDI, with longer alkyl side chains, formed a 3D-ordered crystalline structure at a low temperature, which transformed into a hexagonal columnar liquid crystal structure at a high temperature. Moreover, no significant charge carrier transport signal was examined for linear SPDI, while dendronized SPDI had a charge carrier mobility of 3.5 × 10-3 cm2 V-1 s-1 and 2.1 × 10-3 cm2 V-1 s-1 in the crystalline and liquid crystalline state, respectively. These findings highlight the importance of the structure-function relationship in PDIs, and also offer useful roadmaps for the design of high-performance organic electronics for down-to-earth applications.

Effects of Lactobacillus-fermented low-protein diets on the growth performance, nitrogen excretion, fecal microbiota and metabolomic profiles of finishing pigs.

This study investigated the effects of Lactobacillus-fermented low-protein diet on the growth performance, nitrogen balance, fecal microbiota, and metabolomic profiles of finishing pigs. A total of 90 finishing pigs were assigned to one of three dietary treatments including a normal protein diet (CON) as well as two experimental diets in which a low-protein diet supplemented with 0 (LP) or 1% Lactobacillus-fermented low-protein feed (FLP). In comparison with CON, the LP and FLP significantly increased average daily gain (P = 0.044), significantly decreased feed to gain ratio (P = 0.021), fecal nitrogen (P < 0.01), urine nitrogen (P < 0.01), and total nitrogen (P < 0.01), respectively. The LP group exhibited increased abundances of unclassified_f_Selenomonadaceae, Coprococcus, Faecalibacterium, and Butyricicoccus, while the abundances of Verrucomicrobiae, Verrucomicrobiales, Akkermansiaceae, and Akkermansia were enriched in the FLP group. Low-protein diet-induced metabolic changes were enriched in sesquiterpenoid and triterpenoid biosynthesis and Lactobacillus-fermented low-protein feed-induced metabolic changes were enriched in phenylpropanoid biosynthesis and arginine biosynthesis. Overall, low-protein diet and Lactobacillus-fermented low-protein diet improved the growth performance and reduce nitrogen excretion, possibly via altering the fecal microbiota and metabolites in the finishing pigs. The present study provides novel ideas regarding the application of the low-protein diet and Lactobacillus-fermented low-protein diet in swine production.

Parity changed fecal microbiota of sows and its correlation with milk long-chain fatty acid profiles.

The goal of this study was to characterize the fecal microbiota profiles of gestating sows, along with the fecal microbiota and milk fatty acid contents of lactating sows and their correlations with reproductive performance at different parities. The results showed that the microbiota of third parity gestating sows contained a greater abundance of Prevotella compared to the other two parity groups, while lactating sows exhibiting higher reproductive performance at fifth parity exhibited a greater abundance of Lactobacillus species. The lactating sows with higher reproductive performance also exhibited higher total monounsaturated fatty acid (MUFA) and higher total polyunsaturated fatty acid (PUFA) levels relative to sows with lower reproductive performance at all three analyzed parities, especially sows at fifth parity produced the lowest total saturated fatty acid (SFA) levels, and showed the highest C18:1n9c and C18:2n6c concentrations. In correlational analyses, the abundance of Oligella, Lactobacillus, and Corynebacterium was highly positively correlated with C18:1n9c, C18:2n6c, and C20:4n6. Overall, these results provide a rational basis for efforts to improve sow reproductive performance through the provision of precisely regulated nutrition. KEY POINTS: • Clear differences in the fecal microbiota were evident between sows of different parities. • Lactating sows with high reproductive performance showed distinct milk fatty acid profiles.

Fragment databases from screened ligands for drug discovery (FDSL-DD).

Fragment-based drug design (FBDD) is one major drug discovery method employed in computer-aided drug discovery. Due to its inherent limitations, this process experiences long processing times and limited success rates. Here we present a new Fragment Databases from Screened Ligands Drug Design method (FDSL-DD) that intelligently incorporates information about fragment characteristics into a fragment-based design approach to the drug development process. The initial step of the FDSL-DD is the creation of a fragment database from a library of docked, drug-like ligands for a specific target, which deviates from the traditional in silico FBDD strategy, incorporating structure-based design screening techniques to combine the advantages of both approaches. Three different protein targets have been tested in this study to demonstrate the potential of the created fragment library and FDSL-DD. Utilizing the FDSL-DD led to an increase in binding affinity for each protein target. The most substantial increase was exhibited by the ligand designed for TIPE2, with a 3.6 kcalmol-1 difference between the top ligand from the FDSL-DD and top ligand from the high throughput virtual screening (HTVS). Using drug-like ligands in the initial HTVS allows for a greater search of chemical space, with higher efficiency in fragments selection, less grid boxes, and potentially identifying more interactions.

Content specificity of attentional bias to COVID-19 threat-related information in trait anxiety.

Introduction: Anxious individuals selectively attend to threatening information, but it remains unclear whether attentional bias can be generalized to traumatic events, such as the COVID-19 pandemic. Previous studies suggested that specific threats related to personal experiences can elicit stronger attentional bias than general threats. The current study aimed to investigate the relationship between content-specific attentional bias and trait anxiety during the COVID-19 pandemic. Methods: Attentional bias was assessed using the dot-probe task with COVID-19-related, general threat-related, and neutral words at two exposure times, 200 and 500 ms. Results: We found participants with high trait anxiety exhibited attentional bias toward COVID-19- related stimuli and attentional bias away from general threat-related stimuli, while participants with low trait anxiety showed attentional bias away from both types of stimuli. Discussion: Results suggest that individuals with high trait anxiety show a content-specific attentional bias to COVID-19-related information during the COVID-19 pandemic. Apart from the innate attentional bias toward biological threats, individuals with high trait anxiety may also learn from trauma and develop trauma-specific attentional bias.

Lactobacillus-driven feed fermentation regulates microbiota metabolism and reduces odor emission from the feces of pigs.

IMPORTANCE: Our present study showed that dietary supplementation with feed fermented by Lactobacillus could promote the growth performance of pigs, regulate the microbiota, and inhibit the growth of harmful bacteria. It could prevent the accumulation of toxic substances and reduce odor emission from pig feces, thereby reducing environmental pollution. In addition, one key triumph of the present study was the isolation of Weissella cibaria ZWC030, and the strain could inhibit the production of skatole in vitro in our present results.

Self-anticoagulant sponge for whole blood auto-transfusion and its mechanism of coagulation factor inactivation.

Clinical use of intraoperative auto-transfusion requires the removal of platelets and plasma proteins due to pump-based suction and water-soluble anticoagulant administration, which causes dilutional coagulopathy. Herein, we develop a carboxylated and sulfonated heparin-mimetic polymer-modified sponge with spontaneous blood adsorption and instantaneous anticoagulation. We find that intrinsic coagulation factors, especially XI, are inactivated by adsorption to the sponge surface, while inactivation of thrombin in the sponge-treated plasma effectively inhibits the common coagulation pathway. We show whole blood auto-transfusion in trauma-induced hemorrhage, benefiting from the multiple inhibitory effects of the sponge on coagulation enzymes and calcium depletion. We demonstrate that the transfusion of collected blood favors faster recovery of hemostasis compared to traditional heparinized blood in a rabbit model. Our work not only develops a safe and convenient approach for whole blood auto-transfusion, but also provides the mechanism of action of self-anticoagulant heparin-mimetic polymer-modified surfaces.

Pharmacophore based virtual screening for identification of effective inhibitors to combat HPV 16 E6 driven cervical cancer.

Targeting HPV16 E6 has emerged as an effective drug target for the treatment/management of cervical cancer. We utilized pharmacophore-based virtual screening, molecular docking, absorption, distribution, metabolism and excretion (ADME) prediction, and molecular dynamics simulation approach for identifying potential inhibitors of HPV16 E6. Initially, we generated a ligand-based pharmacophore model based on the features of four known HPV16 E6 inhibitors (CA24, CA25, CA26, and CA27) via the PHASE module implanted in the Schrödinger suite. We constructed four-point pharmacophore features viz., three hydrogen bond acceptors (A) and one aromatic ring (R). The common pharmacophore feature further employed as a query for virtual screening against the ASINEX database via Schrödinger suite. The pharmacophore-based virtual screening filtered out top 2000 hits, based on the fitness score. We then applied the high throughput virtual screening (HTVS), standard precision (SP) and extra precision (XP). 1000 compounds were obtained from HTVS docking. Based on the glide score, they were further filtered to 500 hits by employing docking in standard precision mode. Finally, the best four hits and a negative molecule were identified using docking in XP mode. The four lead compounds and a negative molecule were then further subjected to ADME profile prediction by engaging Qikprop module. The ADME properties of the four lead molecules indicate good pharmacokinetic (PK) properties rather than the negative molecule. The binding stability of the HPV16 E6-hit complexes were investigated at a different time scale (100 ns) by using the desmond package and the results were examined using Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) and it revealed the stability of the protein-ligand complex throughout the simulation. Key residues, CYS 51 and GLN 107, also play a crucial role in enhancing the stability of the protein-ligand complex during the simulation. Furthermore, the binding free energy of the HPV16 E6-leads complexes was analyzed by prime which revealed that the ΔGbind coulomb and ΔGbind vdW interactions are crucially contributes to the binding affinity. In order to validate the computational findings, the efficacy of benzoimidazole and benzotriazole were ascertained for regulating ME180 cervical cancer cell survival, migration and ability to release MMP-2.

Thiadiazole-Derived Covalent Organic Framework Macroscopic Ultralight Aerogel.

Shaping covalent organic frameworks (COFs) into macroscopic objects for practical application remains a huge challenge. Herein, a new thiadiazole-derived COF macroscopic ultralight aerogel (NNS-VCOF) was prepared through acid-catalyzed aldol condensation between 2,5-dimethyl-1,3,4-thiadiazole and a tritopic aromatic aldehyde derivative. NNS-VCOF aerogel shows extremely low density (ca. 0.020 g cm-3), excellent mechanical properties (compression modulus of 16.65 kPa), thermal insulation properties (low thermal conductivity of 0.03270 W m-1 K-1 at 25 °C), and flame retardancy (quickly self-extinguishing after ignition) due to its three-dimensional sponge-like architecture and special nitrogen heterocyclic framework. To our delight, NNS-VCOF aerogel not only can be used as an outstanding macroscopic material but also shows efficient photocatalytic hydrogen evolution properties in a powder state because of the superhydrophilicity and appropriate optical properties.

A New Contactless Cross-Correlation Velocity Measurement System for Gas-Liquid Two-Phase Flow.

Based on the principle of Contactless Conductivity Detection (CCD), a new contactless cross-correlation velocity measurement system with a three-electrode construction is developed in this work and applied to the contactless velocity measurement of gas-liquid two-phase flow in small channels. To achieve a compact design and to reduce the influence of the slug/bubble deformation and the relative position change on the velocity measurement, an electrode of the upstream sensor is reused as an electrode of the downstream sensor. Meanwhile, a switching unit is introduced to ensure the independence and consistency of the upstream sensor and the downstream sensor. To further improve the synchronization of the upstream sensor and the downstream sensor, fast switching and time compensation are also introduced. Finally, with the obtained upstream and downstream conductance signals, the velocity measurement is achieved by the principle of cross-correlation velocity measurement. To test the measurement performance of the developed system, experiments are carried out on a prototype with a small channel of 2.5 mm. The experimental results show that the compact design (three-electrode construction) is successful, and its measurement performance is satisfactory. The velocity range for the bubble flow is 0.312-0.816 m/s, and the maximum relative error of the flow rate measurement is 4.54%. The velocity range for the slug flow is 0.161 m/s-1.250 m/s, and the maximum relative error of the flow rate measurement is 3.70%.

Bulk Polymerization of Acrylic Acid Using Dielectric-Barrier Discharge Plasma in a Mesoporous Material.

This research investigated a non-thermal, dielectric-barrier discharge (DBD) plasma-based approach to prepare poly(acrylic acid) (PAA) from acrylic acid in its liquid state at atmospheric temperature and pressure. Neither additives nor solvents were needed, and the polymerization was accomplished both as a film and inside a sheet of mesoporous paper. All prepared samples were characterized and the DBD plasma-initiated kinetics were analyzed for the polymerization of acrylic acid. Using FTIR semi-quantitative analysis, the degree of polymerization was monitored, and the reaction followed an overall second-order kinetic model with respect to the DBD-initiated polymerization. Additionally, the application of a PAA-modified paper as a water retention cloth or 'wet wipe' was investigated. The results showed that the PAA-modified paper substrates using DBD plasma increased water retention as a function of plasma treatment time.

Zwitterionic and Hydrophilic Vinylene-Linked Covalent Organic Frameworks for Efficient Photocatalytic Hydrogen Evolution.

Developing effective synthetic strategies as well as broadening functionalities for zwitterionic materials that comprise moieties with equimolar cationic and anionic groups still remains a huge challenge. Herein, we develop two zwitterionic vinylene-linked covalent organic frameworks (Zi-VCOF-1 and Zi-VCOF-2) that are a type of novel hydrophilic material. Zi-VCOF-1 and Zi-VCOF-2 are obtained directly through the convenient Knoevenagel condensation of new sulfonic-pyridinium zwitterionic monomers with aromatic aldehyde derivatives. This is the first report on zwitterionic COFs being constructed by the bottom-up functionalization approach from predesigned zwitterionic monomers. Both Zi-VCOFs exhibit a high photocatalytic hydrogen evolution rate (HER) because of their appropriate optical property and outstanding hydrophilicity. Specifically, Zi-VCOF-1 and Zi-VCOF-2 show photocatalytic HER of 13,547 and 5057 µmol h-1 g-1, respectively. Interestingly, the photocatalytic HER of Zi-VCOF-1 is about 2.68 times of that of Zi-VCOF-2, although they differ by only one methyl group in sulfonic-pyridinium zwitterionic pairs. The photocatalytic HER of Zi-VCOF-1 is not only the highest in the vinylene-linked COFs but also outstanding among the most reported COFs. This is the first application of zwitterionic COFs for photocatalytic hydrogen evolution, which would open a new frontier in zwitterionic COFs and be helpful for the design of other photocatalytic materials.

Advances in Enhancing Hemocompatibility of Hemodialysis Hollow-Fiber Membranes.

Hemodialysis, the most common modality of renal replacement therapy, is critically required to remove uremic toxins from the blood of patients with end-stage kidney disease. However, the chronic inflammation, oxidative stress as well as thrombosis induced by the long-term contact of hemoincompatible hollow-fiber membranes (HFMs) contribute to the increase in cardiovascular diseases and mortality in this patient population. This review first retrospectively analyzes the current clinical and laboratory research progress in improving the hemocompatibility of HFMs. Details on different HFMs currently in clinical use and their design are described. Subsequently, we elaborate on the adverse interactions between blood and HFMs, involving protein adsorption, platelet adhesion and activation, and the activation of immune and coagulation systems, and the focus is on how to improve the hemocompatibility of HFMs in these aspects. Finally, challenges and future perspectives for improving the hemocompatibility of HFMs are also discussed to promote the development and clinical application of new hemocompatible HFMs.

Genetic labeling reveals spatial and cellular expression pattern of neuregulin 1 in mouse brain.

BACKGROUND: Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. METHODS: Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. RESULTS: In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. CONCLUSIONS: Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.

Self-Assembled Porous-Reinforcement Microstructure-Based Flexible Triboelectric Patch for Remote Healthcare.

Realizing real-time monitoring of physiological signals is vital for preventing and treating chronic diseases in elderly individuals. However, wearable sensors with low power consumption and high sensitivity to both weak physiological signals and large mechanical stimuli remain challenges. Here, a flexible triboelectric patch (FTEP) based on porous-reinforcement microstructures for remote health monitoring has been reported. The porous-reinforcement microstructure is constructed by the self-assembly of silicone rubber adhering to the porous framework of the PU sponge. The mechanical properties of the FTEP can be regulated by the concentrations of silicone rubber dilution. For pressure sensing, its sensitivity can be effectively improved fivefold compared to the device with a solid dielectric layer, reaching 5.93 kPa-1 under a pressure range of 0-5 kPa. In addition, the FTEP has a wide detection range up to 50 kPa with a sensitivity of 0.21 kPa-1. The porous microstructure makes the FTEP ultra-sensitive to external pressure, and the reinforcements endow the device with a greater deformation limit in a wide detection range. Finally, a novel concept of the wearable Internet of Healthcare (IoH) system for real-time physiological signal monitoring has been proposed, which could provide real-time physiological information for ambulatory personalized healthcare monitoring.

Distributed Optical Measurement System for Plate Fin Heat Exchanger.

The acquirement of the flow information in plate-fin heat exchanger (PFHE) is limited by its metal structure and complex flow condition. This work develops a new distributed optical measurement system to obtain flow information and boiling intensity. The system utilizes numerous optical fibers installed at the surface of the PFHE to detect optical signals. The attenuation and fluctuation of the signals reflect the variation of the gas-liquid interfaces and can be further used to estimate the boiling intensity. Practical experiments of flow boiling in PFHE with different heating fluxes have been carried out. The results verify that the measurement system can obtain the flow condition. Meanwhile, according to the results, the boiling development in PFHE can be divided into four stages with the increase in the heating flux, including the unboiling stage, initiation stage, boiling developing stage, and fully developed stage.

A general method to predict optical rotations of chiral molecules from their structures.

The relationship of the chiroptical response of a molecule to its absolution configuration does not exist now. In this letter, I intend to report a general rule with exceptions to predict the sign of optical rotation of chiral molecules with a RCHXY structure from their absolute configurations using the Hammett constant, σ p, which is based on the electron withdrawing/donating power of functional groups. In this rule, a priority list of functional groups based on the electron withdrawing powers of the groups are used. When the lowest priority group is in the back of the molecule, a clockwise arrangement of the other three priorities from the most electron withdrawing to the least withdrawing (1-2-3) is predicted to be dextrorotatory, the counterclockwise arrangement is predicted to be levorotatory.