Unsupervised Multi-Domain Progressive Stain Transfer Guided by Style Encoding Dictionary.

In histopathology, the tissue slides are usually stained by common H&E stain or special stains (MAS, PAS, and PASM, etc.) to clearly show specific tissue structures. The rapid development of deep learning provides a good solution to generate virtual staining images to significantly reduce the time and labor costs associated with histochemical staining. However, most existing methods need to train a special model for every two stains, which consumes a lot of computing resources with the increasing of staining types. To address this problem, we propose an unsupervised multi-domain stain transfer method, GramGAN, which realizes the progressive transfer through cascaded Style-Guided blocks. For each Style-Guided block, we design a style encoding dictionary to characterize and store all the staining style information. In addition, we propose a Rényi entropy-based regularization term to improve the discrimination ability of different styles. The experimental results show that our method can realize accurate transferring among multiple staining styles with better performance. Furthermore, we build and publish a special stained image dataset suitable for glomeruli segmentation (including H&E staining), where the accuracy of glomeruli detection and segmentation can be significantly improved after transferring H&E-stained images to PAS-stained and PASM-stained ones by our method. The code is publicly available at: https://github.com/xianchaoguan/GramGAN.

Superstructural ordering in self-sorting coacervate-based protocell networks.

Bottom-up assembly of higher-order cytomimetic systems capable of coordinated physical behaviours, collective chemical signalling and spatially integrated processing is a key challenge in the study of artificial multicellularity. Here we develop an interactive binary population of coacervate microdroplets that spontaneously self-sort into chain-like protocell networks with an alternating sequence of structurally and compositionally dissimilar microdomains with hemispherical contact points. The protocell superstructures exhibit macromolecular self-sorting, spatially localized enzyme/ribozyme biocatalysis and interdroplet molecular translocation. They are capable of topographical reconfiguration using chemical or light-mediated stimuli and can be used as a micro-extraction system for macroscale biomolecular sorting. Our methodology opens a pathway towards the self-assembly of multicomponent protocell networks based on selective processes of coacervate droplet-droplet adhesion and fusion, and provides a step towards the spontaneous orchestration of protocell models into artificial tissues and colonies with ordered architectures and collective functions.

Supramolecular Hydrolase Mimics in Equilibrium and Kinetically Trapped States.

The folding of proteins into intricate three-dimensional structures to achieve biological functions, such as catalysis, is governed by both kinetic and thermodynamic controls. The quest to design artificial enzymes using minimalist peptides seeks to emulate supramolecular structures existing in a catalytically active state. Drawing inspiration from the nuanced process of protein folding, our study explores the enzyme-like activity of amphiphilic peptide nanosystems in both equilibrium and non-equilibrium states, featuring the formation of supramolecular nanofibrils and nanosheets. In contrast to thermodynamically stable nanosheets, the kinetically trapped nanofibrils exhibit dynamic characteristics (e.g., rapid molecular exchange and relatively weak intermolecular packing), resulting in a higher hydrolase-mimicking activity. We emphasize that a supramolecular microenvironment characterized by an optimal local polarity, microviscosity, and ß-sheet hydrogen bonding is conducive to both substrate binding and ester bond hydrolysis. Our work underscores the pivotal role of both thermodynamic and kinetic control in impacting biomimetic catalysis and sheds a light on the development of artificial enzymes.

Plant Cell-Inspired Membranization of Coacervate Protocells with a Structured Polysaccharide Layer.

The design of compartmentalized colloids that exhibit biomimetic properties is providing model systems for developing synthetic cell-like entities (protocells). Inspired by the cell walls in plant cells, we developed a method to prepare membranized coacervates as protocell models by coating membraneless liquid-like microdroplets with a protective layer of rigid polysaccharides. Membranization not only endowed colloidal stability and prevented aggregation and coalescence but also facilitated selective biomolecule sequestration and chemical exchange across the membrane. The polysaccharide wall surrounding coacervate protocells acted as a stimuli-responsive structural barrier that enabled enzyme-triggered membrane lysis to initiate internalization and killing of Escherichia coli. The membranized coacervates were capable of spatial organization into structured tissue-like protocell assemblages, offering a means to mimic metabolism and cell-to-cell communication. We envision that surface engineering of protocells as developed in this work generates a platform for constructing advanced synthetic cell mimetics and sophisticated cell-like behaviors.

Dynamical Behaviors of Oscillating Metallosurfactant Coacervate Microdroplets under Redox Stress.

Living systems create complex structures and functions by mastering self-organization in a variety of equilibrium and non-equilibrium states. Mimicking the dynamical phenomena with synthetic cell-like entities (protocells) under non-equilibrium conditions offers an important step toward the representation of minimum life. Here, the cell-sized coacervate microdroplets assembled from associative metallosurfactant coacervation via liquid-liquid phase separation (LLPS) that exhibits non-equilibrium behaviors are reported. The compartmentalized protocell coacervates display collective dynamics that synchronize into system oscillations, showing autonomous death/regeneration and contraction/expansion cycles with external redox stress. The collective oscillation of abiotic metallosurfactant microdroplets can sustain both in solution and at the colloidal interface, allowing for dynamic sequestration, mass transport, and passing through nanosized channels, reminiscent of red blood cells that can deform and squeeze through narrow capillaries. The design of self-oscillating cell-sized constructs will shed a light on the creation of life-like soft materials with autonomous motion driven by complex chemical stimuli, which can be further used as nonbiological models for dynamic aggregates and intercellular communication.

Children's internal migration and subjective wellbeing of older parents left behind: Spiritual or financial support?

Introduction: Against the background of population aging and large-scale internal migration, this study uses an ordered logit with two-way fixed effects to examine the effect of children's internal migration on the subjective wellbeing of parents left behind. The study is based on the China Family Panel Studies database. Methods: Data were obtained from CFPS (China Family Panel Studies), and ordered logit with two-way fixed effects was used to test the total effect of children's internal migration on subjective wellbeing of parents left behind, and KHB test was used to separate intergenerational spiritual support and intergenerational financial support to examine the intergenerational support preferences of parents left behind. Results: The results show that children's internal migration has a significant negative effect on the subjective wellbeing of parents left behind, mainly through the reduction of intergenerational spiritual support. Furthermore, intergenerational financial support significantly mitigates this negative effect. There is heterogeneity in the direction of the total wellbeing effect across parents' preferences, as well as in the masking effect of financial support. However, the effect of financial support never fully offsets the effect of spiritual support. Discussion: To cope with the negative effects of children's internal migration on parents, positive measures should be taken to change parental preferences.

Artificial receptor-mediated phototransduction toward protocellular subcompartmentalization and signaling-encoded logic gates.

Engineering artificial cellular systems capable of perceiving and transmitting external signals across membranes to activate downstream targets and coordinate protocellular responses is key to build cell-cell communications and protolife. Here, we report a synthetic photoreceptor-mediated signaling pathway with the integration of light harvesting, photo-to-chemical energy conversion, signal transmission, and amplification in synthetic cells, which ultimately resulted in protocell subcompartmentalization. Key to our design is a ruthenium-bipyridine complex that acts as a membrane-anchored photoreceptor to convert visible light into chemical information and transduce signals across the lipid membrane via flip-flop motion. By coupling receptor-mediated phototransduction with biological recognition and enzymatic cascade reactions, we further develop protocell signaling-encoded Boolean logic gates. Our results illustrate a minimal cell model to mimic the photoreceptor cells that can transduce the energy of light into intracellular responses and pave the way to modular control over the flow of information for complex metabolic and signaling pathways.

Experimental Investigation on the Machinability Improvement in Magnetic-Field-Assisted Turning of Single-Crystal Copper.

The single-point diamond-turning operation is a commonly used method for ultra-precision machining of various non-ferrous materials. In this paper, a magnetic field was introduced into a single-point diamond-turning system, and magnetic-field-assisted turning experiments were carried out. The results revealed that the magnetic field affects the metal-cutting process in the form of the cutting force, chip morphology, and surface quality. Compared with traditional turning, magnetic-field assisted turning increases the cutting force by 1.6 times, because of the additional induced Lorentz force, and reduces the cutting-force ratio and friction coefficient on the rake surface by 16%, with the improved tribological property of the tool/chip contact-interface. The chip morphology in the magnetic-field-assisted turning shows the smaller chip-compression ratio and the continuous side-morphology. With the magnetoplasticity effect of the metal material and the friction reduction, magnetic-field-assisted turning is helpful for improving metal machinability and achieving better surface-quality.

Small Amphiphile-Based Coacervation.

Coacervation plays an important role in the molecular assembly towards soft materials with a diversity of function (e. g., underwater adhesives of mussels and membraneless organelles). Coacervation is observed when one homogenous solution spontaneously separates into two immiscible liquid phases of low and high solute concentration, also known as liquid-liquid phase separation (LLPS), which enables spatiotemporally local concentration of specific molecules. LLPS is a common physical phenomenon in aqueous solutions of polyelectrolytes, surfactants and biomolecules, which has been extensively explored for applications in the fields of environmental remediation, cosmetic formulation, protein purification, extractive fermentation and pharmaceutical microencapsulation. This review summarizes the development of LLPS with low molecular weight amphiphiles to construct simple and complex coacervates using conventional surfactants and novel amphiphiles such as azobenzene-derivatives and peptides. We also highlight the applications of these amphiphile coacervates in the extraction of biomolecules, construction of protocell models and drug delivery.

Potent Virustatic Polymer-Lipid Nanomimics Block Viral Entry and Inhibit Malaria Parasites In Vivo.

Infectious diseases continue to pose a substantial burden on global populations, requiring innovative broad-spectrum prophylactic and treatment alternatives. Here, we have designed modular synthetic polymer nanoparticles that mimic functional components of host cell membranes, yielding multivalent nanomimics that act by directly binding to varied pathogens. Nanomimic blood circulation time was prolonged by reformulating polymer-lipid hybrids. Femtomolar concentrations of the polymer nanomimics were sufficient to inhibit herpes simplex virus type 2 (HSV-2) entry into epithelial cells, while higher doses were needed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given their observed virustatic mode of action, the nanomimics were also tested with malaria parasite blood-stage merozoites, which lose their invasive capacity after a few minutes. Efficient inhibition of merozoite invasion of red blood cells was demonstrated both in vitro and in vivo using a preclinical rodent malaria model. We envision these nanomimics forming an adaptable platform for developing pathogen entry inhibitors and as immunomodulators, wherein nanomimic-inhibited pathogens can be secondarily targeted to sites of immune recognition.

Insights into the activity of single-atom Fe-N-C catalysts for oxygen reduction reaction.

Single-atom Fe-N-C catalysts has attracted widespread attentions in the oxygen reduction reaction (ORR). However, the origin of ORR activity on Fe-N-C catalysts is still unclear, which hinder the further improvement of Fe-N-C catalysts. Herein, we provide a model to understand the ORR activity of Fe-N4 site from the spatial structure and energy level of the frontier orbitals by density functional theory calculations. Taking the regulation of divacancy defects on Fe-N4 site ORR activity as examples, we demonstrate that the hybridization between Fe 3dz2, 3dyz (3dxz) and O2 π* orbitals is the origin of Fe-N4 ORR activity. We found that the Fe-O bond length, the d-band center gap of spin states, the magnetic moment of Fe site and *O2 as descriptors can accurately predict the ORR activity of Fe-N4 site. Furthermore, these descriptors and ORR activity of Fe-N4 site are mainly distributed in two regions with obvious difference, which greatly relate to the height of Fe 3d projected orbital in the Z direction. This work provides a new insight into the ORR activity of single-atom M-N-C catalysts.

Insulin-related lipohypertrophy: ultrasound characteristics, risk factors, and impact of glucose fluctuations.

BACKGROUND: Lipohypertrophy (LHT) has been suggested as an outcome of the adipogenic effects of insulin injection-related tissue trauma. It commonly occurs in the clinical setting, but the current understanding of LHT by the medical staff and diabetes patients remains insufficient; moreover, it has not garnered attention as a research topic. OBJECTIVE: To investigate the ultrasound characterization of LHT, to identify the factors associated with LHT development by assessing the prevalence of LHT and compare the accuracy of clinical palpation with that of ultrasonography in LHT detection, and to further evaluate the possible impact of LHT on patients' blood glucose fluctuations. METHOD: A cross-sectional study was conducted in 120 patients with type 2 diabetes. Patients' general information were obtained using a questionnaire, and the patients were evaluated for LHT by ultrasonography and clinical palpation of the abdomen. The patients were instructed to inject equal amounts of insulin in tissues with LHT and in normal adipose tissues (NATs) in two non-consecutive d in a selected week; the possible effect of LHT on patients' blood glucose fluctuations was assessed using a continuous glucose monitoring system. RESULTS: LHT has characteristic ultrasonic signs. We found a high rate of missed LHT detection on clinical palpation compared with that on ultrasonography (P < 0.05). The duration of insulin treatment, rotation of injection sites, frequency of needle reuse, and number of insulin injections per day were the primary factors influencing the development of LHT (P < 0.05). Compared with NATs, LHT tissues showed extremely elevated amplitude of glycemic excursion, mean blood glucose levels, standard deviation of blood glucose levels and postprandial glucose excursion, and large fluctuations in blood glucose levels (P < 0.05). CONCLUSION: Ultrasonography can more accurately detect LHT than can clinical palpation. LHT development is associated with several factors and can lead to significant fluctuations in blood glucose levels; thus, sufficient attention should be paid to investigating the underlying mechanism of LHT.

Peer Effects on Real-Time Search Behavior in Experimental Stock Markets.

It is a well-documented phenomenon that individuals stop searching earlier than predicted by the optimal, risk-neutral stopping rule, leading to inefficient searches. Individuals' search behaviors during making investment decisions in financial markets can be easily affected by their peers. In this study, we designed a search game in a simplified experimental stock market in which subjects were required to search for the best sell prices for their stocks. By randomly assigning subjects into pairs and presenting them with real-time information on their peers' searches, we investigated the effects of peers' decisions on search behaviors. The results showed that two subjects in the same group with real-time peer information learned and engaged in similar search behaviors. However, this peer effect did not exist when subjects had access to feedback information on the ex-post best response. In addition, we found that the presence of information about peers' decisions alone had no significant impact on search efficiency, whereas access to both information on peers' decisions and feedback information significantly improved subjects' search efficiency.

Membrane-confined liquid-liquid phase separation toward artificial organelles.

As the basic unit of life, cells are compartmentalized microreactors with molecularly crowded microenvironments. The quest to understand the cell origin inspires the design of synthetic analogs to mimic their functionality and structural complexity. In this work, we integrate membraneless coacervate microdroplets, a prototype of artificial organelles, into a proteinosome to build hierarchical protocells that may serve as a more realistic model of cellular organization. The protocell subcompartments can sense extracellular signals, take actions in response to these stimuli, and adapt their physicochemical behaviors. The tiered protocells are also capable of enriching biomolecular reactants within the confined organelles, thereby accelerating enzymatic reactions. The ability of signal processing inside protocells allows us to design the Boolean logic gates (NOR and NAND) using biochemical inputs. Our results highlight possible exploration of protocell-community signaling and render a flexible synthetic platform to study complex metabolic reaction networks and embodied chemical computation.

Chemical Identification of Catalytically Active Sites on Oxygen-doped Carbon Nanosheet to Decipher the High Activity for Electro-synthesis Hydrogen Peroxide.

Electrochemical production of hydrogen peroxide (H2 O2 ) through two-electron (2 e- ) oxygen reduction reaction (ORR) is an on-site and clean route. Oxygen-doped carbon materials with high ORR activity and H2 O2 selectivity have been considered as the promising catalysts, however, there is still a lack of direct experimental evidence to identify true active sites at the complex carbon surface. Herein, we propose a chemical titration strategy to decipher the oxygen-doped carbon nanosheet (OCNS900 ) catalyst for 2 e- ORR. The OCNS900 exhibits outstanding 2 e- ORR performances with onset potential of 0.825 V (vs. RHE), mass activity of 14.5 A g-1 at 0.75 V (vs. RHE) and H2 O2 production rate of 770 mmol g-1 h-1 in flow cell, surpassing most reported carbon catalysts. Through selective chemical titration of C=O, C-OH, and COOH groups, we found that C=O species contributed to the most electrocatalytic activity and were the most active sites for 2 e- ORR, which were corroborated by theoretical calculations.

Effect of dexmedetomidine on evoked-potential monitoring in patients undergoing brain stem and supratentorial cranial surgery.

BACKGROUND: Dexmedetomidine is used as adjuvant in total intravenous anaesthesia (TIVA), but there have been few studies concerning its effect on intraoperative neurophysiological monitoring (IONM) during cranial surgery. Our aim was to study the effect of dexmedetomidine on IONM in patients undergoing brain stem and supratentorial cranial surgery. METHODS: Two prospective, randomized, double-blind substudies were conducted. In substudy 1, during TIVA with an infusion of propofol and remifentanil, 10 patients received saline solution (SS) (PR group) and another 10 (PRD group) received dexmedetomidine (0.5 mcg/kg/h). Total dosage of propofol and remifentanil, intensity, latency and amplitude of motor-evoked potentials following transcranial electrical stimulation (tcMEPs) as well as somatosensory-evoked potentials (SSEP) were recorded at baseline, 15, 30, 45 minutes, and at the end of surgery. In order to identify differences in the same patient after dexmedetomidine administration, we designed substudy 2 with 20 new patients randomized to two groups. After 30 minutes with TIVA, 10 patients received dexmedetomidine (0.5 mcg/kg/h) and 10 patients SS. The same variables were recorded. RESULTS: In substudy 1, propofol requirements were significantly lower (P = .004) and tcMEP intensity at the end of surgery was significantly higher in PRD group, but no statistically significant differences were observed for remifentanil requirements, SSEP and tcMEP latency or amplitude. In substudy 2, no differences in any of the variables were identified. CONCLUSIONS: The administration of dexmedetomidine at a dosage of 0.5 mg/kg/h may reduce propofol requirements and adversely affect some neuromonitoring variables. However, it can be an alternative on IONM during cranial surgeries. REDEX EudraCT: 2014-000962-23.

PTPN14 deficiency alleviates podocyte injury through suppressing inflammation and fibrosis by targeting TRIP6 in diabetic nephropathy.

Diabetic nephropathy (DN) is a common complication of diabetes, and a leading cause of end-stage renal disease. However, the pathogenesis that contributes to DKD is still not fully understood. Protein tyrosine phosphatase non-receptor type 14 (PTPN14), a non receptor tyrosine phosphatase, has numerous cellular events, such as inflammation and cell death. But its potential on DKD has not been investigated yet. In this study, we found that PTPN14 expression was markedly up-regulated in kidney samples of DKD patients, which were confirmed in diabetic mice and were clearly localized in glomeruli. The diabetic mouse model was established using streptozotocin (STZ) in wild type (WT) or PTPN knockout (KO) mice. After, STZ challenge, STZ mice displayed improved kidney functions. The results also showed that STZ-induced histological changes and podocyte injury in renal tissues, which were effectively alleviated by PTPN14 deletion. Moreover, PTPN14 deficiency significantly mitigated inflammatory response and fibrosis in glomeruli of STZ-challenged mice through restraining the activation of nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-ß1 signaling pathways, respectively. The inhibitory effects of PTPN14 suppression on inflammation and fibrosis were confirmed in high glucose (HG)-incubated podocytes. We further found that thyroid receptor interactor protein 6 (TRIP6) expression was dramatically up-regulated in glomeruli of STZ-challenged mice, and was abolished by PTPN14 deletion, which was confirmed in HG-treated podocytes with PTPN14 knockdown. Intriguingly, our in vitro studies showed that PTPN14 directly interacted with TRIP6. Of note, over-expressing TRIP6 markedly abrogated the effects of PTPN14 silence to restrict inflammatory response and fibrosis in HG-incubated podocytes. Taken together, our findings demonstrated that targeting PTPN14 may provide feasible therapies for DKD treatment.

Modulating electronic structure of metal-organic frameworks by introducing atomically dispersed Ru for efficient hydrogen evolution.

Developing high-performance electrocatalysts toward hydrogen evolution reaction is important for clean and sustainable hydrogen energy, yet still challenging. Herein, we report a single-atom strategy to construct excellent metal-organic frameworks (MOFs) hydrogen evolution reaction electrocatalyst (NiRu0.13-BDC) by introducing atomically dispersed Ru. Significantly, the obtained NiRu0.13-BDC exhibits outstanding hydrogen evolution activity in all pH, especially with a low overpotential of 36 mV at a current density of 10 mA cm-2 in 1 M phosphate buffered saline solution, which is comparable to commercial Pt/C. X-ray absorption fine structures and the density functional theory calculations reveal that introducing Ru single-atom can modulate electronic structure of metal center in the MOF, leading to the optimization of binding strength for H2O and H*, and the enhancement of HER performance. This work establishes single-atom strategy as an efficient approach to modulate electronic structure of MOFs for catalyst design.

Iodide-Mediated Rapid and Sensitive Surface Etching of Gold Nanostars for Biosensing.

Iodide-mediated surface etching can tailor the surface plasmon resonance of gold nanostars through etching of the high-energy facets of the nanoparticle protrusions in a rapid and sensitive way. By exploring the underlying mechanisms of this etching and the key parameters influencing it (such as iodide, oxygen, pH, and temperature), we show its potential in a sensitive biosensing system. Horseradish peroxidase-catalyzed oxidation of iodide enables control of the etching of gold nanostars to spherical gold nanoparticles, where the resulting spectral shift in the surface plasmon resonance yields a distinct color change of the solution. We further develop this enzyme-modulated surface etching of gold nanostars into a versatile platform for plasmonic immunoassays, where a high sensitivity is possible by signal amplification via magnetic beads and click chemistry.

High-Throughput Peptide Derivatization toward Supramolecular Diversification in Microtiter Plates.

The evolution of life on earth eventually leads to the emergence of species with increased complexity and diversity. Similarly, evolutionary chemical space exploration in the laboratory is a key step to pursue the structural and functional diversity of supramolecular systems. Here, we present a powerful tool that enables rapid peptide diversification and employ it to expand the chemical space for supramolecular functions. Central to this strategy is the exploitation of palladium-catalyzed Suzuki-Miyaura cross-coupling reactions to direct combinatorial synthesis of peptide arrays in microtiter plates under an open atmosphere. Taking advantage of this in situ library design, our results unambiguously deliver a fertile platform for creating a set of intriguing peptide functions including green fluorescent protein-like peptide emitters with chemically encoded emission colors, hierarchical self-assembly into nano-objects, and macroscopic hydrogels. This work also offers opportunities for quickly surveying the diversified peptide arrays and thereby identifying the structural factors that modulate peptide properties.