Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.

Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity.

Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.

Honey bees switch mechanisms to drink deep nectar efficiently.

The feeding mechanisms of animals constrain the spectrum of resources that they can exploit profitably. For floral nectar eaters, both corolla depth and nectar properties have marked influence on foraging choices. We report the multiple strategies used by honey bees to efficiently extract nectar at the range of sugar concentrations and corolla depths they face in nature. Honey bees can collect nectar by dipping their hairy tongues or capillary loading when lapping it, or they can attach the tongue to the wall of long corollas and directly suck the nectar along the tongue sides. The honey bee feeding apparatus is unveiled as a multifunctional tool that can switch between lapping and sucking nectar according to the instantaneous ingesting efficiency, which is determined by the interplay of nectar-mouth distance and sugar concentration. These versatile feeding mechanisms allow honey bees to extract nectar efficiently from a wider range of floral resources than previously appreciated and endow them with remarkable adaptability to diverse foraging environments.

Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling.

Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.

Developing and validating a clinlabomics-based machine-learning model for early detection of retinal detachment in patients with high myopia.

BACKGROUND: Retinal detachment (RD) is a vision-threatening disorder of significant severity. Individuals with high myopia (HM) face a 2 to 6 times higher risk of developing RD compared to non-myopes. The timely identification of high myopia-related retinal detachment (HMRD) is crucial for effective treatment and prevention of additional vision impairment. Consequently, our objective was to streamline and validate a machine-learning model based on clinical laboratory omics (clinlabomics) for the early detection of RD in HM patients. METHODS: We extracted clinlabomics data from the electronic health records for 24,440 HM and 5607 HMRD between 2015 and 2022. Lasso regression analysis assessed fifty-nine variables, excluding collinear variables (variance inflation factor > 10). Four models based on random forest, gradient boosting machine (GBM), generalized linear model, and Deep Learning Model were trained for HMRD diagnosis and employed for internal validation. An external test of the models was done. Three random data sets were further processed to validate the performance of the diagnostic model. The primary outcomes were the area under the receiver operating characteristic curve (AUC) and the area under the precision-recall curve (AUCPR) to diagnose HMRD. RESULTS: Nine variables were selected by all models. Given the AUC and AUCPR values across the different sets, the GBM model was chosen as the final diagnostic model. The GBM model had an AUC of 0.8550 (95%CI = 0.8322-0.8967) and an AUCPR of 0.5584 (95%CI = 0.5250-0.5879) in the training set. The AUC and AUCPR in the internal validation were 0.8405 (95%CI = 0.8060-0.8966) and 0.5355 (95%CI = 0.4988-0.5732). During the external test evaluation, it reached an AUC of 0.7579 (95%CI = 0.7340-0.7840) and an AUCPR of 0.5587 (95%CI = 0.5345-0.5880). A similar discriminative capacity was observed in the three random data sets. The GBM model was well-calibrated across all the sets. The GBM-RD model was implemented into a web application that provides risk prediction for HM individuals. CONCLUSION: GBM algorithms based on nine features successfully predicted the diagnosis of RD in patients with HM, which will help ophthalmologists to establish a preliminary diagnosis and to improve diagnostic accuracy in the clinic.

Therapeutic and Prognostic Significance of Arachidonic Acid in Heart Failure.

BACKGROUND: Accurate prediction of death is an unmet need in patients with acute decompensated heart failure (HF). Arachidonic acid (AA) metabolites play an important role in the multiple pathophysiological processes. We aimed to develop an AA score to accurately predict mortality in patients with acute decompensated HF and explore the causal relationship between the AA predictors and HF. METHODS: The serum AA metabolites was measured in patients with acute decompensated HF (discovery cohort n=419; validation cohort n=386) by mass spectroscopy. We assessed the prognostic importance of AA metabolites for 1-year death using Cox regression and machine learning approaches. A machine learning-based AA score for predicting 1-year death was created and validated. We explored the mechanisms using transcriptome and functional experiments in a mouse model of early ischemic cardiomyopathy. RESULTS: Among the 27 AA metabolites, elevated 14,15-DHET/14,15-EET ratio was the strongest predictor of 1-year death (hazard ratio, 2.10, P=3.1×10-6). Machine learning-based AA score using a combination of the 14,15-DHET/14,15-EET ratio, 14,15-DHET, PGD2, and 9-HETE performed best (area under the curve [AUC]: 0.85). The machine learning-based AA score provided incremental information to predict mortality beyond BNP (B-type natriuretic peptide; ΔAUC: 0.19), clinical score (ΔAUC: 0.09), and preexisting Acute Decompensated Heart Failure National Registry, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, and Get With The Guidelines Heart Failure scores (ΔAUC: 0.17, 0.17, 0.15, respectively). In the validation cohort, the AA score accurately predicted mortality (AUC:0.81). False-negative and false-positive findings, as classified by the BNP threshold, were correctly reclassified by the AA score (46.2% of false-negative and 84.5% of false-positive). In a murine model, the expression and enzymatic activity of sEH (soluble epoxide hydrolase) increased after myocardial infarction. Genetic deletion of sEH improved HF and the blockade of 14,15-EET abolished this cardioprotection. We mechanistically revealed the beneficial effect of 14,15-EET by impairing the activation of monocytes/macrophages. CONCLUSIONS: Our studies propose that the AA score predicts death in patients with acute decompensated HF and inhibiting sEH serves as a therapeutic target for treating HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04108182.

Carbonylative Formal Cycloaddition between Alkylarenes and Aldimines Enabled by Palladium-Catalyzed Double C-H Bond Activation.

Double C-H bond activation can enable an expeditious reaction pathway to cyclic compounds, offering an efficient tool to synthesize valuable molecules. However, cyclization reaction enabled by double C-H bond activation at one carbon atom is nearly unknown. Herein, we report a carbonylative formal cycloaddition of alkylarenes with imines via double benzylic C-H bond activation at one carbon atom, allowing a straightforward synthesis of ß-lactams from readily accessible alkylarenes and imines, which paves the way for developing an annulation reaction through double C-H bond activation at one carbon atom.

Jumping of flea beetles onto inclined platforms.

The flea beetle, Altica cirsicola, escapes predators by jumping and landing in a dense maze of leaves. How do they land on such varied surfaces? In this experimental study, we filmed the take-off, flight, and landing of flea beetles on a configurable angled platform. We report three in-flight behaviors: winged, wingless, and an intermediate winged mode. These modes significantly affected take-off speed, acceleration, and the duration that wings were deployed. When wings were closed, flea beetles rolled or pitched up to five times in the air. This work may help to understand how insects can jump and right themselves onto variable surfaces.

Rapid manoeuvre of fan worms (Annelida: Sabellidae) through tubes.

Multiple variables determine the success of an escape response of an animal, and the rapidity of the escape manoeuvre is often the most important. Fan worms (Annelida: Sabellidae) can rapidly withdraw their tentacles, which are covered in heavily ciliated ramifications called pinnules, into their tubes to protect them from approaching threats. Here, we explore the dynamic and mechanistic features behind this escape manoeuvre. The escape responses of fan worms were recorded by high-speed videography and quantified by computerized motion analysis, showing an ultrahigh retraction speed of 272±135 mm s-1 (8±4 body lengths s-1). We found that fan worms possess powerful muscle-driven systems, which can generate contractive forces up to 36 times their body weight. In order to achieve these rapid, forceful movements through seawater without damaging their tentacles, fan worms have developed functional morphological adaptations to reduce fluidic drag, including the flattening of their radiolar pinnules and the deformation of bodily segmental ridges. Our hydrodynamic models indicate that these mechanical processes can decrease fluidic drag by 47%, trapped mass by 75% and friction coefficient by 89%. These strategies allow fan worms to execute rapid escape responses and could inspire the design of fast in-pipe robots.

Inside the coupling of ladybird beetle elytra: elastic setae can facilitate swift deployment.

The ladybird beetle (Coccinella septempunctata) is known for swift deployment of its elytra, an action that requires considerable power. However, actuation by thoracic muscles alone may be insufficient to deploy elytra at high speed because the maximum mechanical power that elytral muscles can produce is only 70% of that required for initiation of deployment. Nevertheless, the elytra open rapidly, within 3 ms in the initial phase, at a maximum angular velocity of 66.49±21.29 rad s-1, rivaling the strike velocity of ant lion (Myrmeleon crudelis) mandibles (65±21 rad s-1). Here, we hypothesize that elytra coupling may function as an energy storage mechanism that facilitates rapid opening by releasing elastic strain energy upon deployment. To test this hypothesis and better understand the biomechanics of elytra deployment, we combined micro-computed tomography and scanning electron microscopy to examine the microstructure of the coupling of paired elytra. We found that two rows of setae on the internal edges of the elytra coupling structure undergo elastic deformation when the elytra are locked together. Kinematics observations and mathematical modeling suggest that the elastic potential energy stored in the compressed setae generates 40% of the power required for deployment of elytra. Our findings broaden insights into how ladybirds actuate elytra opening by a strategy of using both muscles and elastic microstructures, and demonstrate a distributed pattern of actuation that adapts to geometrical constraints in elytra locking.

A study of the antibacterial mechanism of pinocembrin against multidrug-resistant Aeromonas hydrophila.

Aeromonas hydrophila is a common pathogen in fish that has caused severe economic losses in aquaculture worldwide. With the emergence of bacterial resistance, it is necessary to develop new drugs to combat bacterial infection, particularly for multidrug-resistant bacteria. In this study, the antibacterial activity of pinocembrin was investigated by observing bacterial growth and microscopic structure, and its mechanism of action was identified by investigating its effect on protein and DNA. The antibacterial susceptibility test indicated that pinocembrin inhibits A. hydrophila growth. The minimal inhibitory concentration and minimum bactericidal concentration were 256 µg/mL and 512 µg/mL, respectively. Ultrastructurally, the bacteria treated with pinocembrin showed surface roughness and plasmolysis. When bacteria were treated with 512 µg/mL pinocembrin, lactate dehydrogenase activity and soluble protein content decreased significantly, and electrical conductivity and DNA exosmosis levels increased by 4.21 ± 0.64% and 15.98 ± 1.93 mg/L, respectively. Staining with 4', 6-Diamidino-2-phenylindole showed that the nucleic acid fluorescence intensity and density decreased after the treatment with pinocembrin. Pinocembrin may inhibit the growth of A. hydrophila by increasing cell membrane permeability and affecting protein and DNA metabolism. Thus, pinocembrin is a candidate drug for the treatment of A. hydrophila infection in aquaculture.

Collecting differently sized particles on water surface by maneuvering pedal waves on the foot of the water snail Pomacea canaliculata.

The water snail (Pomacea canaliculata) features both broad dietary scope and high feeding rate, possibly making it one of the most successful mollusc invaders globally. The water snail can collect differently sized food particles on the air-water interface by generating pedal waves on the foot surface, such as granular duckweed and animal carrion in wild aquatic environment. While foraging by pedal waves, the biomechanical challenges by manipulating the differently sized particles might be overcome by mediating the waveform for optimized energy costs, the physics and the function of which have not been uncovered yet. Herein, we study the two-dimensional topographic features of the snail foot in the pedal wave feeding pattern by a laser sensor. Feeding on differently sized particles, the average wavelength of the pedal waves remains nearly constant, whereas the amplitude increases while transporting larger particles. We develop a hydrodynamical model and discover that applying a larger amplitude to transport the particle can shorten the transport time, facilitating the food transport rate. However, to maintain a relatively constant mass uptake rate, the water snail exhibits a flexible strategy of collecting larger particles with increased amplitudes. This work demonstrates that the water snail implements a strategy by generating varying waveforms on the foot surface to take up the floating food at an optimized feeding rate. This feeding fashion may open up a new way for developing bio-inspired solid waste collectors at the gas-liquid interface.

Optimal kinematics of the bee tongue for viscous fluid transport.

Honey bees can forage nectar from a large spectrum of nectariferous flowers using their rhythmically erectable tongue hairs in a viscous dipping fashion that involves a faster protraction stroke toward the nectar pool and a slower retraction stroke backward. Since honey bees are capable of using their hairy tongues to adapt to various feeding environments, the kinematic characteristics of the bee tongue, especially the retraction time, would likely represent evolutionary optimization. However, the phenomenon and mechanism remain elusive. In this combined experimental and theoretical study, we established a mathematical model to analyze the effects of tongue retraction time on the energy intake rate considering the unfolding dynamics of tongue hairs in the retraction phase. The theoretical optimal retraction time at which the energy intake rate reached the maximum was governed by the dimensions of tongue hairs, which matched well with the in vivo tests. This study may not only bridge the connection between the kinematics and geometry of the bee tongue but also shed light on a control strategy for micropumps equipped with dynamic surfaces.

Trade-off mechanism of honey bee sucking and lapping.

Animals have developed various drinking strategies in capturing liquid to feed or to stay hydrated. In contrast with most animals, honey bees Apis mellifera that capture nectar with their tongue, can deliberately switch between sucking and lapping methods. They preferentially suck diluted nectar whereas they are prone to lap concentrated nectar. In vivo observations have shown that bees select the feeding method yielding the highest efficiency at a given sugar concentration. In this combined experimental and theoretical investigation, we propose two physical models for suction and lapping mode of capture that explain the transition between these two feeding strategy. The critical viscosity, µ*, at which the transition occurs, is derived from these models, and agrees well with in vivo measurements. The trade-off mechanism of honey bee sucking and lapping may further inspire microfluidics devices with higher capability of transporting liquids across a large range of viscosities.

Neuronal Regulation of Cutaneous Immunity.

The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system-pathogen recognition, secretion of soluble mediators-are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.

Fast Registration of Point Cloud Based on Custom Semantic Extraction.

With the increase in the amount of 3D point cloud data and the wide application of point cloud registration in various fields, the question of whether it is possible to quickly extract the key points of registration and perform accurate coarse registration has become a question to be urgently answered. In this paper, we proposed a novel semantic segmentation algorithm that enables the extracted feature point cloud to have a clustering effect for fast registration. First of all, an adaptive technique was proposed to determine the domain radius of a local point. Secondly, the feature intensity of the point is scored through the regional fluctuation coefficient and stationary coefficient calculated by the normal vector, and the high feature region to be registered is preliminarily determined. In the end, FPFH is used to describe the geometric features of the extracted semantic feature point cloud, so as to realize the coarse registration from the local point cloud to the overall point cloud. The results show that the point cloud can be roughly segmented based on the uniqueness of semantic features. The use of a semantic feature point cloud can make the point cloud have a very fast response speed based on the accuracy of coarse registration, almost equal to that of using the original point cloud, which is conducive to the rapid determination of the initial attitude.

Innovative antimicrobial substances based on uracil S-derivatives.

The problem of antimicrobial resistance is an important global public health challenge. We propose that a development of new antibiotic compounds around known natural substances is a solution to this problem. We investigate reengineer natural products into potent antibiotics. Uracil fragment is abundant in nature and significant to treat infectious diseases due to its affection to the replication of the bacterial chromosome. 12 new uracil S-derivatives were obtained and tested for their in vitro antimicrobial properties. N3 -(thietan-3-yl)- and N3 -(1,1-dioxothietan-3-yl)uracils derivatives were synthesized by thietanylation of 6-methyluracil with 2-chloromethylthiirane and subsequent oxidation of the thietan ring. A method of their alkylation with ethyl-2-chloroacetate was developed and acetohydrazides containing 3-(thietan-3-yl)- and 3-(1,1-dioxothietan-3-yl)uracilyls fragments in the acetyl group were obtained by hydrazinolysis of 2-(thietanyluracil-1-yl)acetic acid ethyl esters. Their interaction with ß-dicarbonyl compounds, anhydride of mono- and dicarboxylic acids was studied. Antimicrobial activity was determined by the agar diffusion method on test organisms: S. aureus, E. coli, P. vulgaris, K. pneumoniae, C. diversus, E. aerogenes, P. aeruginosa, S. abosit. N-acyl-5-hydroxypyrazolines and N,N'-diacylhydrazines of 6-methyluracil thietanyl- and dioxothietanyl derivatives showed high antimicrobial activity, which is consistent with the results of structure activity relationship analysis (MIC 0.1-10 µg/ml).

How honey bees dip nectar: Dynamic spacing of tongue hairs facilitates to collect nectar of various viscosities.

A honey bee can dip nectar of viscosity across two orders of magnitude, by viscous lapping technique using a segmental tongue covered with erectable hairs. The drinking technique suffers risks of leakage occurring between tongue hairs, and the amount of leakage is related to hair spacing as well as nectar viscosity. When lapping, tongue segments are elongated, which enlarges the hair spacing in longitudinal direction. Experimental observations show that the hair spacing of tongue increases with respect to sucrose solution concentration until it reaches the maximum extension when sucrose solution concentration is above 35%. Considering leakage occurring in the hairy tongue, we hypothesize that the dynamical extension of hair spacing may help honey bees minimize the effects of leakage to reach maximal nectar intake rate. A mathematical model is developed for determining the optimal hair spacing that can meet the demands of both augmenting the nectar intake rate and reducing the risk of leakage. Theoretical prediction and experimental measurements demonstrate honey bees are able to adjust the tongue to meet the optimal hair spacing when dipping nectar of concentration more dilute than 35% and maintain a maximum extension to improve the nectar intake rate when concentration is greater than 35%. We then give the prediction of concentration preferences of three bee species, and discuss effects of dipping frequency and gravity on the leakiness between tongue hairs. This work may not only gain insights into adaptive feeding strategy in insects, but inspire the design of adaptive microfluidic transport devices with dynamic brushy surfaces.

Drinking made easier: honey bee tongues dip faster into warmer and/or less viscous artificial nectar.

Optimal concentrations for nectar drinking are limited by the steep increase in the viscosity of sugar solutions with concentration. However, nectar viscosity is inversely related to temperature, which suggests there are advantages to foraging from flowers that are warmer than the surrounding air. The honey bee (Apis mellifera L.) dips nectar using a hairy tongue. However, the microscopic dynamics of the tongue while the bee ingests nectar of varying concentration, viscosity and temperature are unknown. In this study, we found that honey bees respond to the variation of nectar properties by regulating dipping frequency. Through high-speed imaging, we discovered that the honey bee traps warmer sucrose solutions with a quicker tongue. The honey bee dips the warmest and most dilute solution (40°C and 25% w/w sucrose) 1.57 times as fast as the coldest and thickest solution (20°C and 45% w/w sucrose). When the viscosity of different sucrose concentrations was kept constant by adding the inert polysaccharide Tylose, honey bees dipped nectar at constant frequency. We propose a fluid mechanism model to elucidate potential effects on sucrose intake and show that higher dipping frequency can increase the volumetric and energetic intake rates by 125% and 15%, respectively. Our findings broaden insights into how honey bees adapt to foraging constraints from the perspective of tongue dynamics, and demonstrate that elevated intrafloral temperatures and lower nectar viscosity can improve the volumetric and energetic intake rates of pollinators.

Temporal model of fluid-feeding mechanisms in a long proboscid orchid bee compared to the short proboscid honey bee.

Bees (Apidae) are flower-visiting insects that possess highly efficient mouthparts for the ingestion of nectar and other sucrose fluids. Their mouthparts are composed of mandibles and a tube-like proboscis. The proboscis forms a food canal, which encompasses a protrusible and hairy tongue to load and imbibe nectar, representing a fluid-feeding technique with a low Reynolds number. The western honey bee, Apis mellifera ligustica, can rhythmically erect the tongue microtrichia to regulate the glossal shape, achieving a tradeoff between nectar intake rate and viscous drag. Neotropical orchid bees (Euglossa imperialis) possess a proboscis longer than the body and combines this lapping-sucking mode of fluid-feeding with suction feeding. This additional technique of nectar uptake may have different biophysics. In order to reveal the effect of special structures of mouthparts in terms of feeding efficiency, we build a temporal model for orchid bees considering fluid transport in multi-states including active suction, tongue protraction and viscous dipping. Our model indicates that the dipping technique employed by honey bees can contribute to more than seven times the volumetric and energetic intake rate at a certain nectar concentration compared with the combined mode used by orchid bees. The high capability of the honey bee's proboscis to ingest nectar may inspire micropumps for transporting viscous liquid with higher efficiency.