Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.

Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α.

Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1α as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+ ) levels. The HIF-1α/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady-state conditions. In contrast, in activated NK cells under hypoxia, HIF-1α is required for glycolysis, and forced HIF-1α expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1α interferes with NK cell metabolism. While HIF-1α-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1α-dependent tryptophan/NAD+ metabolism.

Self-Assembly of Wheel-Shaped Nanographdiynes and Self-Template Growth of Graphdiyne.

Graphdiyne (GDY) multilayers show stacking-style-dependent physical properties; thus, controlling the stacking style of nanostructures is crucial for utilizing their electrical, optical, and transport properties in electro-optical devices. Herein, we report the assemblies of nanographdiynes decorated with substituents with different steric hindrances to adjust the stacking style. We show that the π-stacked aggregates were influenced by peripheral substituents and the substrate. Steric hexaterphenyl-substituted nanoGDY scaffolds led to dimer structures stacked in the AB-3 configuration with a twist angle of 26.01° or the AB-1 configuration with an in-plane shift along one diyne link. With the interval replacement of steric substituents with long C12 alkyl chains, nanoGDYs were stacked in the AB-2 configuration to decrease the steric congestion, eventually leading to one-dimensional (1D) nanofibrous aggregates. Self-assembly in the presence of substrates can result in ABC-stacked nanoGDYs, which endowed us with the possibility of using nanoGDY as the template for GDY growth in a homogeneous reaction. High-resolution transmission electron microscopy (HRTEM), powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and near-infrared-ultraviolet-visible (NIR-UV-vis) absorption spectroscopy indicate that the crystalline GDY prepared in this way is a 1.18 eV bandgap semiconductor.

Castration reshapes the liver by altering fatty acid composition and metabolism in male mice.

Castration promotes subcutaneous fat deposition that may be associated with metabolic adaptations in the liver. However, fatty acid composition, abundance, and metabolic characteristics of the liver after castration are not fully understood. Our results showed that surgical castration significantly reduced water and food intake, reduced liver weight, and induced liver inflammation in mice. Transcriptome analyses revealed that castration enhanced fatty acid metabolism, particularly that of arachidonic and linoleic acids metabolism. Gas chromatography-mass spectrometry analysis revealed that castration altered the composition and relative abundance of fatty acids in the liver. The relative abundances of arachidonic and linoleic acids were significantly decreased in 4-week-old castrated mice. Analysis of fatty acid synthesis- and metabolism-related genes revealed that castration enhanced the transcription of fatty acid synthesis- and oxidation-related genes. Analyzing the level of key enzymes in the ß-oxidation and tricarboxylic acid cycle pathways of fatty acids in mitochondria, we found that castration enhanced the ß-oxidation of fatty acids in mitochondria, and also enhanced the protein level of the rate-limiting enzyme in the tricarboxylic acid cycle pathway, isocitrate dehydrogenase 2. These results comprehensively clarify metabolic changes in liver fatty acids after castration in mice of different ages and provide a reference for understanding castration-induced fat deposition from the perspective of liver fatty acid metabolism in male mice.

A new, adaptive, self-administered, and generalizable method used to measure visual acuity.

SIGNIFICANCE: Angular Indication Measurement (AIM) is an adaptive, self-administered, and generalizable orientation-judgment method designed to interrogate visual functions. We introduce AIM Visual Acuity (VA) and show its features and outcome measures. Angular Indication Measurement VA's ability to detect defocus was comparable with that of an Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart and showed greater sensitivity to astigmatic blur. PURPOSE: This proof-of-concept study introduces Angular Indication Measurement and applies it to VA. METHODS: First, we compared the ability of AIM-VA and ETDRS to detect defocus and astigmatic blur in 22 normally sighted adults. Spherical and cylindrical lenses in the dominant eye induced blur. Second, we compared repeatability over two tests of AIM-VA and ETDRS. RESULTS: A repeated-measure analysis of variance showed a main effect for defocus blur and test. For the astigmatism experiment, an interaction between blur and orientation was found. Pairwise comparisons showed that AIM was more sensitive to astigmatic-induced VA loss than ETDRS. Bland-Altman plots showed small bias and no systematic learning effect for either test type and improved repeatability with more than two adaptive steps for AIM-VA. CONCLUSIONS: Angular Indication Measurement VA's ability to detect defocus was comparable with that of an ETDRS letter chart and showed greater sensitivity to induced astigmatic blur, and AIM-VA's repeatability is comparable with ETDRS when using two or more adaptive steps. Angular Indication Measurement's self-administered orientation judgment approach is generalizable to interrogate other visual functions, e.g., contrast, color, motion, and stereovision.

Multiple aortic root pseudoaneurysms with dissecting aneurysm of the interventricular septum diagnosed by multimodal imaging.

Aortic root pseudoaneurysm is a devastating complication post aortic valve replacement with a high mortality rate. And dissecting aneurysm into the interventricular septum is a rare variant of aortic root pseudoaneurysm, which is scarcely reported. Multimodal imaging is of great value in its diagnosis and differential diagnosis.

Resting heart rate moderates the relationship between parental emotion socialization and callous-unemotional traits in children.

Although empirical findings have indicated that both familial and neurobiological risk factors contribute to the development of callous-unemotional (CU) traits in children, relatively few studies have investigated how these two factors interact to influence these traits. The current study focused on the combined effects of parental emotion socialization and child's resting heart rate on CU traits. Parents of Chinese children (N = 166) completed the Coping with Children's Negative Scale when children were 9.39 years old (SD = 0.92), while children's resting heart rate data were collected when they were 10.21 years old (SD = 0.72). When they were 11.15 years old (SD = 0.67), parents completed the Inventory of Callous-Unemotional Traits Short-Form. Results showed that parental supportive emotion socialization was negatively associated with CU traits and Callous behaviors in particular. In addition, resting heart rate moderated the relationship between parental emotion socialization and child's CU traits. Findings provide further evidence that an interdisciplinary approach that combines both psychosocial and biological factors is essential to further our understanding of CU traits in youth.

Comparison of Mitochondrial Genome Expression Differences among Four Skink Species Distributed at Different Latitudes under Low-Temperature Stress.

Continual climate change strongly influences temperature conditions worldwide, making ectothermic animals as suitable species for studying the potential impact of climate change on global biodiversity. However, the study of how lizards distributed at different latitudes respond to climate change at the transcriptome level is still insufficient. According to the Climatic Variability Hypothesis (CVH), the range of climate fluctuations experienced by terrestrial animals throughout the year increases with latitude, so individuals at higher latitudes should exhibit greater thermal plasticity to cope with fluctuating environments. Mitochondria, as the energy center of vertebrate cells, may indicate species' plasticity through the sensitivity of gene expression. In this study, we focused on the changes in transcript levels of liver mitochondrial protein-coding genes (PCGs) in skinks from the genus Plestiodon (P. capito and P. elegans) and the genus Scincella (S. modesta and S. reevesii) under low-temperature conditions of 8 °C, compared to the control group at 25 °C. Species within the same genus of skinks exhibit different latitudinal distribution patterns. We found that the two Plestiodon species, P. elegans and P. capito, employ a metabolic depression strategy (decreased transcript levels) to cope with low temperatures. In contrast, the two Scincella species show markedly different patterns: S. modesta exhibits significant increases in the transcript levels of six genes (metabolic compensation), while in S. reevesii, only two mitochondrial genes are downregulated (metabolic depression) compared to the control group. We also found that P. capito and S. modesta, which live at mid-to-high latitudes, exhibit stronger adaptive responses and plasticity at the mitochondrial gene level compared to P. elegans and S. reevesii, which live at lower latitudes. We suggest that this enhanced adaptability corresponds to more significant changes in a greater number of genes (plasticity genes).

The Phylogenetic Relationships of Major Lizard Families Using Mitochondrial Genomes and Selection Pressure Analyses in Anguimorpha.

Anguimorpha, within the order Squamata, represents a group with distinct morphological and behavioral characteristics in different ecological niches among lizards. Within Anguimorpha, there is a group characterized by limb loss, occupying lower ecological niches, concentrated within the subfamily Anguinae. Lizards with limbs and those without exhibit distinct locomotor abilities when adapting to their habitats, which in turn necessitate varying degrees of energy expenditure. Mitochondria, known as the metabolic powerhouses of cells, play a crucial role in providing approximately 95% of an organism's energy. Functionally, mitogenomes (mitochondrial genomes) can serve as a valuable tool for investigating potential adaptive evolutionary selection behind limb loss in reptiles. Due to the variation of mitogenome structures among each species, as well as its simple genetic structure, maternal inheritance, and high evolutionary rate, the mitogenome is increasingly utilized to reconstruct phylogenetic relationships of squamate animals. In this study, we sequenced the mitogenomes of two species within Anguimorpha as well as the mitogenomes of two species in Gekkota and four species in Scincoidea. We compared these data with the mitogenome content and evolutionary history of related species. Within Anguimorpha, between the mitogenomes of limbless and limbed lizards, a branch-site model analysis supported the presence of 10 positively selected sites: Cytb protein (at sites 183 and 187), ND2 protein (at sites 90, 155, and 198), ND3 protein (at site 21), ND5 protein (at sites 12 and 267), and ND6 protein (at sites 72 and 119). These findings suggested that positive selection of mitogenome in limbless lizards may be associated with the energy requirements for their locomotion. Additionally, we acquired data from 205 mitogenomes from the NCBI database. Bayesian inference (BI) and Maximum Likelihood (ML) trees were constructed using the 13 mitochondrial protein-coding genes (PCGs) and two rRNAs (12S rRNA and 16S rRNA) from 213 mitogenomes. Our phylogenetic tree and the divergence time estimates for Squamata based on mitogenome data are consistent with results from previous studies. Gekkota was placed at the root of Squamata in both BI and ML trees. However, within the Toxicofera clade, due to long-branch attraction, Anguimorpha and (Pleurodonta + (Serpentes + Acrodonta)) were closely related groupings, which might indicate errors and also demonstrate that mitogenome-based phylogenetic trees may not effectively resolve long-branch attraction issues. Additionally, we reviewed the origin and diversification of Squamata throughout the Mesozoic era, suggesting that Squamata originated in the Late Triassic (206.05 Mya), with the diversification of various superfamilies occurring during the Cretaceous period. Future improvements in constructing squamate phylogenetic relationships using mitogenomes will rely on identifying snake and acrodont species with slower evolutionary rates, ensuring comprehensive taxonomic coverage of squamate diversity, and increasing the number of genes analyzed.

Synthesis of a Wheel-Shaped Nanographdiyne.

Graphdiyne, a sp- and sp2-hybridized 2D π-conjugated carbon material with well-dispersed pores and unique electronic properties, was well investigated and applied in catalysis, electronics, optics, and energy storage and conversion. Graphdiyne fragments with conjugation in 2D can provide in-depth insights for understanding the intrinsic structure-property relationships of graphdiyne. Herein, an atomic precise wheel-shaped nanographdiyne composed of six dehydrobenzo [18] annulenes ([18]DBAs, the smallest macrocyclic unit of graphdiyne), was realized through the sixfold intramolecular Eglinton coupling in the hexabutadiyne precursors obtained by the sixfold Cadiot-Chodkiewicz cross-coupling of hexaethynylbenzene. Its planar structure was revealed by X-ray crystallographic analysis. The full cross-conjugation of the six 18π electron circuits yields the π-electron conjugation along the giant π core. This work provides a realizable method for the synthesis of future graphdiyne fragments with different functional groups and/or heteroatom doping, as well as the study of the unique electronic/photophysical properties and aggregation behavior of graphdiyne.

Development and validation of web calculators to predict early recurrence and long-term survival in patients with duodenal papilla carcinoma after pancreaticoduodenectomy.

BACKGROUND: Duodenal papilla carcinoma (DPC) is prone to relapse even after radical pancreaticoduodenectomy (PD) (including robotic, laparoscopic and open approach). This study aimed to develop web calculators to predict early recurrence (ER) (within two years after surgery) and long-term survival in patients with DPC after PD. METHODS: Patients with DPC after radical PD were included. Univariate and multivariate logistic regression analyses were used to identify independent risk factors. Two web calculators were developed based on independent risk factors in the training cohort and then tested in the validation cohort. RESULTS: Of the 251 patients who met the inclusion criteria, 180 and 71 patients were enrolled in the training and validation cohorts, respectively. Multivariate logistic regression analysis revealed that tumor size [Odds Ratio (OR) 1.386; 95% confidence interval (CI) 1070-1.797; P = 0.014]; number of lymph node metastasis (OR 2.535; 95% CI 1.114-5.769; P = 0.027), perineural invasion (OR 3.078; 95% CI 1.147-8.257; P = 0.026), and tumor differentiation (OR 3.552; 95% CI 1.132-11.152; P = 0.030) were independent risk factors for ER. Nomogram based on the above four factors achieved good C-statistics of 0.759 and 0.729 in predicting ER in the training and the validation cohorts, respectively. Time-dependent ROC analysis (timeROC) and decision curve analysis (DCA) revealed that the nomogram provided superior diagnostic capacity and net benefit compared with single variable. CONCLUSIONS: This study developed and validated two web calculators that can predict ER and long-term survival in patients with DPC with high degree of stability and accuracy.

Tryptophan metabolism can modulate immunologic tolerance in primitive vertebrate lamprey via IDO-kynurenine-AHR pathway.

Tryptophan is mainly degraded through kynurenine pathway (KP) in vertebrates which is closely related to the nerve and depression, while the studies on immunity is still limited. This study aims to explore the functions of tryptophan in the innate immunity of primitive vertebrate lamprey. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide) assay showed that tryptophan had no obvious effect on cell viability. Tryptophan was transported into leukocytes and degraded via the KP after tryptophan supplement. Tryptophan treatment (T1x and T2x) failed to alter the total antioxidant capacity regardless of stimulation and exposure time. Real-time quantitative PCR and western blotting results revealed that tryptophan was not only able to reduce the expression of pro-inflammatory factors Lj-TNF-α, Lj-IL1ß and Lj-NF-κB, but also to upregulate the expression of anti-inflammatory factor Lj-TGF-ß independent of stimulation and time. In addition, tryptophan can exert immune tolerance function by inhibiting TLR-MyD88 and promoting (Indoleamine 2, 3-Dioxygenase) IDO-kynurenine-AHR (aryl hydrocarbon receptor) pathways. This study provides a new understanding for tryptophan-kynurenine metabolism and mechanism of immune tolerance function in primitive vertebrate lamprey.

Exploration of risk factors of platelet transfusion refractoriness and its impact on the prognosis of hematopoietic stem cell transplantation: a retrospective study of patients with hematological diseases.

Platelet transfusion refractoriness (PTR) is an intractable issue in hematological patients, which increases bleeding risks and hospitalization costs to a great extent. We reviewed 108 patients with hematological diseases including acute leukemia, myelodysplastic syndrome, aplastic anemia, and others who received allogeneic hematopoietic stem cell transplantation (HSCT) from January 2019 through December 2020. After multivariable logistic regression, we found that splenomegaly (odds ratio [OR] = 26.98, p < .001) and JAK mutation (OR = 17.32, p = .024) were independent risk factors for PTR. During the period of transplantation, patients in the PTR group had a significantly higher platelet transfusion demand, which was reflected in the increased number of platelet transfusions (10.23 ± 6.696 vs. 5.06 ± 1.904, p < .001). After multivariate adjustment, PTR turned out to be independently associated with worse overall survival (hazard ratio = 2.794, 95% confidence interval = 1.083-7.207, p = .034). In conclusion, we found that splenomegaly and JAK gene mutation were independent risk factors for PTR in patients with hematological diseases. A history of PTR prior to allo-HSCT indicates a poor prognosis.

What is the context?Platelet transfusion refractoriness is a critical issue, and it greatly increases bleeding risks and hospitalization costs.Patients with hematological diseases tend to develop PTR.PTR results from immune and nonimmune factors and the latter account for 80­90%.At present, there are few studies focused on the inducing factors of PTR, and the specific mechanism is not clear.What is new?In this study, we investigated 108 patients with hematological disorders who received allogeneic HSCT from January 2019 to December 2020.We found that splenomegaly and JAK gene mutation were independent risk factors for PTR in patients with hematological diseases.PTR had a passive effect on the prognosis of patients after HSCT, as indicated by worse OS and a trend toward lower platelets after transplantation.PTR might affect megakaryocyte reconstitution after transplantation.What is the impact?This study provides evidence that hematological patients with splenomegaly should be alert to the occurrence of PTR, which often indicates a worse prognosis of transplantation.Spleen reduction and JAK inhibitors in the treatment of PTR are worth exploring.AbbreviationsPLT: platelets; PTR: platelet transfusion refractoriness; HSCT: hematopoietic stem cell transplantation; OR: odds ratio; HR: hazard ratio; CI: confidence interval; IQR: interquartile range; SD: standard deviation; HLA: human leukocyte antigen; HPA: human platelet antigen; OS: overall survival; RFS: relapse free survival; PI: post-transfusion increment; PPR: percentage platelet recovery; CCI: corrected count increment; ICU: intensive care unit; AA: aplastic anemia; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; ALL: acute lymphocytic leukemia; CML: chronic myeloid leukemia; CMML: chronic myelomonocytic leukemia; MPN: myeloproliferative neoplasm; SI: splenic irradiation; Abs: antibodies; CR: complete remission; DAC: decitabine; GVHD: graft-versus-host disease; BM: bone marrow; PB: peripheral blood.

Rapid measurement and machine learning classification of colour vision deficiency.

Colour vision deficiencies (CVDs) indicate potential genetic variations and can be important biomarkers of acquired impairment in many neuro-ophthalmic diseases. However, CVDs are typically measured with tests which possess high sensitivity for detecting the presence of a CVD but do not quantify its type or severity. In this study, we introduce Foraging Interactive D-prime (FInD), a novel computer-based, generalisable, rapid, self-administered vision assessment tool and apply it to colour vision testing. This signal detection theory-based adaptive paradigm computed test stimulus intensity from d-prime analysis. Stimuli were chromatic Gaussian blobs in dynamic luminance noise, and participants clicked on cells that contained chromatic blobs (detection) or blob pairs of differing colours (discrimination). Sensitivity and repeatability of FInD colour tasks were compared against the Hardy-Rand-Rittler and the Farnsworth-Munsell 100 hue tests in 19 colour-normal and 18 inherited colour-atypical, age-matched observers. Rayleigh colour match was also completed. Detection and discrimination thresholds were higher for atypical than for typical observers, with selective threshold elevations corresponding to unique CVD types. Classifications of CVD type and severity via unsupervised machine learning confirmed functional subtypes. FInD tasks reliably detect inherited CVDs, and may serve as valuable tools in basic and clinical colour vision science.

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis.

Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. In this study, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A-C (1-3), that possess a 6/7/5-fused tricyclic scaffold. In vivo and in vitro experiments systematically established a noncanonical two-step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10-fused bicyclic cis-eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5-fused tricyclic scaffold through C2-C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring closure is shown to be a viable mechanism for AriF-mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

Circulating exosomal mRNA signatures for the early diagnosis of clear cell renal cell carcinoma.

BACKGROUND: There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. METHODS: Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. RESULTS: Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). CONCLUSIONS: We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

Adaptation of prelimbic cortex mediated by IL-6/STAT3/Acp5 pathway contributes to the comorbidity of neuropathic pain and depression in rats.

BACKGROUND: The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown. METHODS: Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats. CONCLUSIONS: These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.

The Sea Route Planning for Survey Vessel Intelligently Navigating to the Survey Lines.

Marine surveying is an important part of marine environment monitoring systems. In order to improve the accuracy of marine surveying and reduce investment in artificial stations, it is necessary to use high-precision GNSS for shipborne navigation measurements. The basic measurement is based on the survey lines that are already planned by surveyors. In response to the needs of survey vessels sailing to the survey line, a method framework for the shortest route planning is proposed. Then an intelligent navigation system for survey vessels is established, which can be applied to online navigation of survey vessels. The essence of the framework is that the vessel can travel along the shortest route to the designated survey line under the limitation of its own minimum turning radius. Comparison and analysis of experiments show that the framework achieves better optimization. The experimental results show that our proposed method can enable the vessel to sail along a shorter path and reach the starting point of the survey line at the specified angle.

Structure-Based Molecular Networking for the Discovery of Anti-HBV Compounds from Saussurea lappa (Decne.) C.B Clarke.

It is a crucial to find target compounds in natural product research. This study presents a concept of structure-guided isolation to find candidate active molecules from herbs. We establish a process of anti-viral sesquiterpene networking. An analysis of the networking suggested that new anti-HBV sesquiterpene may be attributable to eudesmane-, guaiane-, cadinane-, germacane- and bisabolane-type sesquiterpenes. In order to evaluate the efficiency of the structure-based molecular networking, ethanol extract of Saussurea lappa (Decne.) C.B Clarke was investigated, which led to the isolation of two guaiane-type (1 and 14), ten eudesmane-type (2-5 and 8-13), two chain (6 and 7) and one germacrane-type (15) sesquiterpenes, including seven new ones, lappaterpenes A-G (1-7), which are reported on herein. The absolute configurations of the new compounds were established by coupling constants, calculated ECD and ROESY correlations, as well as comparisons of optical rotation values with those of known compounds. The absolute configuration of compound 2 was further confirmed by X-ray diffraction. Compounds 1-15 were evaluated for their potency against hepatitis B virus. Compounds 4, 6, 7 and 9 showed effect on HBsAg with inhibition ratios of more than 40% at 30 µM concentrations. Compounds 14 and 15 inhibited HBsAg secretion with the values of IC50 0.73 ± 0.18 and 1.43 ± 0.54 µM, respectively. Structure-based molecular networking inspired the discovery of target compounds.

Circulating exosomal mRNA profiling identifies novel signatures for the detection of prostate cancer.

The landscape and characteristics of circulating exosomal messenger RNAs (emRNAs) are poorly understood, which hampered the accurate detection of circulating emRNAs. Through comparing RNA sequencing data of circulating exosomes with the corresponding data in tissues, we illustrated the different characteristics of emRNAs compared to tissue mRNAs. We then developed an improved strategy for emRNA detection based on the features of circulating emRNAs. Using the optimized detection strategy, we further validated prostate cancer (PCa) associated emRNAs discovered by emRNA-seq in a large cohort of patients and identified emRNA signatures for PCa screening and diagnosis using logistic regression analysis. The receiver operating characteristic curve (ROC) analysis showed that the circulating emRNA-based screening signature yielded an area under the ROC curve (AUC) of 0.948 in distinguishing PCa patients from healthy controls. The circulating emRNA-based diagnostic signature also showed a great performance in predicting prostate biopsy results (AUC: 0.851). In conclusion, our study developed an optimized emRNA detection strategy and identified novel emRNA signatures for the detection of PCa.