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BACKGROUND AND AIMS Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.

Background & aims Preoperative obstructive jaundice is usually associated with higher post-operative mortality. Although external biliary drainage (EBD) has been widely used to relieve obstructive jaundice, the role of bile reinfusion after EBD is still controversial. The aim of our study was to study the effects of biliary obstruction, biliary drainage and bile reinfusion on bile acid metabolism and gut microbiota. Methods Firstly, we created a mice bile drainage collection (BDC) model to simulate the process of biliary obstruction, drainage and bile reinfusion. Then, we analysed the faecal, serum, liver and bile samples to investigate the effects of the process on bile acid profiles and gut microbiota. Finally, we evaluated the clinical effects of bile reinfusion. Results We evaluated the bile acid profiles of faeces, serum, liver and bile of normal mice. During biliary obstruction, secondary bile acids can still be produced, and increased in the liver and serum of mice. Compared with no bile reinfusion, bile reinfusion was beneficial to the recovery of T-ωMCA in the liver and bile, and can restore the colon crypt length shortened by biliary obstruction. Only Ruminococcus_1 proliferated when the biliary obstruction lasted for 12 days. In the clinic, bile reinfusion cannot accelerate the patient's perioperative recovery or prolong long-term survival. Conclusion We have successfully created a mice bile drainage collection model. Short-term bile reinfusion can partially benefit the recovery of the secondary bile acids in the liver and bile, but hardly benefit the patient's perioperative recovery or long-term survival. (247 words).

The family Nymphalidae is the largest group of butterflies with high species richeness. Rhinopalpa polynice (Cramer, [1779]), a forest species, was discovered in the mid-stream of the Yuanjiang-Red River Valley of Yunnan Province for the first time, which represents the first record of the genus Rhinopalpa in China. The species R. polynice (Cramer, [1779]) is the first record of the genus Rhinopalpa from China. The specimen was collected in the mid-stream of the Yuanjiang-Red River Valley of Yunnan Province. The female genitalia are described for the first time.

Spermatogonial stem cells (SSCs) are crucial for maintaining spermatogenesis, studying germ line stem cell biology, and producing transgenic animals. Growth factors, including leukemia inhibitory factor (LIF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and glial cell line-derived neurotrophic factor (GDNF), are essential for in vitro culture of SSCs as well as their self-renewal and maintenance. In this study, we investigated the effects of these growth factors on porcine spermatogonial germ cell (pSGC) colony formation. We determined round alkaline phosphatase (AP)-positive pSGC colonies in the presence and absence of growth factors after 7 days of pSGC culture. EGF was found to be essential to support the formation of AP-positive pSGC colonies. The expression of epidermal growth factor receptor (EGFR) and Erb-B2 receptor tyrosine kinase 2 (ERBB2) was also altered in cultured pSGCs compared to that in feeder cells. We verified the effect of EGF signaling on pSGC colony formation using AG1478 as an EGFR inhibitor and AG879 as an ERBB2 inhibitor. pSGC colonies were observed in low dose AG1478-treated groups with EGF, whereas a high dose of AG1478 suppressed pSGC colony formation. AP-positive colonies were also observed in all AG879-treated groups. Taken together, EGFR and EGF signaling play a critical role in the initiation of colony formation of pSGCs. Our study provides insights into the mechanisms of EGF-mediated colony formation by SGCs derived from porcine testes, and will aid the development of transplantation techniques for the production of transgenic offspring.

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion., Touch can positively modulate cognitive performance and emotional response. Here the authors demonstrate that enriched tactile experience improves memory and reduces anxiety in adult mice by remodelling the pathway from the primary somatosensory cortex to the dentate gyrus.

The mitogenomes of two insular subspecies of Pazala, G. (P.) eurous asakurae and G. (P.) mullah chungianus from Taiwan Island, are reported. Both mitogenomes are circular, 15,228 bp and 15,240 bp i...

The migration sources and pathways of Sogatella furcifera (Horváth) in topologically complex regions like Yunnan, China, and adjacent montane areas have long been a challenging task and a bottleneck in effective pest forecast and control. The present research reinvestigated this issue using a combination of mtDNA and long‐term historical wind field data in an attempt to provide new insights. Genetic analyses showed that the 60 populations of S. furcufera collected across Myanmar, Thailand, Laos, Vietnam, Yunnan, Guizhou, and Sichuan lack genetic structure and geographic isolation, while spatial analysis of haplotype and diversity indices discovered geographic relevance between populations. Migration rate analysis combined with high‐resolution 10‐year wind field analysis detected the following migration sources, pathways, and impacted areas which could explain the outbreak pattern in Yunnan. (a) Dominating stepwise northward migrations originated from northern Indochina, southern Yunnan, and central‐eastern Yunnan, impacting their northern areas. (b) Concurring summer–autumn southward (return) migration originated from nearly all latitude belts of Sichuan and Yunnan mainly impacting central and southern Yunnan. (c) Regular eastward and summer–autumn westward migrations across Yunnan. The northward migration reflects the temporal rhythm of gradual outbreaks from the south to the north in a year, while the return migration may explain the repeated or very severe outbreaks in the impacted areas. To form a better pest forecast and control network, attention must also be paid to the northern part of Yunnan to suppress the impact of return migration in summers and autumns.

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain–spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention. Neuronal activities in the central amygdala and paraventricular nucleus are transmitted via the splenic nerve to increase plasma cell formation after immunization, and this process can be behaviourally enhanced in mice.

The long-armed scarab (Cheirotonus gestroi) is an endangered large insect in southwestern China and neighboring countries; however, limited information is available regarding its population genetics, hindering conservation efforts. Therefore, we investigated the population genetic structure and evolutionary history of C. gestroi in southwestern China. Twenty-five haplotypes were obtained from 47 specimens across five populations. The Dawei Mountain (DWS) population differed from other populations by a high genetic distance. Population structure analysis generated three distinct clades, corresponding to Hengduan Mountains (HM), Ailao Mountains (AM), and Dawei Mountains (DM), and high-level genetic diversity was found in two HM populations. Collectively, the strong genetic differentiation among populations might be due to limited gene flow, geographical isolation, and habitat fragmentation. Therefore, while developing a conservation strategy, HM, AM, and DM groups should be defined as separate management units. Additionally, the DWS population should be given priority protection due to its uniqueness and low genetic diversity.

Organisms must make sense of a constant stream of sensory inputs from both internal and external sources which compete for attention by determining which ones are salient. The ability to detect and respond appropriately to potentially salient stimuli in the environment is critical to all organisms. However, the neural circuits that process salience are not fully understood. Here, we identify a population of glutamatergic neurons in the ventral pallidum (VP) that play a unique role in salience processing. Using cell-type-specific fiber photometry, we find that VP glutamatergic neurons are robustly activated by a variety of aversion- and reward-related stimuli, as well as novel social and non-social stimuli. Inhibition of the VP glutamatergic neurons reduces the ability to detect salient stimuli in the environment, such as aversive cue, novel conspecific and novel object. Besides, VP glutamatergic neurons project to both the lateral habenula (LHb) and the ventral tegmental area (VTA). Together, our findings demonstrate that the VP glutamatergic neurons participate in salience processing and therefore provide a new perspective on treating several neuropsychiatric disorders, including dementia and psychosis.

Aerobic respiration is the indispensable physiology of higher organism living on earth, since the required energy for biological activities is supplied mainly by this metabolism. It is well established that mitochondria plays an important role in converting the stable chemical energy stored in foods into the active and utilizable energy supplying to life activities. Upon the process, the energy conversion is carried out by the respiratory electron transport chain, which consists of five distinct and coupled protein complexes (termed complex I−V) embedded in the mitochondria intima. Among them, complex I (NADH-ubiquinone oxidoreductase), III (cytochrome bc 1) and IV (cytochrome c oxidase) are the electron-coupled proton-pumping enzymes. Except for the complex V (i.e., ATP synthase), each complex has several redox cofactors to promote the electron transfer within themselves, and the transfer from complex I and II to complex III is shuttled by membrane-embedded ubiquinones, from complex III to IV by the soluble cytochrome c . When the reductive electron is donated by the initial donors NADH or FADH2 to the final acceptor molecular oxygen O2, a transmembrane proton motive force is formed simultaneously. The latter is the driving force for the ATP synthesis via ATP synthase with a ratio of three protons per ATP. All the aforementioned processes are also known as oxidative phosphorylation, and the arrangement of the electron carriers therein is called as respiratory electron transport chain. In the stepwise electron relay, these carriers undergo the redox changes, giving rise to the respective paramagnetic and diamagnetic spin states. These single-electron relays are prone to the electron paramagnetic resonance spectroscopy (EPR), which is a powerful and noninvasive technique to monitor the unpaired electron in situ . As shown in the overwhelming literatures, EPR technique has been adopted to reveal the electron transfer pathway in different biological activities. Herein, the application of EPR to study the dynamic electron transfer in mitochondria is reviewed briefly. However, this conventional application required rather high concentration of the active center at a level of 1–10 µmol/L. Actually, most of the intermediates of the electron carriers are very active and short-life. In the human body, only a few tissues can accumulate such required concentration of paramagnetic substances, e.g., in blood, heart and liver. For the past decade, a more sensitive single-molecule magnetic resonance technique based on the nitrogen-vacancy (NV) center of diamond has been developing dramatically. In principle, this advanced EPR technique requires the less sample or concentration, even down to the single biomolecule, and provides the time-resolved dynamic information. Lately, the studies of single-biomolecule EPR at room temperature or in aqueous solution have been reported consecutively in single protein (MAD2/mitotic arrest deficient-2) and single DNA (tethered DNA duplexes). Finally, a perspective of single-biomolecule magnetic resonance technique is given for the further study on mitochondrion and relative physiological activities. The single molecule EPR technique is also helpful to unveil the other specific information of biological processes, for example, drug screening, personalized medicine and other major applications.

Bhutanitis thaidina is an endemic, rare, and protected swallowtail in China. Deforestation, habitat fragmentation, illegal commercialised capture, and exploitation of larval food plants are believed to be the four major causes of population decline of B. thaidina in the recent decade. However, little attention was paid to the impact of climate change. This study used ecological niche factor analysis and species distribution model to analyse the current suitable areas for B. thaidina with BioClim variables as well as its future suitable areas under four future climate scenarios (represented by four Representative Concentration Pathways: RCP2.6, RCP4.5, RCP6.0, and RCP8.5). Statistical analysis was carried out to compare the possible area and altitude changes to the distribution of B. thaidina under changing climate. Our analyses showed that the suitable areas for B. thaidina are fragmented under the current climate, with four suitable centres in northwestern Yunnan, northeastern Yunnan and northwestern Guizhou, the western margin of Sichuan Basin, and Qinling mountains. Apart from further habitat fragmentation under climate change, slight range expansion (average 6.0–8.9%) was detected under the RCP2.6 and RCP4.5 scenarios, while more range contraction (average 1.3–26.9%) was detected under the RCP6.0 and RCP8.5 scenarios, with the two southern suitable centres suffering most. Also, a tendency of contraction (2,500–3,500 m) and upslope shift (~600 m) in suitable altitude range were detected. The findings of this study supported the climate-vulnerable hypothesis of B. thaidina, especially under future climate like the RCP6.0 and RCP8.5 scenarios, in terms of contraction in suitable areas and altitude ranges. Conservation priority should be given to northwestern Yunnan, northeastern Yunnan, and northwestern Guizhou to alleviate the stress of massive habitat loss and extinction. Refugial areas should be established in all four suitable centres to maintain genetic diversity of B. thaidina in China.

Description, Spatial transcriptome technique was applied to decipher the spatial architecture and TME characteristics of liver cancers., Heterogeneity is the major challenge for cancer prevention and therapy. Here, we first constructed high-resolution spatial transcriptomes of primary liver cancers (PLCs) containing 84,823 spots within 21 tissues from seven patients. The progressive comparison of spatial tumor microenvironment (TME) characteristics from nontumor to leading-edge to tumor regions revealed that the tumor capsule potentially affects intratumor spatial cluster continuity, transcriptome diversity, and immune cell infiltration. Locally, we found that the bidirectional ligand-receptor interactions at the 100-μm-wide cluster-cluster boundary contribute to maintaining intratumor architecture and the PROM1+ and CD47+ cancer stem cell niches are related to TME remodeling and tumor metastasis. Last, we proposed a TLS-50 signature to accurately locate tertiary lymphoid structures (TLSs) spatially and unveiled that the distinct composition of TLSs is shaped by their distance to tumor cells. Our study provides previous unknown insights into the diverse tumor ecosystem of PLCs and has potential benefits for cancer intervention.

The peatlands of the Zoige Plateau are an important global carbon source that is currently under threat as a result of drainage for grazing. How drainage affects the microbial diversity and activity in peatlands is unclear. This study examined the response of microbial communities at two sites to short-term drainage (3 years) and long-term drainage (48 years) in combination with three different water table treatments. Our objective was to examine the changes in the physicochemical properties of the soil, composition of bacterial and fungal communities, and microbial activity. Our results indicated that (1) both duration of drainage and water table drawdown had significant effects on the diversity and composition of the bacterial and fungal communities in the soil, and certain bacteria were replaced by fungal decomposers; (2) duration of drainage affected the structure of fungal communities more than that of bacterial communities, and interactions between microbial species were more complex in peatlands with long-term drainage; (3) drainage significantly altered concentrations of dissolved inorganic nitrogen (NH4+-N and NO3−-N), and these changes correlated with structure of bacterial and fungal communities as well as with changes in abundance of certain dominant microbial species; and (4) fungal communities explained a larger part of microbial activity than bacterial communities. Overall, these findings suggest that fungi play a much more important role than bacteria in microbial-mediated ecosystem functioning in peatlands undergoing drainage.

Archaea communities widely exist in mangrove forest sediments, but their spatial variations among different distribution areas with salinity gradient in mangrove forest sediments is not well understood. This study used 16S rRNA Miseq sequence to investigate the sediment archaeal community structure and diversity of Bruguiera gymnoihiza mangrove forest in China along three different distribution areas. The results showed rich methanogen and ammonia-oxidizing archaea resources in the study site, with Methanobacterium, Methanothrix, Methanomassiliicoccus, Nitrosopumilus and Nitrososphaera (>1%) as the dominant genera. Mantel test and Redundancy analysis (RDA) results revealed that pH was the determinant for archaeal community structure in our study. The RDA result showed that the available K also contributed to archaeal community structure. There was a significant and positive relationship between pH and available P; in addition, the two values were significantly and negatively related to the observed OTU number. These results suggested that pH is the main determinant of the archaeal community structure and diversity in distribution areas of Bruguiera gymnoihiza in Dongzhaigang.

The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive.

Arabidopsis thaliana copper-zinc superoxide dismutase 1 (AtSOD1) is a typical metalloenzyme conferring cellular protection against the excessive accumulation of toxic reactive oxygen species, and is therefore considered as a critical protein. However, the structure and function of the vital amino acids around the active site of AtSOD1 remain poorly understood. Herein, the coordinated geometry of the catalytic center in AtSOD1 was reconstructed by electron paramagnetic resonance (EPR) technique, and it was found to be composed of copper and four histidine (H) residues using site-directed mutagenesis. Analysis of the mutants showed that H45 and H62 play essential roles in the catalytic reaction, and H119 plays an accessary role in facilitating substrate or proton transfer. The results indicated that the redox change of the Cu ion and the overall enzymatic activity of the protein were sustained by the H45-Cu-H62 core structure. In contrast, the residue H47 showed nearly no effect on the SOD catalytic activity. These data should contribute to a deeper understanding of the catalytic mechanism of the enzyme, and provide a new approach for the effective molecular modification of copper/zinc SODs to facilitate further research in this field.

BACKGROUND Gamma-glutamyltransferase (GGT) is one of the most important laboratory tests for the evaluation of liver damage. Through a long-term clinical observation of patients with secondary asymptomatic choledocholithiasis, we found that most patients had abnormal GGT serum levels. AIM To investigate the combination of serum GGT and alkaline phosphatase (ALP) in predicting the diagnosis of asymptomatic choledocholithiasis secondary to cholecystolithiasis. METHODS In this retrospective cohort study, the clinical data of 829 patients with cholecystolithiasis admitted to the Third Affiliated Hospital of Zunyi Medical College from August 2014 to August 2017 were collected. Among these patients, 151 patients had secondary asymptomatic choledocholithiasis and served as the observation group, and the remaining 678 cholecystolithiasis patients served as the control group. Serum liver function indexes were detected in both groups, and the receiver operating characteristic (commonly known as ROC) curves were constructed for markers showing statistical significances. The cutoff value, sensitivity, and specificity of each marker were calculated according to the ROC curves. RESULTS The overall incidence of asymptomatic choledocholithiasis secondary to cholecystolithiasis was 18.2%. The results of liver function indexes including serum aspartate aminotransferase, alanine aminotransferase, direct bilirubin and total bilirubin levels showed no significant differences between the two groups (P > 0.05). However, the serum GGT and ALP levels were significantly higher in the observation group than in the control group (P < 0.05). The ROC curve analysis showed that the area under the curve was 0.881 (95%CI: 0.830-0.932), 0.647 (95%CI: 0.583-0.711) and 0.923 (95%CI: 0.892-0.953) for GGT, ALP, and GGT + ALP, respectively. The corresponding cut-off values of GGT and ALP were 95.5 U/L and 151.5 U/L, sensitivity were 90.8% and 65.1%, and specificity were 83.6% and 59.8%, respectively. The sensitivity and specificity of GGT + ALP were 93.5% and 85.1%, respectively. CONCLUSION An abnormally elevated serum GGT level has an important value in the diagnosis of asymptomatic choledocholithiasis secondary to cholecystolithiasis. The combination of serum GGT and ALP has better diagnostic performance. As a convenient, rapid and inexpensive test, it should be applied in secondary asymptomatic choledocholithiasis routine screening.

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson’s disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins., Tetrathiomolybdate (TM) and Cu-ATPases, e.g. Wilson (WLN) protein, affect the efficacy of common anticancer drug cisplatin. Here, the authors show that TM generates a protein dimer with a WLN domain by expelling copper and provide insight into the synergy of TM and cisplatin in cancer chemotherapy.

The rapid development and application of nanotechnology have led to increasing concern about the environmental implications of released nanomaterials and potential risks to public health and aquatic ecosystems. Information on the joint effect of nanomaterials and co-existing contaminants such as heavy metals is still inadequate. Our work investigated the effect of Al2O3 nanoparticles (NPs; nano-Al2O3) on the toxic effect of Pb in the unicellular marine phytoplankton Isochrysis galbana. Results showed that a dose–response effect of nano-Al2O3 was found. Significant enhancement of fluorescence in cell cytoplasm rather than cell membrane occurred in the presence of nano-Al2O3, indicating that nano-Al2O3 can penetrate cells and affect the fluorescence emitted from the chloropigments inside them. The presence of nano-Al2O3 has no impact on the toxic effect of Pb at an NP concentration of 1 mg/L but increased that at NP concentrations of 10 mg/L and 100 mg/L. A synergistic effect was also found for the toxic effect of Pb in the presence of 10 mg/L nano-Al2O3. The presence of 100 mg/L nano-Al2O3 significantly increased the bio-uptake of Pb in the range of 0.25 mg/L to 2.0 mg/L Pb, and the maximum accumulated Pb in algae can reach up to 18.22 ng/105 cells with 100 mg/L nano-Al2O3 compared with Pb alone at 2.0 mg/L(12.53 ng/105 cells). Inside cells, Pb loaded onto nano-Al2O3 can be more toxic than the same amount of free Pb species. The results of toxicity tests and accumulated Pb in algae imply that, in addition to the total Pb cell content, the bioavailability of Pb inside algae should be taken into consideration in evaluating the joint toxicity effect. Our work enhances understanding of the combined toxicity of NPs and co-existing heavy metals and is of practical significance in the natural environment.

Background Despite the fundamental clinical significance of general anaesthesia, the cortical mechanism underlying anaesthetic-induced loss of consciousness (aLOC) remains elusive. Methods Here, we measured the dynamics of two major cortical neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate, through in vivo two-photon imaging and genetically encoded neurotransmitter sensors in a cell type-specific manner in the primary visual (V1) cortex. Findings We found a general decrease in cortical GABA transmission during aLOC. However, the glutamate transmission varies among different cortical cell types, where in it is almost preserved on pyramidal cells and is significantly reduced on inhibitory interneurons. Cortical interneurons expressing vasoactive intestinal peptide (VIP) and parvalbumin (PV) specialize in disinhibitory and inhibitory effects, respectively. During aLOC, VIP neuronal activity was delayed, and PV neuronal activity was dramatically inhibited and highly synchronized. Interpretation These data reveal that aLOC resembles a cortical state with a disrupted excitatory-inhibitory network and suggest that a functional inhibitory network is indispensable in the maintenance of consciousness. Funding This work was supported by the grants of the National Natural Science Foundation of China (grant nos. 81620108012 and 82030038 to H.D. and grant nos. 31922029, 61890951, and 61890950 to J.H.).

Background The family Pieridae is a large group of butterflies which plays an important role in evolutionary biology and contains many potential pests (Courtney 1986). Pieridae is a cosmopolitan family while the tropics harbour higher species richness. In a very recent expedition to the Chinese-Indian border area in Tibet Autonomous Region, a migratory species, Belenois aurota (Fabricius, 1793), was discovered for the first time, which comprises the first record of the genus Belenois in China and the highest altitude record of this species. New information The species B. aurota (Fabricius, 1793) is the first record of the genus Belenois from China. The specimen was collected at an altitude of about 3,000 m in Tibet Autonomous Region. Relevant details are presented for the species.

In-depth profiling of transmembrane proteins in the brain leads to the identification of GPCR regulators in a disease model., Transmembrane proteins play vital roles in mediating synaptic transmission, plasticity, and homeostasis in the brain. However, these proteins, especially the G protein–coupled receptors (GPCRs), are underrepresented in most large-scale proteomic surveys. Here, we present a new proteomic approach aided by deep learning models for comprehensive profiling of transmembrane protein families in multiple mouse brain regions. Our multiregional proteome profiling highlights the considerable discrepancy between messenger RNA and protein distribution, especially for region-enriched GPCRs, and predicts an endogenous GPCR interaction network in the brain. Furthermore, our new approach reveals the transmembrane proteome remodeling landscape in the brain of a mouse depression model, which led to the identification of two previously unknown GPCR regulators of depressive-like behaviors. Our study provides an enabling technology and rich data resource to expand the understanding of transmembrane proteome organization and dynamics in the brain and accelerate the discovery of potential therapeutic targets for depression treatment.

Simple Summary Butterflies provide numerous ecological and socio-economic services and are important indicator species. China is home to over 2000 species of butterflies and in recent years has elevated biodiversity conservation on the national agenda. This manuscript reviews China’s butterfly conservation efforts and its legal and policy frameworks. We note some of the current limitations in butterfly conservation (inappropriate listing of protected species; over-reliance on inventories, rather than holistic research) and offer numerous recommendations to improve conservation efforts. Our recommendations include those related to integration of scientific data into policy (designation of scientifically-based protected areas; development of appropriate criteria for classifying protected species; use of umbrella species for conservation purposes), adoption of butterfly-friendly land use policies in rural and urban areas, butterfly ranching and farming, use of citizen science to improve data collection, and enhanced public outreach and environmental education campaigns. Our recommendations will help further the goals of China’s National Biodiversity Conservation Strategy and Action Plan (2011–2030). Abstract About 10% of the Earth’s butterfly species inhabit the highly diverse ecosystems of China. Important for the ecological, economic, and cultural services they provide, many butterfly species experience threats from land use shifts and climate change. China has recently adopted policies to protect the nation’s biodiversity resources. This essay examines the current management of butterflies in China and suggests various easily implementable actions that could improve these conservation efforts. Our recommendations are based on the observations of a transdisciplinary group of entomologists and environmental policy specialists. Our analysis draws on other successful examples around the world that China may wish to consider. China needs to modify its scientific methodologies behind butterfly conservation management: revising the criteria for listing protected species, focusing on umbrella species for broader protection, identifying high priority areas and refugia for conservation, among others. Rural and urban land uses that provide heterogeneous habitats, as well as butterfly host and nectar plants, must be promoted. Butterfly ranching and farming may also provide opportunities for sustainable community development. Many possibilities exist for incorporating observations of citizen scientists into butterfly data collection at broad spatial and temporal scales. Our recommendations further the ten Priority Areas of China’s National Biodiversity Conservation Strategy and Action Plan (2011–2030).

International audience; Three Graphium species belonging to two species groups of the subgenus Pazala, the alebion and tamerlanus groups,were examined in molecular and morphological studies, and their female genitalia are reported for the first time. Theirrelationship with other species groups within the subgenus is assessed and their divergence times are estimated. We findthat G. (P.) alebion is the first lineage to diverge within Pazala in the early Miocene (20 Ma) and that G. (P.) tamerlanusand G. (P.) parus are sister species and diverged from each other in the late Miocene (7 Ma). A revision of the fourrecognised taxa belonging to three species is presented, and historical misidentification of these taxa and their geographicranges are explained.

Aim: To study the expression pattern of circular RNAs in diabetic peripheral neuropathy. Materials & methods: Transmission electron microscopy was used to observe the ultrastructure of sciatic nerves and dorsal root ganglion (DRGs). circRNAs in DRGs were identified with high-throughput RNA sequencing. Whole-genome mRNAs were detected by a chip scan. Results: The ultrastructure of sciatic nerves and DRGs in diabetes mellitus mice changed significantly. A total of 11,004 circRNAs and 15 differentially expressed circRNAs, as well as 35,368 mRNAs and 133 differentially expressed mRNAs were identified in DRGs between wild-type and diabetes mellitus mice. 11 circRNAs and 14 mRNAs have a significant correlation using strict coexpression analysis. The expression of circRNA.4614 was validated to be upregulated significantly. Conclusion: Our study suggested that circRNAs might be involved in the regulation of mRNA expressions in diabetic peripheral neuropathy.

Losaria coon (Fabricius, 1793) is currently comprised of ten subspecies, which were originally described under two names, Papilio coon and P. doubledayi before 1909, when they were combined as one species. The main difference between them is the colour of abdomen and hindwing subterminal spots&mdash, yellow in coon and red in doubledayi. Wing morphology, male and female genitalia, and molecular evidence (DNA barcodes) were analysed for multiple subspecies of L. coon and three other Losaria species&mdash, rhodifer, neptunus, and palu. Our molecular data support the separation of L. coon and L. doubledayi stat. rev. as two distinct species, with L. rhodifer positioned between them in phylogenetic analyses. Wing morphology and genitalic structures also confirm the molecular conclusions. Our findings divide L. coon into two species occupying different geographic ranges: with L. coon restricted to southern Sumatra, Java, and Bawean Island, while L. doubledayi occurs widely in regions from North India to northern Sumatra, including Hainan and Nicobar Islands. Hence, future conservation efforts must reassess the status and threat factors of the two species to form updated strategies.

TiO2 nanoparticles (NPs) could adversely impact aquatic ecosystems. However, the aggregation of these NPs could attenuate this effect. In this work, the biological effects of TiO2 NPs on a marine microalgae Isochrysis galbana were investigated. The aggregation kinetics of TiO2 NPs under different conditions was also investigated to determine and understand these effects. Results showed that, though TiO2 NPs had no obvious impact on the size and reproducibility of algal cells under testing conditions, they caused a negative effect on algal chlorophyll, which led to a reduction in photosynthesis. Furthermore, fast aggregation of TiO2 NPs occurred under all conditions, especially at the pH close to the pHzpc. Increasing ionic strength and NP concentration also enhanced the aggregation rate. The aggregation and the following sedimentation of TiO2 NPs reduced their adverse effects on I. galbana.

The design of functional metallohydrogels is attractive but challenging. A rational approach is introduced for designing functional metallohydrogels using chiral ligands, a phenylalanine derivative with a pyridyl group (l/d-PF). Intriguingly, the as-prepared metallohydrogel exhibits excellent O2 binding and activating properties. Insights into the O2 binding pathway reveals the presence of a novel [(l+d)-PF-Cu3+ -O2- ] species, which can efficiently reduce ferric cytochrome c with the reactive O2- by receiving an electron from reductant ascorbic acid. This study provides helpful instructions for developing new artificial systems with specific functions through the effective combination of chiral ligands with metal ions.

The subalpine swordtail butterfly Graphium (Pazala) parus (Niceville, 1900) is endemic to the Hengduan Mountains centered in West China, its biological and ecological characters still remain poorly...

The long-armed scarab Cheirotonus gestroi is an endangered large insect in southwestern China and neighboring countries. Herein, we present the first complete mitochondrial genome of C. gestroi. The 16,899 bp long circular genome consists of 2 ribosomal RNA genes, 22 transfer RNA genes, 13 protein-coding genes, and a non-coding control region. Phylogenetic analysis showed that C. gestroi shared the closest evolutionary relationship with C. jansoni and that Scarabaeidae and Lucanidae were correctly identified within superfamily Scarabaeoidea. The complete mitogenome sequence will provide a basis for further phylogenetic studies and conservation genetics of the genus Cheirotonus.

One of the central questions in the characterization of enzyme inhibitors is determining the mode of inhibition (MOI). Classically, this is done with a number of low-throughput methods in which inhibition models are fitted to the data. The ability to rapidly characterize the MOI for inhibitors arising from high-throughput screening in which hundreds to thousands of primary inhibitors may need to be characterized would greatly help in lead selection efforts. Here we describe a novel method for determining the MOI of a compound without the need for curve fitting of the enzyme inhibition data. We provide experimental data to demonstrate the utility of this new high-throughput MOI classification method based on nonparametric analysis of the activity derived from a small matrix of substrate and inhibitor concentrations (e.g., from a 4S × 4I matrix). Lists of inhibitors from four different enzyme assays are studied, and the results are compared with the previously described IC50-shift method for MOI classification. The MOI results from this method are in good agreement with the known MOI and compare favorably with those from the IC50-shift method. In addition, we discuss some advantages and limitations of the method and provide recommendations for utilization of this MOI classification method.

// Ru Yang 1, * , Yingzi Zhang 2, * , Lin Wang 3, * , Ji Hu 4 , Jian Wen 1 , Leixi Xue 1 , Mei Tang 1 , Zhichun Liu 1 , Jinxiang Fu 5 1 Department of Rheumatology, The Second Affiliated Hospital to Soochow University, Jiangsu, China 2 Department of Orthopaedics, The Second Affiliated Hospital to Soochow University, Jiangsu, China 3 Department of Laboratory Medicine, The First Affiliated Hospital to Soochow University, Jiangsu, China 4 Department of Endocrinology, The Second Affiliated Hospital to Soochow University, Jiangsu, China 5 Department of Hematology, The Second Affiliated Hospital to Soochow University, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Jinxiang Fu, email: fjx3000@126.com Zhichun Liu, email: lzchun5190@sina.com Keywords: rheumatoid arthritis, autophagy, fibroblast-like synoviocytes, IL-6 Received: May 23, 2016 Accepted: November 01, 2016 Published: December 28, 2016 ABSTRACT The incidence of rheumatoid arthritis (RA) has been reported to be correlated with a disorder of immunregulation. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) play an important role in regulating the local immune microenvironment. However, the potential mechanism of RA-FLS in regulating the immnue response is not clearly understood. In this study, we demonstrated that the expression of HIF-1α was significantly up-regulated in rheumatoid arthritis tissue which indicated that the hypoxia condition in the microenvironment. We also observed that RA-FLSs demonstrated the potential to up-regulate immune activation. Meanwhile, the level of autophagy increased in RA-FLSs compared with control group. Besides that, the expression of IL-6 was up-regulated not only in RA-FLSs but also in the fibroblasts that treated with hypoxia condition. Accordingly, we found that autophagy inhibitiors could effectively inhibit the immune activation function of RA-FLSs medicated by IL-6. Taken together, the results we demonstrated above indicated that the hypoxia microenvironment could effectively induce the incidence of autophagy and then lead to the immune activation function of RA-FLSs medicated by IL-6.

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive WNK1-4 kinase inhibitors, the optimization of which enabled cocrystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.

The strength of methane (CH4) source of mangroves is not well understood, especially when including all CH4 pathways in consideration. This study measured CH4 fluxes by five pathways (sediments, pneumatophores, water surface, leaves, and stems) from four typical mangrove forests, including Kandelia candel without pneumatophores and three species with pneumatophores: Sonneratia apetala, Laguncularia racemosa and Bruguiera gymnorhiza-Bruguiera sexangula. The CH4 fluxes from sediments were 4.82 ± 1.46 mg CH4 m−2 h−1 for K. candel and 1.36 ± 0.17 mg CH4 m−2 h−1 for the other three with pneumatophores. Among the three communities with pneumatophores, S. apetala community had significantly greater emission rate than the other two (P

Corticotropin-releasing hormone (CRH) is a critical neuropeptide modulating the mammalian stress response. It is involved in many functional activities within various brain regions, among which there is a subset of CRH neurons occupying a considerable proportion of the cortical GABAergic interneurons. Here, we utilized rabies virus-based monosynaptic retrograde tracing system to map the whole-brain afferent presynaptic partners of the CRH neurons in the anterior cingulate cortex (ACC). We find that the ACC CRH neurons integrate information from the cortex, thalamus, hippocampal formation, amygdala, and also several other midbrain and hindbrain nuclei. Furthermore, our results reveal that ACC CRH neurons receive direct inputs from two neuromodulatory systems, the basal forebrain cholinergic neurons and raphe serotoninergic neurons. These findings together expand our knowledge about the connectivity of the cortical GABAergic neurons and also provide a basis for further investigation of the circuit function of cortical CRH neurons.

Oxidative stress contributes substantially to podocyte injury, which plays an important role in the development of diabetic kidney disease. The mechanism of hyperglycemia-induced oxidative stress in podocytes is not fully understood. Glucose-6-phosphate dehydrogenase (G6PD) is critical in maintaining NADPH, which is an important cofactor for the antioxidant system. Here, we hypothesized that high glucose induced ubiquitination and degradation of G6PD, which injured podocytes by reactive oxygen species (ROS) accumulation. We found that G6PD protein expression was decreased in kidneys of both diabetic patients and diabetic rodents. G6PD activity was also reduced in diabetic mice. Overexpressing G6PD reversed redox imbalance and podocyte apoptosis induced by high glucose and palmitate. Inhibition of G6PD with small interfering RNA induced podocyte apoptosis. In kidneys of G6PD-deficient mice, podocyte apoptosis was significantly increased. Interestingly, high glucose had no effect on G6PD mRNA expression. Decreased G6PD protein expression was mediated by the ubiquitin proteasome pathway. We found that the von Hippel-Lindau (VHL) protein, an E3 ubiquitin ligase subunit, directly bound to G6PD and degraded G6PD through ubiquitylating G6PD on K366 and K403. In summary, our data suggest that high glucose induces ubiquitination of G6PD by VHL E3 ubiquitin ligase, which leads to ROS accumulation and podocyte injury.-Wang, M., Hu, J., Yan, L., Yang, Y., He, M., Wu, M., Li, Q., Gong, W., Yang, Y., Wang, Y., Handy, D. E., Lu, B., Hao, C., Wang, Q., Li, Y., Hu, R., Stanton, R. C., Zhang, Z. High glucose-induced ubiquitination of G6PD leads to the injury of podocytes.

The Graphium (Pazala) mandarinus group was recently defined and the status of taxa as well as the number of species was revised. We report here the discovery of a new species from Kon Tum plateau of the Truong Son (Annamite) Range of Central Vietnam, which we describe based on morphological and molecular evidence. Molecular phylogeny shows that the new taxon, G. (P.) wenlingae Hu, Cotton & Monastyrskii sp. nov., is sister to G. (P.) daiyuanae Hu, Zhang & Cotton, 2018 plus G. (P.) confucius Hu, Duan & Cotton, 2018. Molecular dating analysis further suggests that this new species diverged from its sister clade in the Pliocene (~3.5 million years ago). The new taxon constitutes the eighth and southernmost species of the mandarinus group.

The white-backed planthopper, Sogatella furcifera (Horváth), is a devastating migratory rice pest in South China; lack of effective methods to identify immigrating populations is the main cause of difficulties in outbreak forecasting, active prevention, and control. The current study set up field cages (2 × 2 × 3 m each, US-80 standard nylon mesh) in both early- and mid-season paddies in Yuanjiang (Red River) Valley in Yunnan, China, in 2012 and 2014. The immigrating population was successfully separated from the local population of S. furcifera and identified using statistical comparisons. The findings showed that densities of macropterous adults outside the cages were all significantly higher than those inside the cages on both early- and mid-season rice in both years, whereas the densities of young nymphs and old nymphs showed no significant differences. This indicated that immigrations were occurring, the earliest of which occurred on early-season rice in early May and reached its peak in mid-late May before a rapid collapse in both years. In contrast, the immigration on mid-season rice showed a continuous decline or fluctuation throughout the entire period. Analyses demonstrated that the migration process of S. furcifera in the Yuanjiang Valley features continuous immigration from the adjacent southern parts of Yunnan, which may represent most migration events in Yunnan during the outbreak period of a year. The findings of this case study could benefit our understanding of planthopper migration and outbreaks in other parts of China, especially where the outbreak pattern is very different from Yunnan.

Neonatal diabetes mellitus (NDM) is caused by mutations in the genes responsible for pancreatic β cell mass or function. This study aimed to screen the mutations in the KCNJ11, ABCC8, and INS genes in a Chinese patient with clinical features of NDM. The entire coding sequence and exon/intron boundaries of KCNJ11, ABCC8, and INS genes were detected by Sanger sequencing. The pathogenicity of the mutation was determined by using online prediction programs SIFT and Mutation Taser. The conformational alterations which contribute to the change of protein function were analyzed at the structural level. A novel mutation L35Q (B11) of the INS gene was discovered in the patient. As L35 residue contributes to its hydrophobic core of the protein, the L35Q substitution is predicated to affect B19-A20 disulfide bond and therefore disrupt the folding of the proinsulin, which ultimately results in beta cell apoptosis by inducing ER stress. This case could help us understand the role of the INS mutation in the development of diabetes.

Early life stages of marine organisms are the most sensitive stages to environment stressors including pollutants. In order to understand the toxicological effects induced by MeHg exposure on juveniles of large yellow croaker (Pseudosciaena crocea), a toxicity test was performed wherein fish were exposed to sub-lethal concentrations of MeHg under laboratory conditions (18 ± 1°C; 26 ± 1 in salinity). After 30 days of 0–4.0 μg L-1 MeHg exposure, SOD activity was significantly decreased in the 0.25, 1.0, and 4.0 μg L-1 treatments; while CAT activity was significantly increased in the 4.0 μg L-1 treatments; GSH level, GPx activity were significantly elevated in the 4.0 μg L-1 treatments, respectively. Meanwhile, malondialdehyde content was also significantly increased in the 1.0 and 4.0 μg L-1 treatments with respect to the control. Acetylcholinesterase activity was significantly decreased by 18.3, 25.2, and 21.7% in the 0.25, 1.0, and 4.0 μg L-1 treatments, respectively. The expression of TCTP, GST3, Hsp70, Hsp27 mRNA were all up-regulated in juveniles with a dose-dependent manner exposed to MeHg. These results suggest that large yellow croaker juveniles have the potential to regulate the levels of antioxidant enzymes and initiate immune response in order to protect fish to some extent from oxidative stress induced by MeHg.

Developing new visible light-triggered fluorescent molecular photoswitches is highly desirable for potential application in the fields of photoresponsive optoelectronics and photopharmacology. In this contribution, two novel tetra-/triphenylethene-dithienylethene-BF2bdk triads (TDB1 and TDB2) have been designed and prepared by appending tetra-/triphenylethene and BF2bdk moieties at the termini of dithienylethene unit. Before irradiation with blue light at 460-470 nm, they showed an intense emission in solution and in the PMMA film state, suggesting that the AIE effect of tetra-/triphenylethene was inhibited, and functioned only as electron-donating groups. Moreover, upon alternating irradiation with blue/NIR light, TDB1 and TDB2 displayed effective fluorescent switching behaviors and NIR photochromism in toluene and the PMMA film. Therefore, they would be utilized as novel visible light-triggered switches integrated in smart optoelectronic materials. The DFT calculations further validate the differences for their optical properties in the experiments.

Background: Endotracheal tube (ETT) is often necessary to achieve airway control during general anesthesia. Recent studies have showed that sore throat following endotracheal intubation is a common complaint after surgery. The objective of this systematic review and meta-analysis was to estimate whether ETT cuff pressure affects the incidence of postoperative sore throat (POST) after general anesthesia.Methods: The following databases were searched electronically: PubMed (updated to Nov 2015), EMBASE (updated to Nov 2015), World Health Organization International Clinical Trials Registry Platform (updated to Jul 2015), Chinese BioMedical Literature Database (1978 to Oct 2015), and China National Knowledge Infrastructure (1994 to Oct 2015). Trials comparing EET cuff pressure for elective surgery were included.Results: Three trials with a total of 609 patients were included in current analysis. Pool results from these trials showed that a lower ETT cuff pressure significantly decreased the incidence of POST at 24 hours after surgery (relative ratio [RR]=0.76, 95% confidence interval [CI] 0.61-0.95, P

SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models. The tyrosine phosphatase SHP2 is a key mediator of receptor tyrosine kinase (RTK) signalling, as well as being important in immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth, and SHP2 is a potential, but so far elusive, therapeutic target in cancer. Pascal Fortin and colleagues report the development of a selective SHP2 inhibitor with drug-like properties. The inhibitor, SHP099, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation. It also suppresses RAS–ERK signalling to inhibit RTK-driven proliferation in human cancer cell lines and mouse tumour xenograft models. The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1,2,3,4,5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2,3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6,7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8,9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

In aquatic ecosystems, mercuric compounds are considered to be highly toxic to a great variety of aquatic biota ranging from bacteria to fishes. In the present study, the effects of different concentrations (0, 2.0, 6.0, 10.0, 14.0 and 18.0 μg·L − 1 ) of Hg 2 + on the life table demography of Brachionus calyciflorus were investigated at three densities (1.0 × 10 6 , 2.0 × 10 6 and 4.0 × 10 6 cells·mL − 1 ) of Scenedesmus obliquus . The results showed that compared to the controls, Hg 2 + at 14.0 and 18.0 μg·L − 1 significantly decreased both the average lifespan and the life expectancy at hatching, Hg 2 + at 2.0–18.0 μg·L − 1 shortened the generation time, and Hg 2 + at 18.0 μg·L − 1 decreased the net reproductive rate of B. calyciflorus cultured at 1.0 × 10 6 cells·mL − 1 of S. obliquus . Increase in algal food level reduced the negative effects of high concentrations of Hg 2 + on survival, reproduction and population growth of the rotifers. Hg 2 + at 6.0 μg·L − 1 , and 6.0 and 18.0 μg·L − 1 increased the intrinsic rate of population increase of the rotifers cultured at 1.0 × 10 6 and 2.0 × 10 6 cells·mL − 1 of S. obliquus , respectively. But Hg 2 + at 18.0 μg·L − 1 decreased the intrinsic rate of population increase of the rotifers cultured at 4.0 × 10 6 cells·mL − 1 of S. obliquus . Significantly nominal concentration–response relationships existed between Hg 2 + concentration and each of all the five life history variables of B. calyciflorus cultured at 1.0 × 10 6 cells·mL − 1 of S. obliquus , the generation time of the rotifers cultured at 2.0 × 10 6 cells·mL − 1 of S. obliquus , as well as the intrinsic rate of population increase of the rotifers cultured at 4.0 × 10 6 cells·mL − 1 of S. obliquus . Among all the life history variables, generation time was the most sensitive to mercury pollution. Since algal levels chosen in the present study are much higher than those available in natural waters, except in eutrophic water bodies, the effects of mercury on survival, reproduction and population growth of the rotifers in natural waters may be more severe than those extrapolated from the present study.

This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used forin vivoexperiments and human proximal tubular cells (HK2 cells) were used forin vitroexperiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, andα-SMA proteins.In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2,α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway.

Summary This study investigated ten polyphenolic compounds in the peel of 145 apple cultivars grown in the same location while originated from different countries over two successive years. Despite significant year effect of individual and total polyphenol concentrations on each cultivar, both concentrations showed similar distributions in the 2 years, and genotypic correlations among them were relatively stable. Genotypic variations were considerable, with total polyphenol concentration ranging from 363.9 to 2516.9 μg g−1 FW. Cyanidin-3-galactoside was found only in red apple peels, at levels of 67.8–371.6 μg g−1 FW. Flavanols (epicatechin and catechin) and dihydrochalcones (mainly phloridzin) accounted for 8.8–66.1% and 8.58–61.2% of total polyphenols, respectively. Six flavonols (quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside, quercetin-3-xyloside, quercetin-3-arabinoside, and quercetin-3-rhamnoglucoside) were identified. The proportion of flavonols was 9.3–70.6% of total polyphenols. This wide variation could help in selecting cultivars with different polyphenol patterns in the peel. Principal component analysis showed that cultivars originated from different countries could not be distinguished in terms of polyphenol profiles.

Pollinating butterflies are an important asset to agriculture, which still depends on wild resources. Yunnan Province in Southwest China is a region with typical montane agriculture, but this resource is poorly investigated. From literature reference and specimen examination, the present study identified 554 species of pollinating butterflies (50.8% of the total butterflies) from Yunnan, with family Nymphalidae possessing the least number of pollinators (80 species, 16.0%), while the remaining four families are pollinator-rich (&gt, 73%). Tropical lowlands and mountain-valley areas possess higher species richness than those with plain terrains. The species richness of pollinating butterflies in Yunnan does not simply decline with the increase of latitude, nor is significantly different between West and East Yunnan. Zonation of pollinating butterflies using the parsimony analysis of endemicity (PAE) identified nine distribution zones and ten subzones. Most areas of endemism (AOE) are found in lowlands or mountain-valley areas, complexity of terrains, climates, and vegetation types are believed to be the main causes of such endemicity. The potential pollinating service of these butterflies could be great to montane agriculture with expanding areas of cash crops and fruit horticulture. Conservation strategies for pollinating butterflies may consist of preserving habitats and establishing butterfly-friendly agriculture based on local traditions.

Itch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.