Identification of two miRNAs regulating cardiomyocyte proliferation in an Antarctic icefish.

The hemoglobinless Antarctic icefish develop large hearts to compensate for reduced oxygen-carrying capacity, which serves as a naturally occurred model to explore the factors regulating cardiogenesis. Through miRNAome and microRNAome comparisons between an icefish (Chionodraco hamatus) and two red-blooded notothenioids, we discovered significant upregulation of factors in the BMP signaling pathways and altered expression of many miRNAs, including downregulation of 14 miRNAs in the icefish heart. Through knocking down of these miRNAs, we identified two of them, miR-458-3p and miR-144-5p, involved in enlarged heart development. The two miRNAs were found to regulate cardiomyocyte proliferation by targeting bone morphogenetic protein-2 (bmp2). We further validated that activation of the miRNA-bmp2 signaling in the fish heart could be triggered by hypoxic exposure. Our study suggested that a few miRNAs play important roles in the hypoxia-induced cardiac remodeling of the icefish which shed new light on the mechanisms regulating cardiomyocyte proliferation in heart.

Anti-immunoglobulin E provides an additional therapy to conventional steroids for Kimura's disease.

Kimura's disease (KD) is a chronic inflammatory disease characterized by painless subcutaneous head and neck swelling, eosinophilia, and elevated serum immunoglobulin (Ig) E levels. There are various therapies, including surgery, radiation, systemic steroids, and immune suppressants, but their efficacy remains moderate due to the high recurrence rate. Biologics, like monoclonal antibodies, have shown tremendous effectiveness for chronic inflammatory diseases. Omalizumab is a monoclonal antibody against IgE and has not been approved for KD so far. We describe two refractory KD cases that responded to a small dose of steroids plus omalizumab. Additionally, we reviewed another 13 KD cases that were treated with biologics, including omalizumab, rituximab, dupilumab, and mepolizumab. The results indicate that biologics provide an alternative treatment strategy for KD.

Antibiotics and antibiotic resistance genes in the water sources of the Wuhan stretch of the Yangtze River: Occurrence, distribution, and ecological risks.

Given the ubiquitous detection of antibiotics and antibiotic resistance genes (ARGs) in waterbodies worldwide and increasing public attention to water resource safety, this study investigated the presence of antibiotics and ARGs in the water sources of the Wuhan stretch of the Yangtze River (YR) as well as potential ecological risks. In this study, 15 antibiotics and 10 ARGs in a source of drinking water were analyzed using solid-phase extraction-ultra performance liquid chromatography-mass spectrometry technology (SPE-UPLC-MS/MS) and real-time fluorescence quantitative polymerase chain reaction (qPCR). Fourteen antibiotics were detected in the samples from 18 water sources, with the highest concentration detected for tetracycline, reaching up to 1708.33 ng/L. The detection rates of norfloxacin, enrofloxacin, ofloxacin, tetracycline, and roxithromycin were 100%. The concentrations of antibiotics were highest in She Shui, followed by the Wuhan stretch of the lower reaches of the YR, whereas the lowest concentrations were found in the Wuhan stretch of the upper reaches of the YR which were approximately equal to those in the Han River (HR). Ofloxacin and roxithromycin presented a substantial threat to aquatic organisms with high sensitivity at the majority of the sampling sites. The overall abundance of ARGs was notably greater in the lower reaches of the YR compared with the upper reaches and the HR. The highest absolute abundance was observed for sulfa ARGs. Integron intl1 strongly correlated with sul1, sul2, ermB, and qnrS, and antibiotics, strongly correlated with multiple ARGs, suggesting that antibiotics and ARGs are present in water sources in Wuhan and may present a plausible hazard to both human and ecological well-being. Hence, regulating the spread and dissemination of antibiotics and ARGs in the environment is imperative. The findings of this research offer significant insights into the stewardship and safeguarding of aquatic reserves in the Wuhan stretch of the YR.

Efficacy and associated neurotransmitters of digital cognitive behavior therapy for atopic dermatitis: A comparative effectiveness research.

BACKGROUND: Negative emotions are a major comorbidity of atopic dermatitis (AD). Evidence that supports the effectiveness of digital cognitive behavioral therapy (dCBT) as an adjuvant therapy for AD remains limited. OBJECTIVE: To investigate the preliminary efficacy of additional dCBT and potential neurotransmitter biomarkers for AD accompanied by negative emotions. METHODS: Thirty-two patients with AD were recruited and examined for clinical severity and negative emotions including insomnia, anxiety, and depression. Patients with mild-to-moderate negative emotions were divided into two groups that received standard care (N = 9) or mobile app-delivered CBT plus standard care (N = 11) for 12 weeks. Plasma levels of 40 neurotransmitters were determined using liquid chromatography tandem mass spectrometry pre- and post-treatment. RESULTS: Skin lesions, itch, and insomnia were significantly improved in both treatment groups. Improvements of itch (P = 0.0449) and insomnia (P = 0.0089) were more robust in the combination treatment group than those in the standard treatment group. Neurotransmitters that involve tryptophan, dopamine, and histidine pathways were markedly altered in patients with AD compared with healthy controls. Taurine levels were selectively increased following dCBT plus standard care (P = 0.0259). Baseline levels of L-tyrosine were negatively correlated with the reduction of skin lesions (r = -0.9073, P = 0.0334) and itch intensity (r = -0.9322, P = 0.0210) in the combination therapy group. CONCLUSIONS: dCBT provides an efficacious supplementary approach for AD accompanied by negative emotions. Emotion-related neurotransmitters may contribute to AD and serve as indicators for treatment effects.

Reduced expression of CXCL16/CXCR6 is involved in the pathogenesis of hidradenitis suppurativa.

Mutations in the γ-secretase complex have been well-described in familial hidradenitis suppurativa (HS). No gene mutations have been identified in sporadic HS, which comprises 60%-70% of all HS cases. Obesity and smoking are risk factors for HS and are closely related to DNA methylation, an essential epigenetic phenomenon. Hence, we hypothesized that epigenetic modifications might be involved in sporadic HS. To investigate genes with aberrant methylation in sporadic HS cases and assess their expression in skin lesions and blood from patients with HS. Skin lesion samples and corresponding normal skin were obtained from three patients with HS and subjected to whole-genome DNA methylation sequencing. Blood samples were collected from 20 patients with HS and 20 healthy controls (HCs). The HS mouse model was established by applying tamoxifen to NcstnΔKC mice. Target gene expression was analysed by immunohistochemistry, immunofluorescence, western blotting, enzyme-linked immunosorbent assay (ELISA) and semiquantitative real-time polymerase chain reaction (RT-qPCR). Among 10 807 differentially methylated genes, we filtered 2101 genes with hypermethylated promoter regions, and following bioinformatics analyses, we focused on CXC chemokine ligand 16 (CXCL16). Subsequent functional experiments confirmed the downregulation of CXCL16 and its receptor, CXC chemokine receptor (CXCR) 6, in skin tissue from HS patients and NcstnΔKC mice. Serum CXCL16 concentrations were also significantly decreased in patients with HS. Our data revealed the downregulation of CXCL16 and CXCR6 in HS.

Population genomics of an icefish reveals mechanisms of glacier-driven adaptive radiation in Antarctic notothenioids.

BACKGROUND: Antarctica harbors the bulk of the species diversity of the dominant teleost fish suborder-Notothenioidei. However, the forces that shape their evolution are still under debate. RESULTS: We sequenced the genome of an icefish, Chionodraco hamatus, and used population genomics and demographic modelling of sequenced genomes of 52 C. hamatus individuals collected mainly from two East Antarctic regions to investigate the factors driving speciation. Results revealed four icefish populations with clear reproduction separation were established 15 to 50 kya (kilo years ago) during the last glacial maxima (LGM). Selection sweeps in genes involving immune responses, cardiovascular development, and photoperception occurred differentially among the populations and were correlated with population-specific microbial communities and acquisition of distinct morphological features in the icefish taxa. Population and species-specific antifreeze glycoprotein gene expansion and glacial cycle-paced duplication/degeneration of the zona pellucida protein gene families indicated fluctuating thermal environments and periodic influence of glacial cycles on notothenioid divergence. CONCLUSIONS: We revealed a series of genomic evidence indicating differential adaptation of C. hamatus populations and notothenioid species divergence in the extreme and unique marine environment. We conclude that geographic separation and adaptation to heterogeneous pathogen, oxygen, and light conditions of local habitats, periodically shaped by the glacial cycles, were the key drivers propelling species diversity in Antarctica.

Toll-Like Receptor Evolution: Does Temperature Matter?

Toll-like receptors (TLRs) recognize conserved pathogen-associated molecular patterns (PAMPs) and are an ancient and well-conserved group of pattern recognition receptors (PRRs). The isolation of the Antarctic continent and its unique teleost fish and microbiota prompted the present investigation into Tlr evolution. Gene homologues of tlr members in teleosts from temperate regions were present in the genome of Antarctic Nototheniidae and the non-Antarctic sister lineage Bovichtidae. Overall, in Nototheniidae apart from D. mawsoni, no major tlr gene family expansion or contraction occurred. Instead, lineage and species-specific changes in the ectodomain and LRR of Tlrs occurred, particularly in the Tlr11 superfamily that is well represented in fish. Positive selective pressure and associated sequence modifications in the TLR ectodomain and within the leucine-rich repeats (LRR), important for pathogen recognition, occurred in Tlr5, Tlr8, Tlr13, Tlr21, Tlr22, and Tlr23 presumably associated with the unique Antarctic microbiota. Exposure to lipopolysaccharide (Escherichia coli O111:B4) Gram negative bacteria did not modify tlr gene expression in N. rossii head-kidney or anterior intestine, although increased water temperature (+4°C) had a significant effect.

A symbiotic bacterium of Antarctic fish reveals environmental adaptability mechanisms and biosynthetic potential towards antibacterial and cytotoxic activities.

Antarctic microbes are important agents for evolutionary adaptation and natural resource of bioactive compounds, harboring the particular metabolic pathways to biosynthesize natural products. However, not much is known on symbiotic microbiomes of fish in the Antarctic zone. In the present study, the culture method and whole-genome sequencing were performed. Natural product analyses were carried out to determine the biosynthetic potential. We report the isolation and identification of a symbiotic bacterium Serratia myotis L7-1, that is highly adaptive and resides within Antarctic fish, Trematomus bernacchii. As revealed by genomic analyses, Antarctic strain S. myotis L7-1 possesses carbohydrate-active enzymes (CAZymes), biosynthetic gene clusters (BGCs), stress response genes, antibiotic resistant genes (ARGs), and a complete type IV secretion system which could facilitate competition and colonization in the extreme Antarctic environment. The identification of microbiome gene clusters indicates the biosynthetic potential of bioactive compounds. Based on bioactivity-guided fractionation, serranticin was purified and identified as the bioactive compound, showing significant antibacterial and antitumor activity. The serranticin gene cluster was identified and located on the chrome. Furthermore, the multidrug resistance and strong bacterial antagonism contribute competitive advantages in ecological niches. Our results highlight the existence of a symbiotic bacterium in Antarctic fish largely represented by bioactive natural products and the adaptability to survive in the fish living in Antarctic oceans.

Specific immunity proteomic profile of the skin mucus of Antarctic fish Chionodraco hamatus and Notothenia coriiceps.

The white-blooded Antarctic icefish is the only known vertebrate lacking oxygen-transporting haemoglobins. Fish skin mucus, as the first line of defence against pathogens, can reflect fish welfare. In this study, we analysed the skin mucus proteome profiles of the two Antarctic fish species, the white-blooded Antarctic icefish, Chionodraco hamatus, and the red-blooded Antarctic fish, Notothenia coriiceps, unfolding the different proteins by liquid chromatography coupled with tandem mass spectrometry isobaric tags for relative and absolute quantitation (iTRAQ) technology. Of the 4444 totally identified proteins, 227 differentially expressed proteins (DEPs) were found in the comparison between C. hamatus and N. coriiceps, of which 121 were upregulated and 106 were downregulated in the icefish. In the Kyoto Encyclopedia of Genes and Genomes pathway annotation, we found two pathways "Legionellosis" and "Complement and coagulation cascades" were significantly enriched, among of which innate immune candidate proteins such as C3, CASP1, ASC, F3 and C9 were significantly upregulated, suggesting their important roles in C. hamatus immune system. Additionally, the DEP protein-protein interaction network analysis and "Response to stress" GO category provided candidate biomarkers for deep understanding of the distinct immune response of the two Antarctic fish underlying the cold adaptation.

Cu2+-Regulated reversible coordination interaction of GQD@Tb/GMP ICP nanoparticles: towards directly monitoring cerebrospinal acetylcholinesterase as a biomarker for cholinic brain dysfunction.

This work demonstrates a new strategy for sensing cerebrospinal acetylcholinesterase (AChE) as a cholinergic biomarker for brain dysfunction based on graphene quantum dot (GQD)-functionalized lanthanide infinite coordination polymer (Ln-ICP) nanoparticles. The ICPs used in this work were comprised of two components, i.e. a supramolecular Ln-ICP host formed by the coordination between the GMP ligand and central metal ion Tb3+, and guest GQDs with abundant functional groups, which were utilized as antenna ligands to further sensitize the fluorescence of Tb/GMP. Upon excitation at 300 nm, the obtained GQD@Tb/GMP ICP nanoparticles exhibited enhanced green fluorescence from Tb/GMP. With the addition of Cu2+, the competitive coordination between Cu2+ and GQDs weakened the antenna effect, leading to a decrease in the fluorescence of GQD@Tb/GMP ICPs. However, in the presence of thiocholine (TCh), a thiol-containing compound hydrolyzed from acetylthiocholine (ATCh) by AChE, a stronger coordination interaction between Cu2+ and TCh occurred, resulting in the restoration of the fluorescence of GQD@Tb/GMP ICPs. Using the method established herein, the cerebrospinal AChE fluctuation of rats with acute organophosphorus pesticide (OP) poisoning or chronic Alzheimer's disease (AD) could be monitored. This study essentially provides a novel approach to realize the direct monitoring of a biomarker for brain dysfunction by regulating the competitive coordination interaction reversibly, which is critical in the early diagnosis and therapy of brain diseases.

A Potential Role for the Gsdf-eEF1α Complex in Inhibiting Germ Cell Proliferation: A Protein-Interaction Analysis in Medaka (Oryzias latipes) From a Proteomics Perspective.

Gonadal soma-derived factor (gsdf) has been demonstrated to be essential for testicular differentiation in medaka (Oryzias latipes). To understand the protein dynamics of Gsdf in spermatogenesis regulation, we used a His-tag "pull-down" assay coupled with shotgun LC-MS/MS to identify a group of potential interacting partners for Gsdf, which included cytoplasmic dynein light chain 2, eukaryotic polypeptide elongation factor 1 alpha (eEF1α), and actin filaments in the mature medaka testis. As for the interaction with transforming growth factor ß-dynein being critical for spermatogonial division in Drosophila melanogaster, the physical interactions of Gsdf-dynein and Gsdf-eEF1α were identified through a yeast 2-hybrid screening of an adult testis cDNA library using Gsdf as bait, which were verified by a paired yeast 2-hybrid assay. Coimmunoprecipitation of Gsdf and eEF1α was defined in adult testes as supporting the requirement of a Gsdf and eEF1α interaction in testis development. Proteomics analysis (data are available via ProteomeXchange with identifier PXD022153) and ultrastructural observations showed that Gsdf deficiency activated eEF1α-mediated protein synthesis and ribosomal biogenesis, which in turn led to the differentiation of undifferentiated germ cells. Thus, our results provide a framework and new insight into the coordination of a Gsdf (transforming growth factor ß) and eEF1α complex in the basic processes of germ cell proliferation, transcriptional and translational control of sexual RNA, which may be fundamentally conserved across the phyla during sexual differentiation.

Modulation of the MAPKs pathways affects Aß-induced cognitive deficits in Alzheimer's disease via activation of α7nAChR.

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aß1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aß-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aß internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aß-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aß-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aß-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts.

Ultraviolet (UV) irradiation from the sunlight is a major etiologic factor for premature skin aging. Long noncoding RNAs (lncRNAs) are involved in various biological processes, and their roles in UV irradiation-induced skin aging have recently been described. Previously, we found that the lncRNA RP11-670E13.6 was up-regulated and delayed cellular senescence in UVB-irradiated primary human dermal fibroblasts. Here, we performed further investigations of RP11-670E13.6 function. The results showed that this lncRNA directly bound to miR-663a and functioned as a sponge for miR-663a to modulate the derepression of Cdk4 and Cdk6, thereby delaying cellular senescence during UV irradiation-induced skin photoaging. Moreover, we found that RP11-670E13.6 may facilitate DNA damage repair by increasing ATM and γH2A.X levels. In addition, heterogeneous nuclear ribonucleoprotein H physically interacted with RP11-670E13.6 and blocked its expression. Collectively, our results suggested that the RP11-670E13.6/miR-663a/CDK4 and RP11-670E13.6/miR-663a/CDK6 axis, which may function as competitive endogenous RNA networks, played important roles in UVB-induced cellular senescence.

The genomic basis for colonizing the freezing Southern Ocean revealed by Antarctic toothfish and Patagonian robalo genomes.

BACKGROUND: The Southern Ocean is the coldest ocean on Earth but a hot spot of evolution. The bottom-dwelling Eocene ancestor of Antarctic notothenioid fishes survived polar marine glaciation and underwent adaptive radiation, forming >120 species that fill all water column niches today. Genome-wide changes enabling physiological adaptations and the rapid expansion of the Antarctic notothenioids remain poorly understood. RESULTS: We sequenced and compared 2 notothenioid genomes-the cold-adapted and neutrally buoyant Antarctic toothfish Dissostichus mawsoni and the basal Patagonian robalo Eleginops maclovinus, representing the temperate ancestor. We detected >200 protein gene families that had expanded and thousands of genes that had evolved faster in the toothfish, with diverse cold-relevant functions including stress response, lipid metabolism, protein homeostasis, and freeze resistance. Besides antifreeze glycoprotein, an eggshell protein had functionally diversified to aid in cellular freezing resistance. Genomic and transcriptomic comparisons revealed proliferation of selcys-transfer RNA genes and broad transcriptional upregulation across anti-oxidative selenoproteins, signifying their prominent role in mitigating oxidative stress in the oxygen-rich Southern Ocean. We found expansion of transposable elements, temporally correlated to Antarctic notothenioid diversification. Additionally, the toothfish exhibited remarkable shifts in genetic programs towards enhanced fat cell differentiation and lipid storage, and promotion of chondrogenesis while inhibiting osteogenesis in bone development, collectively contributing to the achievement of neutral buoyancy and pelagicism. CONCLUSIONS: Our study revealed a comprehensive landscape of evolutionary changes essential for Antarctic notothenioid cold adaptation and ecological expansion. The 2 genomes are valuable resources for further exploration of mechanisms underlying the spectacular notothenioid radiation in the coldest marine environment.

Protective effects of tanshinone IIA on SH-SY5Y cells against oAß1-42-induced apoptosis due to prevention of endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress caused by ß-amyloid protein (Aß) may play an important role in the pathogenesis of Alzheimer disease (AD). Our previous data have indicated that tanshinone IIA (tan IIA) protected primary neurons from Aß induced neurotoxicity. To further explore the neuroprotection of tan IIA, here we study the effects of tan IIA on the ER stress response in oligomeric Aß1-42 (oAß1-42)-induced SH-SY5Y cell injury. Our data showed that tan IIA pretreatment could increase cell viability and inhibit apoptosis caused by oAß1-42. Furthermore, tan IIA markedly suppressed ER dilation and prevented oAß1-42-induced abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), activating transcription factor 6 (ATF6), as well as inhibited the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways. Moreover, tan IIA ameliorated oAß1-42-induced Bcl-2/Bax ratio reduction, prevented cytochrome c translocation into cytosol from mitochondria, reduced oAß1-42-induced cleavage of caspase-9 and caspase-3, suppressed caspase-3/7 activity, and increased mitochondrial membrane potential (MMP) and ATP content. Meanwhile, oAß1-42-induced cell apoptosis and activation of ER stress can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA). Taken together, these data indicated that tan IIA protects SH-SY5Y cells against oAß1-42-induced apoptosis through attenuating ER stress, modulating CHOP and JNK pathways, decreasing the expression of cytochrome c, cleaved caspase-9 and cleaved caspase-3, as well as increasing the ratio of Bcl-2/Bax, MMP and ATP content. Our results strongly suggested that tan IIA may be effective in treating AD associated with ER stress.

Activation of α7 nicotinic acetylcholine receptor alleviates Aß1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.

Amyloid ß peptide 1-42 (Aß1-42) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aß1-42-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aß1-42-induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The Aß degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aß1-42-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aß degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aß1-42-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.

The Presence or Absence of Intestinal Microbiota Affects Lipid Deposition and Related Genes Expression in Zebrafish (Danio rerio).

Understanding how intestinal microbiota alters energy homeostasis and lipid metabolism is a critical process in energy balance and health. However, the exact role of intestinal microbiota in the regulation of lipid metabolism in fish remains unclear. Here, we used two zebrafish models (germ-free and antibiotics-treated zebrafish) to identify the role of intestinal microbiota in lipid metabolism. Conventional and germ-free zebrafish larvae were fed with egg yolk. Transmission electron microscopy was used to detect the presence of lipid droplets in the intestinal epithelium. The results showed that, microbiota increased lipid accumulation in the intestinal epithelium. The mRNA sequencing technology was used to assess genes expression level. We found majority of the differentially expressed genes were related to lipid metabolism. Due to the limitation of germ-free zebrafish larvae, antibiotics-treated zebrafish were also used to identify the relationship between the gut microbiota and the host lipid metabolism. Oil-red staining showed antibiotics-treated zebrafish had less intestinal lipid accumulation than control group. The mRNA expression of genes related to lipid metabolism in liver and intestine was also quantified by using real-time PCR. The results indicated that apoa4, hsl, cox15, slc2a1a, and lss were more related to intestinal bacteria in fish, while the influence of intestinal microbiota on the activity of fabp6, acsl5, cd36, and gpat2 was different between the liver and intestine. This study identified several genes regulated by intestinal microbiota. Furthermore, the advantages and disadvantages of each model have been discussed. This study provides valuable information for exploring host-microbiota interactions in zebrafish in future.

Environmental concentrations of antibiotics impair zebrafish gut health.

Antibiotics have been widely used in human and veterinary medicine to both treat and prevent disease. Due to their high water solubility and low bioavailability, many antibiotic residues have been found in aquatic environments. Fish are an indispensable link between the environmental pollution and human health. However, the chronic effects of environmental concentrations of antibiotics in fish have not been thoroughly investigated. Sulfamethoxazole (SMX) and oxytetracycline (OTC) are frequently detected in aquatic environments. In this study, zebrafish were exposed to SMX (260 ng/L) and OTC (420 ng/L) for a six-week period. Results indicated that exposure to antibiotics did not influence weight gain of fish but increased the metabolic rate and caused higher mortality when treated fish were challenged with Aeromonas hydrophila. Furthermore, exposure to antibiotics in water resulted in a significant decrease in intestinal goblet cell numbers, alkaline phosphatase (AKP), acid phosphatase (ACP) activities, and the anti-oxidant response while there was a significant increase in expression of inflammatory factors. Antibiotic exposure also disturbed the intestinal microbiota in the OTC-exposed group. Our results indicated that environmental antibiotic concentrations can impair the gut health of zebrafish. The potential health risk of antibiotic residues in water should be evaluated in the future.

The p38 mitogen activated protein kinase regulates ß-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular ß-amyloid protein (Aß) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aß caused cognition. It has high affinity with Aß and could mediate Aß internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aß internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aß is internalized by cholinergic and GABAergic neurons. The internalized Aß were found deposits in lysosomes/endosomes and mitochondria. Aß could form Aß-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aß internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aß-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aß. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.

Genetic Adaptation of Schizothoracine Fish to the Phased Uplifting of the Qinghai-Tibetan Plateau.

Many species of Schizothoracine, a subfamily of Cyprinidae, are highly endemic to the Qinghai-Tibetan Plateau (QTP). To characterize the adaptive changes associated with the Schizothoracine expansion at high altitudes, we sequenced tissue transcriptomes of two highland and two subhighland Schizothoracines and analyzed gene evolution patterns by comparing with lowland cyprinids. Phylogenetic tree reconstruction and divergence time estimation indicated that the common ancestor of Schizothoracine fish lived ∼32.7 million years ago (MYA), coinciding with the timing of the first phase of QTP uplifting. Both high- and subhigh-Schizothoracines demonstrated elevated dN/dS ratios in the protein-coding genes compared to lowland cyprinids, from which some biological processes implicated in altitude adaptation were commonly identified. On the other hand, the highland and subhighland lineages presented drastically divergent landscapes of positively selected genes (PSGs), enriched with very different gene ontology (GO) profiles, including those in "sensory organ morphogenesis," "regulation of protein ubiquitination," "blood circulation," and "blood vessel development." These results indicated different selection pressures imposed on the highland and subhighland lineages of the Schizothoracine subfamily, with a higher number of genes in the high-altitude species involved in adaptations such as sensory perception, blood circulation, and protein metabolism. Our study indicated divergent genetic adaptations in the aquatic species facing the phased uplifting of QTP.