Urea Fertilization Significantly Promotes Nitrous Oxide Emissions from Agricultural Soils and Is Attributed to the Short-Term Suppression of Nitrite-Oxidizing Bacteria during Urea Hydrolysis.

The application of urea in agricultural soil significantly boosts nitrous oxide (N2O) emissions. However, the reason for nitrite accumulation, the period of nitrite-oxidizing bacteria (NOB) suppression, and the main NOB species for nitrite removal behind urea fertilization have not been thoroughly investigated. In this study, four laboratory microcosm experiments were conducted to simulate urea fertilization in agricultural soils. We found that within 36 h of urea application, nitrite oxidation lagged behind ammonia oxidation, leading to nitrite accumulation and increased N2O emissions. However, after 36 h, NOB activity recovered and then removed nitrite, leading to reduced N2O emissions. Urea use resulted in an N2O emission rate tenfold higher than ammonium. During incubation, Nitrobacter-affiliated NOB growth decreased initially but increased later with urea use, while Nitrospira-affiliated NOB appeared unaffected. Chlorate suppression of NOB lasted longer, increasing N2O emissions. Urease inhibitors effectively reduced N2O emissions by slowing urea hydrolysis and limiting free ammonia production, preventing short-term NOB suppression. In summary, short-term NOB suppression during urea hydrolysis played a crucial role in increasing N2O emissions from agricultural soils. These findings revealed the reasons behind the surge in N2O emissions caused by extensive urea application and provided guidance for reducing N2O emissions in agricultural production processes.

DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.

Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.

Synthesis, evaluation and molecular dynamics study of human toll-like receptor 2/6 specific monoacyl lipopeptides as candidate immunostimulants.

TLR2 agonists typified by the S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (Pam2CS) motif have exhibited powerful immunostimulatory activities. Based on simplified monoacyl lipopeptide (Carbamate-linked N-Ac PamCS), we describe interesting SAR investigations where modifications are done to alter the size of substituents on the cysteine amine, introduce ionizable groups to the terminal and insert aromatic substitutions to the aliphatic chain. Our structural modifications have led to a highly specific human TLR2/6 agonist 14a (EC50 = 0.424 nM), which behaves like Pam2CSK4 by inducing NF-κB activation to trigger downstream signaling pathways, such as subsequent phosphorylation of related proteins (p65, p38) and production of key inflammatory cytokines (IL-6, IL-1ß, TNF-α). Importantly, the ability to stimulate enhanced T cell response compared to Carbamate-linked N-Ac PamCS makes compound 14a a further potential candidate immunostimulant.

Hyperglycemia disturbs trophoblast functions and subsequently leads to failure of uterine spiral artery remodeling.

Uterine spiral artery remodeling is necessary for fetal growth and development as well as pregnancy outcomes. During remodeling, trophoblasts invade the arteries, replace the endothelium and disrupt the vascular smooth muscle, and are strictly regulated by the local microenvironment. Elevated glucose levels at the fetal-maternal interface are associated with disorganized placental villi and poor placental blood flow. Hyperglycemia disturbs trophoblast proliferation and invasion via inhibiting the epithelial-mesenchymal transition, altering the protein expression of related proteases (MMP9, MMP2, and uPA) and angiogenic factors (VEGF, PIGF). Besides, hyperglycemia influences the cellular crosstalk between immune cells, trophoblast, and vascular cells, leading to the failure of spiral artery remodeling. This review provides insight into molecular mechanisms and signaling pathways of hyperglycemia that influence trophoblast functions and uterine spiral artery remodeling.

Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation.

Fatty-acid binding protein 4 (FABP4) is an essential driver for the progression of metabolic-related inflammatory diseases including obesity, diabetes, atherosclerosis, and various lipid metabolism-related tumors. However, FABP4 inhibitors are not yet available for clinical use, which may be associated with their poor selectivity of FABP3, unsatisfactory efficacy and physicochemical properties. Herein, we reported a systematic optimization of a class of biphenyl scaffold molecules as potent FABP4 inhibitors. Further in vitro and in vivo pharmacokinetic studies identified a selective and orally bioavailable compound 10g, with Ki of 0.51 µM against FABP4, Ki of 33.01 µM against FABP3 and bioavailability F% value of 89.4%. In vivo anti-inflammatory efficacy and multi-organ protection study in LPS-induced inflammatory mice model highlighted the potential of compound 10g as a therapeutic candidate in inflammation-related diseases.

LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion.

Dysregulated trophoblast proliferation, invasion, and apoptosis may cause several pregnancy-associated complications, such as unexplained recurrent spontaneous abortion (URSA). Recent studies have shown that metabolic abnormalities, including glycolysis inhibition, may dysregulate trophoblast function, leading to URSA. However, the underlying mechanisms remain unclear. Herein, we found that lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, was significantly reduced in the placental villus of URSA patients. The human trophoblast cell line HTR-8/SVneo was used to investigate the possible LDHA-mediated regulation of trophoblast function. LDHA knockdown in HTR-8/SVneo cells induced G0/G1 phase arrest and increased apoptosis, whereas LDHA overexpression reversed these effects. Next, RNA sequencing combined with Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the PI3K/AKT signaling pathway is potentially affected by downstream genes of LDHA. Especially, we found that LDHA knockdown decreased the phosphorylation levels of PI3K, AKT, and FOXO1, resulting in a significant downregulation of CyclinD1. In addition, treatment with an AKT inhibitor or FOXO1 inhibitor also verified that the PI3K/AKT/FOXO1 signaling pathway influenced the gene expression of CyclinD1 in trophoblast. Moreover, p-AKT expression correlated positively with LDHA expression in syncytiotrophoblasts and extravillous trophoblasts in first-trimester villus. Collectively, this study revealed a new regulatory pathway for LDHA/PI3K/AKT/FOXO1/CyclinD1 in the trophoblast cell cycle and proliferation.

Identification and immunological evaluation of novel TLR2 agonists through structural optimization of Diprovocim.

As an important family member of Toll-like receptors (TLRs), TLR2 can recognize various pathogen-associated molecular patterns (PAMPs) such as bacteria and viral components. Accumulating evidence demonstrates that TLR2 agonists play a critical role in cancer immunotherapy and infectious diseases. Diprovocim is the most potent small molecule TLR2 agonist known, showing remarkably immune adjuvant activity in mice. However, the further clinical research and development of Diprovocim was hampered because of its structural complexity as well as high molecular weight. Here, we designed and synthesized 21 structurally simplified derivatives of Diprovocim, performed their TLR2 agonistic activities by HEK-Blue hTLR2 SEAP assay, and evaluated the toxicity in two human normal cell lines. Compounds B3-B4 and B9-B12 with excellent TLR2 agonistic activity were found through the structure-activity relationship study. Among them, diastereomer B10 and B12 substituted (S)-2-phenylcyclopropylamide side chain of Diprovocim with simple (R)- and (S)-n-butyl groups exhibited comparable TLR2 agonistic activities with EC50 values of 35 nM and 39 nM, respectively. ELISA and western blot experiments on THP-1 cells showed that B10 and B12 displayed remarkable immunostimulatory activity in the release of various inflammatory cytokines through activating MyD88-dependent NF-κB and MAPK signaling pathways. Importantly, B10 and B12 have less structural complexity and better safety compared to Diprovocim, and the chiral center of right pyrrolidine ring has negligible influence on TLR2 activition. Our study provides simplified Diprovocim derivatives with high agonistic activity, providing a clue to further optimize Diprovocim.

Synthesis of Isoquinolone, 1,2-Benzothiazine, and Naphtho[1',2':4,5]imidazo[1,2-a]pyridine Derivatives via Rhodium(III)-Catalyzed (4 + 2) Annulation.

In this study, we report a novel and efficient synthetic method to construct isoquinolone scaffold via the Rh(III)-catalyzed (4 + 2) annulation of benzamide with an unreported coupling reagent methyl 2-chloroacrylate. Accordingly, other valuable 1,2-benzothiazine and naphtho[1',2':4,5]imidazo[1,2-a]pyridine derivatives are also obtained through a similar synthetic protocol. Thus, our developed method is highlighted by high yield and reaction versatility.

The potential toxicity of polystyrene nanoplastics to human trophoblasts in vitro.

Nanoplastics (NPs), the emerging contaminants in recent years, widely distributed in the environment and are bioaccumulated and biomagnified in organisms through food chain. A growing number of studies have detected plastic particulates in human placenta and blood. However, few studies have focused on their effects during human pregnancy. Herein, human trophoblast HTR-8/Svneo cells were used to evaluate the effects and the possible mechanism of 100-nm polystyrene NPs on placental trophoblasts at the maternal-fetal interface. The results showed that NPs entered the trophoblastic cytoplasm, decreased cell viability, caused cell cycle arrest, reduced the cell migration and invasion abilities, increased level of intracellular reactive oxygen species and the production of proinflammatory cytokines (TNF-α and IFN-γ) in a dose-dependent manner. Furthermore, global transcriptome sequencing (RNA-Seq) was performed on HTR-8/Svneo cells with or without 100 µg/mL PS-NP exposure for 24 h. A total of 344 differentially expressed genes were detected. The gene functions for regulation of leukocyte differentiation, response to stimulus, cell cycle, apoptotic process, and cell adhesion were enriched. Thyroid hormone, Hippo, TGF-ß and FoxO signaling pathways were activated. Collectively, our data provided evidences for the adverse consequences of NPs on the biological functions of trophoblasts, which provided new insights into the potential trophoblast toxicity of NPs in mammals.

Perioperative lymphocyte-to-monocyte ratio changes plus CA199 in predicting the prognosis of patients with gastric cancer.

Background: This study aimed to investigate the value of perioperative lymphocyte-to-monocyte ratio (LMR) changes in predicting postoperative survival among patients undergoing radical gastrectomy, and explore whether the combination of preoperative carbohydrate antigen 199 (CA199) and LMR changes would further improve the prognostic accuracy. Methods: A total of 456 patients who underwent radical gastrectomy at the Affiliated Hospital of Nantong University were included as the training set, and 210 patients from the Nantong Tumor Hospital were enrolled as the validation set. The patients' peripheral complete blood counts, including lymphocytes, monocytes, and tumor marker CA199 level, were checked regularly in all patients 1 week before and after radical gastrectomy by two technicians who were blinded to their clinical characteristics. The LMR was calculated by dividing the lymphocyte count by the monocyte count in the peripheral blood. ΔLMR could be obtained by subtracting the preoperative LMR from the postoperative LMR. The serum CA199 level was determined through a latex immunoassay (Mitsubishi Chemical Ltd., Japan). The survival curve was drawn according to the Kaplan-Meier method, and variables with P<0.05 in univariate analyses were transferred to multivariate Cox regression analysis. A nomogram was constructed using the finalized separated prognostic factors of gastric cancer (GC). The main prognostic indicator was overall survival (OS). Results: In the training and validation sets, the prognostic predictive ability of CA199 and ΔLMR (postoperative LMR minus preoperative LMR) was independently evaluated (both P<0.05). ΔLMR and CA199 were used to establish the ΔLMR-CA199 score. The results showed that the higher the ΔLMR-CA199 risk score, the worse the prognosis, especially in patients with advanced GC. Postoperative adjuvant chemotherapy improved the long-term prognosis of patients with a ΔLMR-CA199 score of 1 but had no significant effect on the survival rate of patients with 0 and 2 points. Conclusions: ΔLMR-CA199 can better predict the long-time survival of patients with GC. In addition, it can also predict the response of postoperative adjuvant chemotherapy in patients with GC.

Discovery of non-substrate, environmentally sensitive turn-on fluorescent probes for imaging HDAC8 in tumor cells and tissue slices.

Histone deacetylase 8 (HDAC8) is overexpressed in multiple cancers and lack of effective chemical probes which could detect and visualize HDAC8 in tumor cells and tissues remains unsolved. In this work, three novel turn-on HDAC8 fluorescent probes 17-19 derived from solvatochromic fluorophore 4-sulfamonyl-7-aminobenzoxadiazole (SBD) conjugating with a potent HDAC8 inhibitor PCI-34051 (IC50 = 10 nM) as the recognition group were fabricated. The probes exhibited much stronger fluorescence when they transfer from hydrophilic environment (Φ < 8%) to hydrophobic environment (Φ > 46%). Compared with PCI-34051 (KD = 9.16 × 10-6 M), probes 17 (KD = 5.37 × 10-6 M), 18 (KD = 3.57 × 10-6 M) and 19 (KD = 8.89 × 10-6 M) possessed slightly better affinity for HDAC8. Probe 19 was selected for cell imaging and it showed significantly enhanced fluorescence only after binding into the cavity of HDAC8 in SH-SY5Y and MDA-MB-231 tumor cells. Co-localization results demonstrated that HDAC8 is expressed in cytoplasm and nucleus. Furthermore, probe 19 was successfully utilized to distinguish the expression level of HDAC8 in SH-SY5Y tumor and normal tissue slices.

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.

Prognostic Value of the Combination of HB (hemoglobin) and CEA in Resectable Gastric Cancer.

Objective: In order to investigate the prognostic value of a novel biomarker combining serum carcinoembryonic antigen (CEA) and hemoglobin (HB) levels in patients with resectable gastric cancer. Introduction: This retrospective study assessed the relationship between CEA, hemoglobin levels, a novel combined prognostic biomarker (HB-CEA) and clinicopathological features of gastric cancer. Their prognostic values in gastric cancer were also analyzed. Materials and Methods: This retrospective study evaluated the CEA, hemoglobin levels and clinicopathological features of patients with resectable gastric cancer. Kaplan-Meier curves, univariate and multivariate Cox proportional models were used to determine the prognostic significance of these factors for overall survival (OS) in the training and validation sets (n=353 and n=388, respectively). Based on optimal cutoff values of CEA and hemoglobin (3.395 ng/mL and 125.5 g/L, respectively), patients were stratified into three groups: HB-CEA=0, 1, and 2 (CEA <3.395 ng/mL and HB ≥125.5 g/L; CEA ≥3.395 ng/mL or HB <125.5 g/L; and CEA ≥3.395 ng/mL and HB <125.5 g/L, respectively). Results: The area under the curve was larger for HB-CEA than for either HB or CEA alone (training set: 0.677, 0.650, and 0.629; validation set: 0.670, 0.605, and 0.605, respectively). HB-CEA was strongly associated with age, tumor size, differentiation, pathological TNM stage (pTNM), depth of tumor invasion, lymph node metastasis, and survival status (all p<0.05). A higher HB-CEA score correlated with poor survival (Kaplan-Meier curves, all p<0.05). Multivariate analysis showed that HB-CEA was an independent prognostic factor for OS (p<0.05). Conclusion: Preoperative HB-CEA, as a potential novel hematological biomarker, can predict the progression of gastric cancer and the prognosis of patients, and is of great value in guiding clinical practice. Therefore, patients with a higher HB-CEA score should receive more extensive follow-up for early detection and intervention of tumor progression.

Contrasting patterns of bacterial communities in the rearing water and gut of Penaeus vannamei in response to exogenous glucose addition.

Supplementing exogenous carbon sources is a practical approach to improving shrimp health by manipulating the microbial communities of aquaculture systems. However, little is known about the microbiological processes and mechanisms of these systems. Here, the effects of glucose addition on shrimp growth performance and bacterial communities of the rearing water and the shrimp gut were investigated to address this knowledge gap. The results showed that glucose addition significantly improved the growth and survival of shrimp. Although the α-diversity indices of both bacterioplankton communities and gut microbiota were significantly decreased by adding glucose, both bacterial communities exhibited divergent response patterns to glucose addition. Glucose addition induced a dispersive bacterioplankton community but a more stable gut bacterial community. Bacterial taxa belonging to Ruegeria were significantly enriched by glucose in the guts, especially the operational taxonomic unit 2575 (OTU2575), which showed the highest relative importance to the survival rate and individual weight of shrimp, with the values of 43.8 and 40.6%, respectively. In addition, glucose addition increased the complexity of interspecies interactions within gut bacterial communities and the network nodes from Rhodobacteraceae accounted for higher proportions and linked more with the nodes from other taxa in the glucose addition group than that in control. These findings suggest that glucose addition may provide a more stable gut microbiota for shrimp by increasing the abundance of certain bacterial taxa, such as Ruegeria. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00124-9.

Polystyrene microplastics disturb maternal-fetal immune balance and cause reproductive toxicity in pregnant mice.

Microplastics (MPs), which are emerging as a new type of environmental pollutants, have raised great concerns regarding their threats to human health. A successful pregnancy depends on the sophisticated regulation of the maternal-fetal immune balance, but the risks of polystyrene MP (PS-MP) exposure in early pregnancy remain unclear. In this study, we exposed the C57BL/6-mated BALB/c mice to PS-MP particles and used the flow cytometry to explore threats towards the immune system. Herein, the allogeneic mating murine model showed an elevated embryo resorption rate with a 10 µm PS-MP particle exposure during the peri-implantation period. Both the number and diameter of uterine arterioles decreased, which might reduce the uterine blood supply. Moreover, the percentage of decidual natural killer cells was reduced, whereas the helper T cells in the placenta increased. In addition, the M1/M2 ratio in macrophages reversed significantly to a dominant M2-subtype. Lastly, the cytokine secretion shifted towards an immunosuppressive state. Overall, our results demonstrated that PS-MPs have the potential to cause adverse effects on pregnancy outcomes via immune disturbance, providing new insights into the study of reproductive toxicity of MP particles in the human body.

Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.

The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 µM as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment.

Regulated delayed attenuation improves vaccine efficacy in preventing infection from avian pathogenic Escherichia coli O78 and Salmonella typhimurium.

Avian pathogenic Escherichia coli (APEC) O78 and Salmonella typhimurium (S. Typhimurium) are two leading bacterial pathogens that cause significant economic loss in the poultry industry. O-antigen is an important immunogen of these two bacteria to induce host protective immune responses during infection. To develop a bivalent vaccine against APEC O78 and S. Typhimurium, the attenuated Salmonella ST01 (Δasd ΔrfbP Δcrp) was genetically constructed to deliver APEC O78 O-antigen polysaccharide (OPS), which stably expresses OPS with asd+ balanced-lethal system in vitro and in vivo. After oral immunization, the recombinant attenuated Salmonella vaccine (RASV) strain ST01 (pSS26-O78) provided insufficient protection against the APEC O78 challenge. Therefore, the regulated delayed attenuation strain ST02 (Δasd ΔrfbP ΔPcrp::TTaraC PBADcrp) was further constructed by regulating cyclic AMP receptor protein (crp) with araC PBAD cassette to better present the heterologous O-antigen to the host immune system. The innovative recombinant strain ST02 (pSS26-O78) stimulated robust antibody responses against APEC O78 and S. Typhimurium OPS, with serum titers over 1:800 for both IgG and IgA, thereby providing the complement-mediated bactericidal activity and stronger protection against APEC O78 and S. Typhimurium infection. Collectively, this study demonstrates a biologically-conjugated polysaccharide vaccine candidate that can enhance homologous protection against APEC O78 and S. Typhimurium.

Online quantitative partial discharge monitor based on interferometry.

Interferometry-based online partial discharge (PD) monitor presented in this paper can detect the occurrence of PD sensitively, evaluate the peak value of the discharge inception voltage with random waveform and the damage extent relatively cost effectively. The interferograms affected by the PD are collected online. By extracting the phase information of the interference fringes quantitatively, the peak value of the discharge inception voltage with random waveform can be retrieved real-time. Merits of the proposed method as an online quantitative PD monitor are validated via theoretical analysis as well as experimentations by the use of an artificially localized PD source. Furthermore, the proposed method can capture the light signal emitted by the discharge. Quite in contrast to many commonly used sensor-based methods, our approach avoids the need of amplifying the light signal strength making its practical implantation much convenient. The proposed method promises strong potential for field application.

Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole.

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole's macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five-nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol. A molecular modeling study provided rational explanation and structural evidence for the enhanced inhibitory activity. This new finding will aid the design of novel potent HDAC inhibitors.

Effects of Carbon/Nitrogen Ratio on Growth, Intestinal Microbiota and Metabolome of Shrimp (Litopenaeus vannamei).

Increasing the C/N ratio of input feed has been reported as a practical approach for improving water quality and enhancing shrimp growth through changing the bacterial community of rearing water. However, little is known about the effects of different C/N ratios of feed input on the intestinal microbiota and metabolome of shrimp. In the present study, the effects of three different C/N ratio levels (CN6, CN10, and CN15) maintained by adding sucrose on the growth, intestinal microbiota and metabolome of Litopenaeus vannamei, and bioflocs formation were investigated after 17 days of feeding. The results indicated that higher C/N ratio (10 and 15), especially CN15, of feed input significantly enhance the length and weight of shrimp individuals accompanied by a significant accumulation of bioflocs, compared to that of CN6. The increase of C/N ratio input decreased the α-diversity of the intestinal microbiota and changed the microbial community structure through increasing the relative abundance of Actinobacteria, Rhodobacteraceae (mainly consist of Roseobacter and Paracoccus groups), Alteromonadaceae, and inhibiting the growth of Cyanobacteria, certain Rhodobacteraceae, Mycoplasmataceae and Vibrio. The change of microbial community caused by increasing C/N ratio input was closely associated with various bioactive metabolites of flavonoids, benzenoids, prenol lipids, and indole derivatives, which are benefit for shrimp growth either as an antimicrobial agent or as a nutrient component. Overall, this study demonstrated that manipulating high C/N ratio of feed input helps to the growth of shrimp through increasing the relative abundance of potential beneficial bacteria and the accumulation of various bioactive metabolites to suppress the growth of detrimental bacteria.