Publications by authors named "Weijun Shen"

87 Publications

Soil chemical properties rather than the abundance of active and potentially active microorganisms control soil enzyme kinetics.

Sci Total Environ 2021 May 19;770:144500. Epub 2021 Jan 19.

College of Natural Resources and Environment, Northwest A&F University, Key Laboratory of Plant Nutrition and Agro-environment in Northwest China, Ministry of Agriculture, Yangling 712100, Shaanxi, China. Electronic address:

Soil enzymes secreted by microorganisms play a critical role in nutrient cycling, soil structure maintenance, and crop production. However, understanding of the linkage between soil enzyme kinetics and microbial metabolism and active microbial communities is remarkably limited. In this study, we measured the kinetics of three hydrolase enzymes, active microbial abundance and substrate-induced respiration (SIR) from 21 farmlands differing in their fertilities collected from the Loess Plateau, China. Results showed the high fertility soils had higher total organic carbon (TOC) and nutrient contents, potential microbial activity, the colony-forming units (CFU) of actinomycetes, and values of enzyme V and K than those of low fertility soils. We also observed that the CFU of fungi and other bacterial groups did not change with soil fertility status. Soil chemical properties explained 74.0% of the variance in V and 28.3% of the variance in K, respectively. Whereas, the abundance of main microbial groups and fungi/bacteria ratio only explained 10.2% and 7% of the variance of V and K, respectively. The interactive effect of soil properties and microbial community could explain 20.2% of the variance in K. Our results suggest that the substrate availability would mainly drive enzyme kinetics compared to the abundance of active/potentially active microbes in the farmland soils.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144500DOI Listing
May 2021

Three-year-period nitrogen additions did not alter soil organic carbon content and lability in soil aggregates in a tropical forest.

Environ Sci Pollut Res Int 2021 Mar 15. Epub 2021 Mar 15.

Key Laboratory of Vegetation Restoration and Management of Degraded Ecosystems, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, 510650, China.

Soil immobilizes a considerable proportion of carbon (C) as organic matter in terrestrial ecosystems and is thus critical to stabilize the global climate system. Atmospheric nitrogen (N) deposition could influence soil C storage and stabilization, but how N deposition changes soil organic C (SOC) fractions and lability remains elusive. We investigated the effects of 3-year-period N inputs on SOC fractions and lability along three soil depths (0-10, 10-20, and 20-40 cm) in a tropical forest of southern China. Results showed that N additions did not significantly change contents of SOC fractions and the C lability, either in bulk or aggregate-based soils at any of the three depths, and it showed no significant interaction with soil aggregate or soil depth. The SOC content was 43.7 ± 1.5, 18.2 ± 1.0, and 10.7 ± 0.4 mg g at the three soil layers downwards, with the non-readily oxidizable SOC (NROC) contributing over 70% while the remaining SOC consisting of readily oxidizable SOC at each soil layer. Moreover, contents of SOC and NROC were consistently higher in small soil aggregates, but the C decrement with increasing size of soil aggregates declined along soil profile downwards. This scenario suggests that physical protection of the small soil aggregate is limited, but its greater specific surface area could obviously contribute to the SOC pattern among soil aggregates. These results indicate that the highly developed forests could be resistant to short-term N deposition, even with a high load, to maintain its SOC stabilization.
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http://dx.doi.org/10.1007/s11356-021-13466-9DOI Listing
March 2021

YAP-dependent proliferation by a small molecule targeting annexin A2.

Nat Chem Biol 2021 Mar 15. Epub 2021 Mar 15.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.
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http://dx.doi.org/10.1038/s41589-021-00755-0DOI Listing
March 2021

Fermented Soybean Meal Replacement in the Diet of Lactating Holstein Dairy Cows: Modulated Rumen Fermentation and Ruminal Microflora.

Front Microbiol 2021 29;12:625857. Epub 2021 Jan 29.

Nanshan Dairy Co., Ltd., Shaoyang, China.

This study was conducted to examine the influences of replacing soybean meal (SBM) with fermented soybean meal (FSBM) in the diet of lactating Holstein cattle on rumen fermentation and ruminal bacterial microbiome. Twenty-four lactating Chinese Holstein dairy cattle were assigned to each of the two treatments in a completely randomized design: the SBM group [the basal total mixed ration (TMR) diet containing 5.77% SBM] and the FSBM group (the experimental TMR diet containing 5.55% FSBM). This trial lasted for 54 days (14 days for adjustment and 40 days for data and sample collection), and samples of rumen liquid were collected on 34 d and 54 d, respectively. The results showed that replacing SBM with FSBM significantly increased the molar percentages of propionate ( < 0.01) and valerate ( < 0.05), but reduced the total volatile fatty acid (TVFA) concentration ( < 0.05), butyrate molar proportion ( < 0.05), and the acetate to propionate ratio ( < 0.01). The copy numbers of total bacteria ( < 0.05), ( < 0.01), ( < 0.01), and spp. ( < 0.05) in the FSBM group were greater, while the density of ( < 0.05) was lower than those in the SBM treatment. Additionally, and were significantly enriched ( < 0.05) in the rumen fluid of FSBM-fed cows, despite the fact that there was no remarkable difference in the Alpha diversity indexes, structure and KEGG pathway abundances of the bacterial community across the two treatments. It could hence be concluded that the substitution of FSBM for SBM modulated rumen fermentation and rumen bacterial microbiota in lactating Holstein dairy cows. Further research is required to elucidate the relevant mechanisms of FSBM, and provide more insights into the application of FSBM in dairy cattle.
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http://dx.doi.org/10.3389/fmicb.2021.625857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879537PMC
January 2021

Reference carbon cycle dataset for typical Chinese forests via colocated observations and data assimilation.

Sci Data 2021 02 2;8(1):42. Epub 2021 Feb 2.

Key Laboratory of Ecosystem Network Observation and Modeling, Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences, Beijing, 100101, China.

Chinese forests cover most of the representative forest types in the Northern Hemisphere and function as a large carbon (C) sink in the global C cycle. The availability of long-term C dynamics observations is key to evaluating and understanding C sequestration of these forests. The Chinese Ecosystem Research Network has conducted normalized and systematic monitoring of the soil-biology-atmosphere-water cycle in Chinese forests since 2000. For the first time, a reference dataset of the decadal C cycle dynamics was produced for 10 typical Chinese forests after strict quality control, including biomass, leaf area index, litterfall, soil organic C, and the corresponding meteorological data. Based on these basic but time-discrete C-cycle elements, an assimilated dataset of key C cycle parameters and time-continuous C sequestration functions was generated via model-data fusion, including C allocation, turnover, and soil, vegetation, and ecosystem C storage. These reference data could be used as a benchmark for model development, evaluation and C cycle research under global climate change for typical forests in the Northern Hemisphere.
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http://dx.doi.org/10.1038/s41597-021-00826-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854661PMC
February 2021

Effect of indel variants within the sorting nexin 29 (SNX29) gene on growth traits of goats.

Anim Biotechnol 2020 Nov 19:1-6. Epub 2020 Nov 19.

Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China.

The sorting nexin 29 gene () is a well-known regulator of myocyte differentiation and proliferation. In this work, two indels (17-bp and 21-bp) were identified in the goat gene, and their effects on the growth traits of 1,759 Shaanbei white cashmere (SBWC) goats were analyzed. Both indels had three genotypes [homozygote wild type (II), heterozygote (ID), and homozygote mutation (DD)] and displayed medium genetic diversity (0.25 < polymorphism information content (PIC) < 0.50) in the population. The 17-bp indel was significantly associated with chest width ( = 0.009), body weight ( = 0.021), and chest depth ( = 0.032), with the II genotype dominant. The 21-bp indel was significantly associated with chest width ( = 0.001), chest depth ( = 4.8E-5), heart girth ( = 0.007), and hip width ( = 0.002). Because the two indels were in the upstream (17-bp) and intron (21-bp) regions of the gene, transcription factor binding sites were predicted. The IRF5 and MYC could bind with the 17-bp indel and 21-bp indel sequences, respectively. This study indicates that is a promising candidate gene that can be used to improve meat production in goat breeding.
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http://dx.doi.org/10.1080/10495398.2020.1846547DOI Listing
November 2020

Engineering of a Potent, Long-Acting NPY2R Agonist for Combination with a GLP-1R Agonist as a Multi-Hormonal Treatment for Obesity.

J Med Chem 2020 09 26;63(17):9660-9671. Epub 2020 Aug 26.

The Scripps Research Institute, d/b/a Calibr, a division of Scripps Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.

Bariatric surgery results in increased intestinal secretion of hormones GLP-1 and anorexigenic PYY, which is believed to contribute to the clinical efficacy associated with the procedure. This observation raises the question whether combination treatment with gut hormone analogs might recapitulate the efficacy and mitigate the significant risks associated with surgery. Despite PYY demonstrating excellent efficacy and safety profiles with regard to food intake reduction, weight loss, and glucose control in preclinical animal models, PYY-based therapeutic development remains challenging given a low serum stability and half-life for the native peptide. Here, combined peptide stapling and PEG-fatty acid conjugation affords potent PYY analogs with >14 h rat half-lives, which are expected to translate into a human half-life suitable for once-weekly dosing. Excellent efficacy in glucose control, food intake reduction, and weight loss for lead candidate in combination with our previously reported long-acting GLP-1 analog is demonstrated in a diet-induced obesity mouse model.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00740DOI Listing
September 2020

Experimental investigation on water adsorption and desorption isotherms of the Longmaxi shale in the Sichuan Basin, China.

Sci Rep 2020 Aug 10;10(1):13434. Epub 2020 Aug 10.

Key Laboratory for Mechanics in Fluid Solid Coupling Systems, Institute of Mechanics, Chinese Academy of Sciences, Beijing, 100190, China.

The understanding of water adsorption and desorption behavior in the shale rocks is of great significance in the reserve estimation, wellbore stability and hydrocarbon extraction in the shale gas reservoirs. However, the water sorption behavior in the shales remains unclear. In this study, water vapor adsorption/desorption isotherms of the Longmaxi shale in the Sichuan Basin, China were conducted at various temperatures (30 °C, 60 °C) and a relative pressure up to 0.97 to understand the water sorption behavior. Then the effects of temperature and shale properties were analyzed, and the water adsorption, hysteresis, saturation and capillary pressure were discussed. The results indicate that water adsorption isotherms of the Longmaxi shale exhibit the type II characteristics. The water molecules initially adsorb on the shale particle/pore surfaces at low relative pressure while the capillary condensation dominates at high relative pressure. Temperature favors the water sorption in the shales at high relative pressure, and the GAB isotherm model is found to be suitable for describe the water adsorption/desorption behavior. The high organic carbon and full bedding are beneficial to water adsorption in the shales while the calcite inhibits the behavior. There exists the hysteresis between water adsorption and desorption at the whole relative pressure, which suggests that the depletion of condensed water from smaller capillary pores is more difficult than that from larger pores, and the chemical interaction contributes to the hysteresis loop for water sorption. The capillary pressure in the shales can be up to the order of several hundreds of MPa, and thus the desorption of water from the shales may not be as easy as the water adsorption due to the high capillary pressure, which results in water retention behavior in the shale gas reservoirs. These results can provide insights into a better understanding of water sorption behavior in the shale so as to optimize extraction conditions and predict gas productivity in the shale gas reservoirs.
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http://dx.doi.org/10.1038/s41598-020-70222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417566PMC
August 2020

Neuroprotective Activities of Long-Acting Granulocyte-Macrophage Colony-Stimulating Factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice.

Neurotherapeutics 2020 10;17(4):1861-1877

Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Loss of dopaminergic neurons along the nigrostriatal axis, neuroinflammation, and peripheral immune dysfunction are the pathobiological hallmarks of Parkinson's disease (PD). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been successfully tested for PD treatment. GM-CSF is a known immune modulator that induces regulatory T cells (Tregs) and serves as a neuronal protectant in a broad range of neurodegenerative diseases. Due to its short half-life, limited biodistribution, and potential adverse effects, alternative long-acting treatment schemes are of immediate need. A long-acting mouse GM-CSF (mPDM608) was developed through Calibr, a Division of Scripps Research. Following mPDM608 treatment, complete hematologic and chemistry profiles and T-cell phenotypes and functions were determined. Neuroprotective and anti-inflammatory capacities of mPDM608 were assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice that included transcriptomic immune profiles. Treatment with a single dose of mPDM608 resulted in dose-dependent spleen and white blood cell increases with parallel enhancements in Treg numbers and immunosuppressive function. A shift in CD4 T-cell gene expression towards an anti-inflammatory phenotype corresponded with decreased microgliosis and increased dopaminergic neuronal cell survival. mPDM608 elicited a neuroprotective peripheral immune transformation. The observed phenotypic shift and neuroprotective response was greater than observed with recombinant GM-CSF (rGM-CSF) suggesting human PDM608 as a candidate for PD treatment.
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http://dx.doi.org/10.1007/s13311-020-00877-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851309PMC
October 2020

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877.

ChemMedChem 2020 08 2;15(16):1562-1570. Epub 2020 Jul 2.

Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.
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http://dx.doi.org/10.1002/cmdc.202000183DOI Listing
August 2020

Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist.

Molecules 2020 May 28;25(11). Epub 2020 May 28.

The Scripps Research Institute, d/b/a Calibr, a division of Scripps Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.
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http://dx.doi.org/10.3390/molecules25112508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321126PMC
May 2020

The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1.

Sci Adv 2020 May 15;6(20):eaaz4988. Epub 2020 May 15.

Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA.

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.
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http://dx.doi.org/10.1126/sciadv.aaz4988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228743PMC
May 2020

New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice.

Bioconjug Chem 2020 04 3;31(4):1167-1176. Epub 2020 Apr 3.

Calibr at The Scripps Research Institute, La Jolla, California 92037, United States.

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower potency and short half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00093DOI Listing
April 2020

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.

J Med Chem 2020 03 20;63(6):2958-2973. Epub 2020 Feb 20.

Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. , GNF2133 is able to proliferate both rodent and human β-cells. , GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
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http://dx.doi.org/10.1021/acs.jmedchem.9b01624DOI Listing
March 2020

Effect of inclusion of HMBi in the ration of goats on feed intake, nutrient digestibility, rumen bacteria community and blood serum parameters.

J Anim Physiol Anim Nutr (Berl) 2020 Jul 18;104(4):987-997. Epub 2020 Feb 18.

Institute of Animal and Dairy Sciences, University of Agriculture, Faisalabad, Pakistan.

The objective of this experiment was to test the effect of supplementation of analogues of methionine 2-hydroxy-4-methylthio butanoic acid isopropyl ester (HMBi) on growth, digestibility, antioxidant index, abundance and composition of rumen bacterial community in Xiangdong Black Goats. Thirty-six growing Xiangdong Black Goats were divided into four groups in such a way that each group had three replicate and each replicate had three animals. Experimental groups were assigned four levels of HMBi in basal diet: 0% HMBi (on dietary DM basis); 0.05% HMBi; 0.10% HMBi and 0.20% HMBi. Goats fed 0.10% HMBi in basal diet had higher average daily weight gain (p < .05). Goats fed 0.05% HMBi had higher apparent digestibility of gross energy (p < .01). The group 0% HMBi supplementation had a higher level of superoxide dismutase and malondialdehyde (p < .01). The goats fed 0.20% HMBi in basal diet had a higher level of insulin and leptin (p < .01) than 0% HMBi supplementation goats. 16S rRNA high-throughput sequencing analysis revealed similarities in the community composition, species diversity and relative abundance of dominant bacteria at the phylum and genus levels among the four groups. In conclusion, HMBi supplementation has no negative effect on apparent digestibility, antioxidant index and the ruminal bacteria composition. Therefore, 0.10% supplementation of HMBi is recommended in the diet of goats to improve the growth performance.
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http://dx.doi.org/10.1111/jpn.13270DOI Listing
July 2020

Synchrony Degree of Dietary Energy and Nitrogen Release Influences Microbial Community, Fermentation, and Protein Synthesis in a Rumen Simulation System.

Microorganisms 2020 Feb 9;8(2). Epub 2020 Feb 9.

State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, 100193 Beijing, China.

Synchrony of energy and nitrogen release in rumen has been proposed to maximize ruminal microbial fermentation. However, the information regarding bacterial community composition and its metabolism under a higher or lower degree of synchronization is limited. In our study, a 0 to 6 h post-feeding infusion (first half infusion, FHI), 6 to 12 h post-feeding infusion (second half infusion, SHI), and 0 to 12 h post-feeding infusion (continuous infusion, CI) of maltodextrin were used to simulate varying degrees of synchronization of energy and nitrogen release in a rumen simulation system. In addition, the bacterial community, metabolite, enzyme activity, and microbial protein synthesis (MPS) were evaluated. Compared with the FHI and CI, the relative abundance of , , BF311, and CF231 decreased in the SHI, but that of and increased in the SHI. The NH-N and branched-chain volatile fatty acids were significantly higher, but propionate content and activities of glutamate dehydrogenase (GDH) and alanine dehydrogenase were significantly lower in the SHI than those in the FHI and CI. The SHI had lower MPS and less efficiency of MPS than the FHI and CI, which indicated that the SHI had a lower degree of synchronization. Correlation analysis showed that MPS was positively related to GDH activity and relative abundance of but negatively related to NH-N and relative abundance of . Therefore, a higher degree of synchronization of energy and nitrogen release increased MPS partly via influencing the bacterial community, metabolism, and enzyme activities of ammonia assimilation in the in vitro fermenters.
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http://dx.doi.org/10.3390/microorganisms8020231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074744PMC
February 2020

Responses of litter, organic and mineral soil enzyme kinetics to 6 years of canopy and understory nitrogen additions in a temperate forest.

Sci Total Environ 2020 Apr 3;712:136383. Epub 2020 Jan 3.

Key Laboratory of Vegetation Restoration and Management of Degraded Ecosystems and Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China; Core Botanical Gardens, Chinese Academy of Sciences, Guangzhou 510650, China. Electronic address:

Increasing atmospheric nitrogen (N) deposition could profoundly impact soil carbon, N and phosphorus cycling that are often regulated by extracellular enzymes. The potential activities of enzymes in response to N deposition have been studied extensively, but the kinetic mechanisms in response to canopy and understory N additions in different soil layers are poorly understood. Here, we conducted a six-year-long field manipulation experiment in a temperate deciduous forest to reveal the kinetic characteristics of seven extracellular hydrolytic enzymes in the litter, organic and mineral soil layers in response to canopy and understory N additions. Canopy N addition and understory N addition exerted similar effects on the kinetics parameters (V and K) of most enzymes under study. The kinetics parameters of most enzymes generally increased in the litter layer but decreased in the organic layer and had little change in the mineral soil layer in response to N addition. In addition, the changed kinetic parameters were mainly correlated with moisture in the litter layer, with pH, substrate properties (TC, TN, DOC and DON) and microbial communities (G, G, total bacterial and fungal biomass) in the organic and mineral soil layers. These findings indicate that enzyme kinetics responses to N deposition differ in soil layers with varying determinant factors, and therefore are driven by various physical, chemical and microbial mechanisms.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136383DOI Listing
April 2020

Disentangling the Contributions of Plant Taxonomic and Functional Diversities in Shaping Aboveground Biomass of a Restored Forest Landscape in Southern China.

Plants (Basel) 2019 Dec 16;8(12). Epub 2019 Dec 16.

Key Laboratory of Vegetation Restoration and Management of Degraded Ecosystem, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China.

Restoration is essential for supporting key ecosystem functions such as aboveground biomass production. However, the relative importance of functional versus taxonomic diversity in predicting aboveground biomass during restoration is poorly studied. Here, we used a trait-based approach to test for the importance of multiple plant diversity attributes in regulating aboveground biomass in a 30-years-old restored subtropical forest in southern China. We show that both taxonomic and functional diversities are significant and positive regulators of aboveground biomass; however, functional diversity (FD) was more important than taxonomic diversity (species richness) in controlling aboveground biomass. FD had the strongest direct effect on aboveground biomass compared with species richness, soil nutrients, and community weighted mean (CWM) traits. Our results further indicate that leaf and root morphological traits and traits related to the nutrient content in plant tissues represent the existence of a leaf and root economic spectrum, and the acquisitive resource use strategy influenced aboveground biomass. Our results suggest that both taxonomic and FD play a role in shaping aboveground biomass, but FD is more important in supporting aboveground biomass in this type of environments. These results imply that enhancing FD is important to restoring and managing degraded forest landscapes.
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http://dx.doi.org/10.3390/plants8120612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963651PMC
December 2019

Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects.

J Med Chem 2020 01 18;63(1):382-390. Epub 2019 Dec 18.

Calibr at The Scripps Research Institute , La Jolla , California 92037 , United States.

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog () in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01862DOI Listing
January 2020

Neratinib is an MST1 inhibitor and restores pancreatic β-cells in diabetes.

Cell Death Discov 2019 5;5:149. Epub 2019 Dec 5.

1Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.

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http://dx.doi.org/10.1038/s41420-019-0232-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895035PMC
December 2019

Plant Taxonomic Diversity Better Explains Soil Fungal and Bacterial Diversity than Functional Diversity in Restored Forest Ecosystems.

Plants (Basel) 2019 Nov 6;8(11). Epub 2019 Nov 6.

Key Laboratory of Vegetation Restoration and Management of Degraded Ecosystem, South China Botanical Garden (SCBG), Chinese Academy of Sciences, Guangzhou 510650, China.

Plant attributes have direct and indirect effects on soil microbes via plant inputs and plant-mediated soil changes. However, whether plant taxonomic and functional diversities can explain the soil microbial diversity of restored forest ecosystems remains elusive. Here, we tested the linkage between plant attributes and soil microbial communities in four restored forests ( species, species, mixed coniferous species, mixed native species). The trait-based approaches were applied for plant properties and high-throughput Illumina sequencing was applied for fungal and bacterial diversity. The total number of soil microbial operational taxonomic units (OTUs) varied among the four forests. The highest richness of fungal OTUs was found in the forest. However, bacterial OTUs were highest in the forest. Species richness was positively and significantly related to fungal and bacterial richness. Plant taxonomic diversity (species richness and species diversity) explained more of the soil microbial diversity than the functional diversity and soil properties. Prediction of fungal richness was better than that of bacterial richness. In addition, root traits explained more variation than the leaf traits. Overall, plant taxonomic diversity played a more important role than plant functional diversity and soil properties in shaping the soil microbial diversity of the four forests.
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http://dx.doi.org/10.3390/plants8110479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918236PMC
November 2019

Neratinib protects pancreatic beta cells in diabetes.

Nat Commun 2019 11 1;10(1):5015. Epub 2019 Nov 1.

Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Lepr) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.
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http://dx.doi.org/10.1038/s41467-019-12880-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825211PMC
November 2019

The Structure and Species Co-Occurrence Networks of Soil Denitrifying Bacterial Communities Differ Between A Coniferous and A Broadleaved Forests.

Microorganisms 2019 Sep 18;7(9). Epub 2019 Sep 18.

Research Institute of Tropical Forestry, Chinese Academy of Forestry, Longdong, Guangzhou 510520, China.

(AM) and (PM) are widely planted in tropical regions, whereas their effects on soil microbial communities remain unclear. We did a comprehensive investigation of soil denitrifying bacterial communities in AM and PM monoculture plantations in Southern China based on the high throughput sequencing data of their functional genes: , , and . The average abundance of (1.3 × 10) was significantly higher than (5.6 × 10) and (4.9 × 10). Shannon estimator revealed a markedly higher α-diversity of and communities in PM than in AM plantations. The AM and PM plantations were dominated by different and taxa belonging to proteobacteria, actinobacteria, thermoleophilia, chloroflexia, and acidobacteria, while the dominant taxa were mainly categorized into proteobacteria in both types of plantations. The structure of and communities shifted substantially from AM to PM plantations with changes in soil moisture, NH, and microbial biomass nitrogen content. The species co-occurrence network of community was better organized in a more modular manner compared to and communities, and the network keystone species mostly occurred in PM plantations. These results indicated a highly species corporation of community in response to environmental changes, especially in PM plantations. AM and PM plantations can form different soil denitrifying microbial communities via altering soil physicochemical properties, which may further affect soil N transformations.
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http://dx.doi.org/10.3390/microorganisms7090361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780695PMC
September 2019

Molecular interaction site on procoagulant myosin for factor Xa-dependent prothrombin activation.

J Biol Chem 2019 10 3;294(41):15176-15181. Epub 2019 Sep 3.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037

Skeletal muscle myosin has potent procoagulant activity that is based on its ability to enhance thrombin generation due to binding coagulation factors Xa and Va and accelerating prothrombin activation. A well-studied myosin inhibitor that binds to myosin's neck region inhibits myosin-dependent prothrombin activation. Hence, to identify a potential binding site(s) on skeletal muscle myosin for factor Xa, 19 peptides (25-40 residues) representing the neck region, which consists of a regulatory light chain, an essential light chain, and a heavy chain (HC), were screened for inhibition of myosin-supported prothrombin activation. Peptide HC796-835 comprising residues 796-835 of the heavy chain strongly inhibited myosin-enhanced prothrombin activation by factors Xa and Va (50% inhibition at 1.2 μm), but it did not inhibit phospholipid vesicle-enhanced prothrombin activation. Peptide inhibition studies also implicated several myosin light chain sequences located near HC796-835 as potential procoagulant sites. A peptide comprising HC796-835's C-terminal half, but not a peptide comprising its N-terminal half, inhibited myosin-enhanced prothrombin activation (50% inhibition at 1.2 μm). This inhibitory peptide (HC816-837) did not inhibit phospholipid-enhanced prothrombin activation, indicating its specificity for inhibition of myosin-dependent procoagulant mechanisms. Binding studies showed that purified factor Xa was bound to immobilized peptides HC796-835 and HC816-837 with apparent values of 0.78 and 1.3 μm, respectively. In summary, these studies imply that HC residues 816-835 in the neck region of the skeletal muscle myosin directly bind factor Xa and, with contributions from light chain residues in this neck region, contribute to provision of myosin's procoagulant surface.
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http://dx.doi.org/10.1074/jbc.AC119.010236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791324PMC
October 2019

Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog.

ACS Med Chem Lett 2019 Aug 5;10(8):1166-1172. Epub 2019 Jul 5.

Calibr at Scripps Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.

Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and half-life. Our lead compound exhibits good potency and selectivity against GPR10, improved serum stability, and extended half-life (7.8 h) in mouse. Furthermore, demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691568PMC
August 2019

Experimental study on flow characteristics of gas transport in micro- and nanoscale pores.

Sci Rep 2019 Jul 15;9(1):10196. Epub 2019 Jul 15.

School of Civil and Resource Engineering, University of Science and Technology Beijing, Beijing, 100083, China.

Gas flow behavior in porous media with micro- and nanoscale pores has always been attracted great attention. Gas transport mechanism in such pores is a complex problem, which includes continuous flow, slip flow and transition flow. In this study, the microtubes of quartz microcapillary and nanopores alumina membrane were used, and the gas flow measurements through the microtubes and nanopores with the diameters ranging from 6.42 μm to 12.5 nm were conducted. The experimental results show that the gas flow characteristics are in rough agreement with the Hagen-Poiseuille (H-P) equation in microscale. However, the flux of gas flow through the nanopores is larger than the H-P equation by more than an order of magnitude, and thus the H-P equation considerably underestimates gas flux. The Knudsen diffusion and slip flow coexist in the nanoscale pores and their contributions to the gas flux increase as the diameter decreases. The slip flow increases with the decrease in diameter, and the slip length decreases with the increase in driving pressure. Furthermore, the experimental gas flow resistance is less than the theoretical value in the nanopores and the flow resistance decreases along with the decrease in diameter, which explains the phenomenon of flux increase and the occurrence of a considerable slip length in nanoscale. These results can provide insights into a better understanding of gas flow in micro- and nanoscale pores and enable us to exactly predict and actively control gas slip.
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http://dx.doi.org/10.1038/s41598-019-46430-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629846PMC
July 2019

Engineering PEG-fatty acid stapled, long-acting peptide agonists for G protein-coupled receptors.

Methods Enzymol 2019 12;622:183-200. Epub 2019 Mar 12.

The Scripps Research Institute, d/b/a Calibr, a Division of Scripps Research, La Jolla, CA, United States. Electronic address:

G protein-coupled receptors (GPCRs) play a key role in signal transduction and human pathophysiological processes. Family B GPCRs are activated by a number of secreted peptide hormones, and engineering of these peptide ligands in order to improve stability and half-life, and therefore clinical efficacy has proven successful for drug discovery. In this chapter we discuss a novel peptide engineering strategy that combines peptide side chain stapling with covalent incorporation of a serum protein binding motif in a single step. The application of this approach to the enhancement of the helicity and stability of GLP-1R peptide agonists, resulting in their improved in vitro potencies, in vivo half-lives and ultimately efficacies, will be described. Discussion of the stapling technology and target selection rationale, peptide engineering and final biological characterization of the long-acting agonists will also be provided.
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http://dx.doi.org/10.1016/bs.mie.2019.02.008DOI Listing
February 2020

Warming but Not Nitrogen Addition Alters the Linear Relationship Between Microbial Respiration and Biomass.

Front Microbiol 2019 10;10:1055. Epub 2019 May 10.

Key Laboratory of Vegetation Restoration and Management of Degraded Ecosystems, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China.

Soil contains a large amount of organic matter, which constitutes the largest terrestrial carbon pool. Heterotrophic or microbial respiration (R) that results from microbial decomposition of soil organic carbon (SOC) constitutes a substantial proportion of soil C efflux. Whether soil microbial biomass is of primary importance in controlling R remains under debate, and the question of whether the microbial biomass-decomposition relationship changes with warming and nitrogen (N) deposition has rarely been assessed. We conducted an incubation experiment to test the relationship between R and the size of soil microbial communities in two layers of soil collected from a natural subtropical forest and to examine whether the relationship was affected by changes in temperature and by added N in different forms. The results showed that regardless of the added N species, the N load did not significantly affect R or the size of the soil microbial communities. These results could be due to a long-term N-rich soil condition that acclimates soil microbial communities to resist N inputs into the studied forest; however, warming may significantly stimulate SOC decomposition, reducing soil microbial biomass under high temperatures. A significant linear soil microbial biomass-decomposition relationship was observed in our study, with the coefficients of determination ranging from 54 to 70%. Temperature rather than N additions significantly modified the linear relationship between soil microbial biomass and respiration. These results suggest that warming could impose a more substantial impact than N addition on the relationship between soil microbial biomass and SOC decomposition.
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http://dx.doi.org/10.3389/fmicb.2019.01055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522881PMC
May 2019

Diurnal Temperature Variation and Plants Drive Latitudinal Patterns in Seasonal Dynamics of Soil Microbial Community.

Front Microbiol 2019 2;10:674. Epub 2019 Apr 2.

Key Laboratory of Alpine Ecology and Biodiversity, Institute of Tibetan Plateau Research, Chinese Academy of Sciences, Beijing, China.

Seasonality, an exogenous driver, motivates the biological and ecological temporal dynamics of animal and plant communities. Underexplored microbial temporal endogenous dynamics hinders the prediction of microbial response to climate change. To elucidate temporal dynamics of microbial communities, temporal turnover rates, phylogenetic relatedness, and species interactions were integrated to compare those of a series of forest ecosystems along latitudinal gradients. The seasonal turnover rhythm of microbial communities, estimated by the slope ( value) of similarity-time decay relationship, was spatially structured across the latitudinal gradient, which may be caused by a mixture of both diurnal temperature variation and seasonal patterns of plants. Statistical analyses revealed that diurnal temperature variation instead of average temperature imposed a positive and considerable effect alone and also jointly with plants. Due to higher diurnal temperature variation with more climatic niches, microbial communities might evolutionarily adapt into more dispersed phylogenetic assembly based on the standardized effect size of MNTD metric, and ecologically form higher community resistance and resiliency with stronger network interactions among species. Archaea and the bacterial groups of , and were sensitive to diurnal temperature variation with greater turnover rates at higher latitudes, indicating that greater diurnal temperature fluctuation imposes stronger selective pressure on thermal specialists, because bacteria and archaea, single-celled organisms, have extreme short generation period compared to animal and plant. Our findings thus illustrate that the dynamics of microbial community and species interactions are crucial to assess ecosystem stability to climate variations in an increased climatic variability era.
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http://dx.doi.org/10.3389/fmicb.2019.00674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454054PMC
April 2019

The Composition of Nitrogen-Fixing Microorganisms Correlates With Soil Nitrogen Content During Reforestation: A Comparison Between Legume and Non-legume Plantations.

Front Microbiol 2019 14;10:508. Epub 2019 Mar 14.

Research Institute of Tropical Forestry, Chinese Academy of Forestry, Guangzhou, China.

Numerous reforestation projects have been conducted to improve soil fertility in degraded forests, often causing alterations to the soil microbial communities. However, it remains unclear whether microbial functional groups are affected and how these groups correlate with an increase in the nutrient contents during reforestation. We investigated the abundance and composition of free-living nitrogen-fixing microorganisms (diazotrophs) by quantifying and sequencing the marker gene in bulk soils from five reforestation approaches, including legumes and non-legumes, in subtropical China. The relationships between diazotrophic community attributes and soil nitrogen (N) content [NO, NH, and microbial biomass N (MBN)] were examined under various approaches. Abundance of diazotrophs was highest in the native tree plantation ( spp. and ) and monoculture (AM), and lowest in the monoculture. The diazotrophic abundance correlated positively with soil organic matter and water content while there was a negative correlation to pH. The composition of diazotrophic community differed significantly among the five reforestation approaches examined and was closely correlated with variations in soil pH, NH and water content. Diazotrophic community composition was closely related to soil NH content, whereas abundance was not. The AM contained higher NH, NO and MBN contents than the other reforestation approaches, which may be associated with the indicator species of diazotrophs (, , and ). However, there were more indicator species of in the mixed plantation ( and ) than in AM, which might have contributed to the remarkedly lower N content compared to AM. Overall, the soil N content under reforestation appeared to be more related to the composition of diazotroph community than to the abundance of diazotrophs.
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http://dx.doi.org/10.3389/fmicb.2019.00508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427063PMC
March 2019