bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimization of the precursor supply for an enhanced FK506 production in Streptomyces tsukubaensis
Authors: Schulz Susann , Schall Christoph , Stehle Thilo , Breitmeyer Christian , Krysenko Sergii , Mitulski Agnieszka , Wohlleben Wolfgang 
Published: November 2022

Tacrolimus (FK506) is a macrolide widely used as immunosuppressant to prevent transplant rejection. Synthetic production of FK506 is not efficient and costly, whereas the biosynthesis of FK506 is complex and the level produced by the wild type strain, Streptomyces tsukubaensis, is very low. We therefore engineered FK506 biosynthesis and the supply of the precursor L-lysine to generate strains with improved FK506 yield. To increase FK506 production, first the intracellular supply of the essential precursor lysine was improved in the native host S. tsukubaensis NRRL 18488 by engineering the lysine biosynthetic pathway. Therefore, a feedback deregulated aspartate kinase AskSt* of S. tsukubaensis was generated by site directed mutagenesis. Whereas overexpression of AskSt* resulted only in a 17% increase in FK506 yield, heterologous overexpression of a feedback deregulated AskCg* from Corynebacterium glutamicum was proven to be more efficient. Combined overexpression of AskCg* and DapASt, showed a strong enhancement of the intracellular lysine pool following increase in the yield by approximately 73% compared to the wild type. Lysine is coverted into the FK506 building block pipecolate by the lysine cyclodeaminase FkbL. Construction of a ∆fkbL mutant led to a complete abolishment of the FK506 production, confirming the indispensability of this enzyme for FK506 production. Chemical complementation of the ∆fkbL mutant by feeding pipecolic acid and genetic complementation with fkbL as well as with other lysine cyclodeaminase genes (pipAf, pipASt, originating from Actinoplanes friuliensis and Streptomyces pristinaespiralis, respectively) completely restored FK506 production. Subsequently, FK506 production was enchanced by heterologous overexpression of PipAf and PipASp in S. tsukubaensis. This resulted in a yield increase by 65% compared to the WT in the presence of PipAf from A. friuliensis. For further rational yield improvement, the crystal structure of PipAf from A. friuliensis was determined at 1.3 Å resolution with the cofactor NADH bound and at 1.4 Å with its substrate lysine. Based on the structure the Ile91 residue was replaced by Val91 in PipAf, which resulted in an overall increase of FK506 production by approx. 100% compared to the WT.
Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties
Authors: El-Sheref Essmat M. , Tawfeek Hendawy N. , Hassan Alaa A. , Bräse S. , Elbastawesy Mohammed A. I. , Gomaa Hesham A. M. , Mostafa Yaser A. , Youssif Bahaa G. M. 
Published: November 2022

Novel series of amidines were synthesized via the interaction between alicyclic amines, cyclic ketones, and a highly electrophilic 4-azidoquinolin-2(1H)-ones without any catalyst or additive. All the obtained products were elucidated based on NMR spectroscopy, mass spectrometry, and elemental analysis. The reaction conditions were optimized using cyclohexanone (2), piperidine (3a), and 4-azido-quinolin-2(1H)-one (1a) under an air atmosphere. The new compounds 4a-l and 5a-c were tested for antiproliferative activity against four cancer cell lines using doxorubicin as a reference drug. The most potent derivatives were compounds 4b, 4d, 4e, 4i, and 5c, with GI50 ranging from 1.00 µM to 1.50 µM. Compound 5c was the most effective derivative against the four cancer cell lines, outperforming doxorubicin. The compounds 4b, 4d, 4e, 4i, and 5c were studied further as topoisomerase I and IIα inhibitors. The compounds tested showed selective inhibition of topo I over topo IIα. Finally, docking studies explain why these compounds prefer topo I over topo IIα.
Osteoarthritis and cardiovascular disease: A Mendelian randomization study
Authors: Wang Zhao , Kang Chan , Xu Pai , Zhang Shuyi , Song Jae Hwang , Wang Dongyang , Yuan Shuai , Lee Hyun Jong , Zhang Meng , Wang Zhihui , Sun Hao , Fan Ruobing 
Published: November 2022

ObjectiveThis Mendelian randomization (MR) study aimed to investigate the causal relationship between osteoarthritis (OA) and cardiovascular disease (CVD).MethodsFrom a genome-wide association study of European ancestry, we selected single nucleotide polymorphisms for two types of OA, knee osteoarthritis (KOA) and hip osteoarthritis (HOA), as instrumental variables. We evaluated three types of CVD: coronary heart disease (CHD), heart failure (HF), and stroke. We used the traditional inverse variance weighting (IVW) method and other methods to estimate causality. Heterogeneity and sensitivity tests were also applied. Finally, we conducted a MR analysis in the opposite direction to investigate reverse causality.ResultsIVW analysis showed that HOA significantly affected the incidence of HF [odds ratio (OR): 1.0675; 95% confidence interval (CI): 0.0182–0.1125, P = 0.0066]. HOA significantly affected the incidence of stroke (OR: 1.1368; 95% CI: 1.0739–1.2033, P = 9.9488e-06). CHD could dramatically affect the incidence of KOA (OR: 0.9011; 95% CI: 0.8442–0.9619, P = 0.0018). The rest of the results were negative.ConclusionsOur results revealed a potential causal relationship between HOA and risk of HF, and a potential causal relationship between HOA and risk of stroke. Our findings also suggested that CHD has a significant causal relationship with the risk of KOA. This paper may provide new ideas for the treatment of OA and CVD.
Asynchrony between urban expansion and water environmental protection reshapes the spatial patterns of nitrogen and phosphorus concentrations and N:P stoichiometry in inland small water bodies in Changsha, China
Authors: Zhou Jiaogen , Li Ying , Lei Qiuliang , Feng Qingyu , Luo Jiafa , Lindsey Stuart 
Published: November 2022

The asynchrony of urban expansion and urban water environmental protection is a common problem in the process of urbanization. Although urban expansion results in population agglomeration and dramatic changes of land use, it also brings municipal water infrastructures to enhance the water quality of urban water bodies. In order to understand the relationship between water quality and urban expansion and water environmental management, total nitrogen (TN) and total phosphorus (TP) concentrations were measured, which were taken from 68 small urban water bodies in three distance bands (&lt;5 km, 5–10 km and &gt;10 km away from the city center of Changsha City, China) and four main water management types of protection, recovery, degradation and fisheries. The results showed that: 1) with increase in distance away from the city center, TN and TP concentrations in small water bodies and the percentage of polluted samples (IV ∼ inferior V) showed an increasing trend. 2) The degree of protection of small urban water bodies in the study area has not been synchronistic with urban expansion. The protected water bodies (long-term protected and recovering) are mainly distributed in the &lt;5 km distance band, and anthropogenic disturbances (degraded water bodies and small water bodies used for fish farming) were mainly distributed in the 5–10 km and &gt;10 km distance bands. Also, degraded and fish-managed water bodies had higher TN and TP contents than protected and recovering water bodies, but their TN:TP ratios were significantly lower. 3) Overall, urban expansion and water body management contributed 55.8% of the variance of TN and TP concentrations and TN:TP ratios in the study area. Water body management alone contributed 22.2%, which was higher than the contribution of urban expansion (7.6%). This shows that the insufficient application of water environmental protection measures has significantly changed the spatial distribution patterns of N and P concentrations and TN:TP ratios in urban small water bodies as the Changsha urban area has expanded. In the process of urban expansion, the simultaneous development of urban water ecological management is essential to ensure the health protection of the urban water environment.
Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
Authors: Xie Fang , Xu Hang-fei , Zhang Jing , Liu Xiao-ni , Kou Bu-xin , Cai Meng-yin , Wu Jing , Dong Jin-ling , Meng Qing-hua , Wang Yi , Chen Dexi , Zhang Yang 
Published: November 2022

BackgroundGrowing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice.MethodsASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman’s rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice.ResultsCompared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family.ConclusionOur findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.
Benthic species patterns in and around the Cape Canyon: A large submarine canyon off the western passive margin of South Africa
Authors: Filander Zoleka , Smith Adam N. H. , Cawthra Hayley C. , Lamont Tarron 
Published: November 2022

Although submarine canyons are internationally recognized as sensitive ecosystems and reported to be biological hotspots, regional studies are required to validate this consensus. To this end, hydrographic and benthic biodiversity data were collected during three cruises (2016-2017) to provide insights on the benthic patterns within South African canyon and non-canyon offshore areas. A total of 25 stations, sampled at 200-1000 m depth range, form the basis of the multivariate analysis. Diversity gradients were calculated and then differences were compared across substrate types and depth zones represented within 12 canyon and 13 non-canyon stations. Significant differences in both substrate and depth were evident, despite measures being highly variable. This observation of varying diversity in different substrates is in line with previous studies. No clear pattern was observed for species diversity (delta+). However, non-canyon stations overall showed a higher diversity in comparison to canyon stations. A notable peak in diversity is observed in canyon areas in the 401-500 m depth zone. Species richness followed an opposing pattern, as it decreased with depth and was consistently higher in canyon areas. These results align with the well-defined influence of depth-related variables on the distribution of taxonomic groups and the substrate available, at various scales. The eutrophic characteristic of the Benguela region may have attributed to the insignificant diversity differences between canyon and non-canyon stations. To assess the benthic species structure in canyon and non-canyon areas, we converted the 108 benthic species into a gamma+ matrix. We then modelled the biological response to predictor variables (substrate and depth). Although the canyon and non-canyon areas have an overlapping species composition, the main effects (canyon vs. non-canyon, depth, and substrate) showed significant differences. Thirteen species were characteristic of canyon areas, whilst only three distinguished non-canyon areas. The region has a long history of anthropogenic activities, so the observed benthic profiles may already be altered. The current study therefore provides the first detailed taxonomic description and analysis of benthic species profiles in the Cape Canyon, and advances important baseline information necessary for understanding the ecological importance of the Cape Canyon.
Inter and intra-observer agreement of arterial wall contrast-enhanced ultrasonography in giant cell arteritis
Authors: Espitia Olivier , Robin Olivier , Hersant Jeanne , Roncato Christophe , Théry Arthur , Vibet Marie-Anne , Gautier Giovanni , Raimbeau Alizée , Lapébie François-Xavier 
Published: November 2022

ObjectiveThe aim of this study was to analyze inter- and intra-observer agreement for contrast-enhanced ultrasonography (CEUS) for monitoring disease activity in Giant Cell Arteritis (GCA) in the wall of axillary arteries, and common carotid arteries.MethodsGiant cell arteritis patients have CEUS of axillary arteries and common carotid. These images were rated by seven vascular medicine physicians from four hospitals who were experienced in duplex ultrasonography of GCA patients. Two weeks later, observers again rated the same images. GCA patients were recruited in from December 2019 to February 2021. An analysis of the contrast of the ultrasound images with a gradation in three classes (grade 0, 1, and 2) was performed. Grade 0 corresponds to no contrast, grade 1 to moderate wall contrast and grade 2 to intense contrast. A new analysis in 2 classes: positive or negative wall contrast; was then performed on new series of images.ResultsSixty arterial segments were evaluated in 30 patients. For the three-class scale, intra-rater agreement was substantial: κ 0.70; inter-rater agreement was fair: κ from 0.22 to 0.27. Thirty-four videos had a wall thickness of less than 2 mm and 26 videos had a wall thickness greater than 2 mm. For walls with a thickness lower than 2 mm: intra-rater agreement was substantial: κ 0.69; inter-rater agreement was fair: κ 0.35. For walls with a thickness of 2 mm or more: intra-rater agreement was substantial: κ 0.53; inter-rater agreement was fair: κ 0.25. For analysis of parietal contrast uptake in two classes: inter-rater agreement was fair to moderate: κ from 0.35 to 0.41; and for walls with a thickness of 2 mm or more: inter-rater agreement was fair to substantial κ from 0.22 to 0.63.ConclusionThe visual analysis of contrast uptake in the wall of the axillary and common carotid arteries showed good intra-rater agreement in GCA patients. The inter-rater agreement was low, especially when contrast was analyzed in three classes. The inter-rater agreement for the analysis in two classes was also low. The inter-rater agreement was higher in two-class analysis for walls of 2 mm thickness or more.
Land use differentially affects fungal communities and network complexity in northeast China
Authors: Xu Yanxia , Yang Zhao , Wang Xiaolong , Chai Hua , Li Shasha , Wu Yue , Wang Ruoding 
Published: November 2022

BackgroundThe soil fungal community is one of the most important drivers of the soil nutrient cycling that sustains plant growth. However, little research has been done on the effects of different land uses on soil fungal communities in northeast China.MethodsIn this study, we conducted a field experiment to investigate the effects of continuous cropping of grass, maize, and alfalfa on their respective fungal communities and co-occurrence networks.ResultsWe showed that the physicochemical properties of the soil, such as nitrate (NO3-N), available phosphorus, and soil pH, were the most important driving factors affecting the structure of the soil fungal community in different cropping systems. In addition, compared to the cultivation of grass and maize, the continuous cropping of alfalfa increased the abundance of several beneficial as well as pathogenic species, such as Mortierella and Gaiellales. In addition, the networks differed among plant species and according to the number of years of continuous cultivation.ConclusionThis suggests that the continuous cropping of alfalfa results in greater cooperation among fungi, which may be beneficial to the soil as well as to the development of the alfalfa.
A multi-omics study to characterize the transdifferentiation of human dermal fibroblasts to osteoblast-like cells
Authors: Pihlström Sandra , Määttä Kirsi , Öhman Tiina , Mäkitie Riikka E. , Aronen Mira , Varjosalo Markku , Mäkitie Outi , Pekkinen Minna 
Published: November 2022

Graphical AbstractIn this study, we developed an in vitro technique to transdifferentiate human dermal fibroblasts into osteoblast-like cells. Bone marrow-derived mesenchymal stem cells, the true progenitors of osteoblasts, were utilized as reference cell lines. We characterized the osteoblastic differentiation in the two cell types using transcriptomics and quantitative MS-based proteomics and phosphoproteomics. The osteoblastic-like phenotype was confirmed in both cell types by positive alkaline phosphatase and mineralization staining methods. In addition, both cell types showed altered gene and protein profiles in compliance with an osteoblastic differentiation.
Use of peripheral electrical stimulation on healthy individual and patients after stroke and its effects on the somatosensory evoked potentials. A systematic review
Authors: Mijic Marko , Jung Andres , Schoser Benedikt , Young Peter 
Published: November 2022

IntroductionTo date, a few studies have used somatosensory evoked potentials (SEP) to demonstrate cortical sensory changes among healthy subjects or to estimate cortical plasticity and rehabilitation prognosis in stroke patients after peripheral electrical stimulation (PES) intervention. The primary aim was to systematically review whether PES has a role in changing latencies and amplitudes of SEPs in healthy subjects and stroke patients. Moreover, we searched for a correlation between sensory and motor function assessments and changes in SEP components of included studies.MethodsThe following databases were searched: Pubmed/MEDLINE, Scopus/ScienceDirect, Web of Science/Clarivate, Cochrane Library, The Physiotherapy Evidence Database (PEDro), andClinicalTrials.gov. Titles and abstracts, as well as full-text reports, were screened for eligibility by two independent reviewers according to a priori defined eligibility criteria. There were no study limitations concerning the treatment of the upper limb, lower limb, or torso with PES.ResultsThe final systematic search resulted in 11,344 records, however only 10 were evaluated. We could not find enough evidence to confirm use of SEP as a predictor to estimate the rehabilitation prognosis after stroke. However, we found a correlation between different sensory and motor function assessments and changes in SEP components. The stroke studies involving PES that initiate a voluntary contraction used for a specific movement or task indicate a positive relationship and correlation to assessments of motor function. It could be indicated that PES have a predictive impact of sensory reorganization, as mirrored by the change in SEP amplitude and latency. However, it is not possible to verify the degree of connectivity between SEP and cortical plasticity. To confirm this hypothesis, we propose the conduction of randomized controlled trials in healthy volunteers and stroke patients.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/U7PSY.
Associations between dietary copper intake, general obesity and abdominal obesity risk: A nationwide cohort study in China
Authors: Wang Weiqi , Liu Lin , Shan Ruiqi , Wang Changhong 
Published: November 2022

ObjectiveCopper plays a crucial role in redox reactions. The aims of this research are to examine the effects of copper consumption on general obesity and abdominal obesity risk.MethodsOverall, data of 13,282 participants were obtained from the China Health and Nutrition Survey (1997–2011). A combination of individual 24-h recall and household survey was used to assess dietary intake. Time-dependent mixed effect Cox regression model treating family as a random effect were used to assess the associations between quintiles of copper intake, general obesity and abdominal obesity risk. Obesity was defined by BMI ≥ 28 kg/m2, and abdominal obesity was defined as waist circumference ≥85 cm in men and ≥80 cm in women.ResultsDuring follow-up, 1,073 and 4,583 incident cases of general obesity and abdominal obesity occurred respectively. There were U-shaped associations of dietary copper intakes with general obesity and abdominal obesity (P for nonlinearity &lt;0.001). In the general obesity track, compared with quintile 3 (reference category), participants in the top quintile and bottom quintile showed higher general obesity risk (HR, 2.00; 95%CI: 1.63, 2.45 for the top quintile, HR, 1.34; 95%CI: 1.08, 1.68 for the bottom quintile). In the abdominal obesity track, compared with quintile 3, the top quintile and bottom quintile were also associated with a significantly increased risk of abdominal obesity (HR, 1.68; 95%CI: 1.52, 1.87 for the top quintile, HR, 1.36; 95%CI: 1.22, 1.52 for the bottom quintile).ConclusionsWe demonstrated U-shaped associations between dietary copper, general and abdominal obesity risk in Chinese and emphasized the importance of maintaining appropriate copper intake level for the prevention of obesity.