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Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas. [ABSTRACT FROM AUTHOR]

The effects of the interaction between polygenes and the parent–child relationship on junior high school students' aggressive behaviors were explored through the frameworks of gene‐endophenotype‐behavior and neurophysiological basis. A total of 892 junior high school students participated in this study. They were asked to complete self‐reported questionnaires, and saliva samples were collected. Results showed that 5‐HTTLPR, MAOA‐uVNTR, COMT (rs4680), and Taq1 (rs1800497) of the DRD2 gene affected students' aggressive behaviors in an accumulative way. The polygenic risk score explained 3.4% of boys' aggression and 1.1% of girls' aggression. The interactions between polygenic risk score and parent–child conflict significantly affected the aggressive behaviors of male students, but did not show any significant effect on those of female students. The interactional effect of polygenic risk score and parent–child conflict on junior high school students' aggressive behaviors was completely mediated by frustration. However, the interaction effect of polygenic risk score and parent–child affinity on aggression was not affected by frustration. This study helps us better understand junior high school students' aggressive behaviors and promotes the prevention and correction of adolescents' problem behaviors. [ABSTRACT FROM AUTHOR]

Objective: Risk stratification plays a critical role in patients with asymptomatic carotid atherosclerotic stenosis. Heavy macrophage infiltration (HMC) is an important factor of plaque destabilization. However, in vivo imaging technologies and screening criteria for HMC remain limited. We aimed to (i) introduce algorithms for in vivo detection of macrophage infiltrations using optical coherence tomography (OCT) and (ii) to investigate the threshold of HMC and its association with plaque vulnerability. Methods: Ex vivo OCT images were co‐registered with histopathology in 282 cross‐sectional pairs from 19 carotid endarterectomy specimens. Of these, 197 randomly selected pairs were employed to define the parameters, and the remaining 85 pairs were used to evaluate the accuracy of the OCT‐based algorithm in detecting macrophage infiltrations. Clinical analysis included 93 patients receiving carotid OCT evaluation. The prevalence and burden of macrophage infiltration were analyzed. Multivariable and subgroup analysis were performed to investigate the association between HMC and plaque rupture. Results: The sensitivity and specificity of algorithm for detecting macrophage infiltration were 88.0% and 74.9%, respectively. Of 93 clinical patients, ruptured plaques exhibited higher prevalence of macrophage infiltration than nonruptured plaques (83.7% [36/43] vs 32.0% [16/50], p < 0.001). HMC was identified when the macrophage index was greater than 60.2 (sensitivity = 74.4%, specificity = 84.0%). Multivariable analysis showed that HMC and multiple calcification were independent risk factors for non‐lipid‐rich plaque rupture. Interpretation: This study provides a novel approach and screening criteria for HMC, which might be valuable for atherosclerotic risk stratification. [ABSTRACT FROM AUTHOR]

The immunity‐related GTPases (IRGs) belong to the interferon‐inducible GTPase protein family, which mediates cell autonomous and innate immunity response to intracellular pathogens. Yet, the cellular and physiological function of IRGC, a member of the IRG subfamily, has not been elucidated. Here, we show that testis‐specific IRGC is specifically and highly expressed in mature spermatozoa and is required for sperm motility. IRGC induction results in the clustering of lipid droplets and initiation of their physical contact with mitochondria. When examining clinical semen samples, IRGC expression is significantly lower in asthenozoospermia patients relative to healthy individuals. These unique effects of IRGC identify it as an important player in sperm motility, and show the potential of lipid metabolism‐targeting therapeutic intervention aimed at controlling asthenozoospermia. [ABSTRACT FROM AUTHOR]

Soil net nitrogen (N) mineralization is a key biogeochemical process influencing plant available N and net primary productivity in terrestrial ecosystems. However, the spatial variations and controlling factors of soil net N mineralization (RPNM) in arid and semi‐arid grasslands are less studied and unclear.In this study, we investigated the soil RPNM by performing a laboratory incubation experiment. Soil samples were collected from 30 sites in three east–west transects on the Inner Mongolia Plateau (MP), Loess Plateau (LP) and Tibetan Plateau (TP) along a 3200 km arid and semi‐arid grassland gradient, with each transect containing three different grassland types (meadow steppe [MS], typical steppe [TS] and desert steppe [DS], respectively).Results showed that the average RPNM values ranged from −0.37 to 1.29 mg N kg−1 day−1, with a significantly lower RPNM found in the DS (0.08 ± 0.01 mg N kg−1 day−1) compared with those in the MS (0.30 ± 0.03 mg N kg−1 day−1) and in the TS (0.33 ± 0.03 mg N kg−1 day−1) in the MP and LP transects (p < 0.05). This difference could be explained by variations in climatic and soil factors, such as hydrothermal index (HT), the soil pH, soil organic matter (SOM) and precipitation. However, no significant differences in RPNM were found among different grassland types in the TP transect, possibly due to the similarly low microbial activity, as indicated by the microbial biomass carbon values. Across all three grassland transects, HT, SOM and microbial variables were the major factors controlling RPNM, which together explained 20.7% of the variation in RPNM. Further structural equation model analysis indicated HT was an integral predictor of RPNM, directly or indirectly via SOM, under different conditions of precipitation and temperature.Our findings provide field evidence and parameters for biogeochemical cycling to better predict future N transformation processes under changing precipitation and temperature regimes across a wide range of arid and semi‐arid grassland ecosystems. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

In this work, a novel, low molecular weight amphiphilic polymer (LAP) with high content of surface‐active functional groups was developed, and its effectiveness for emulsion‐based enhanced oil recovery (EOR) in relatively low permeability reservoirs was evaluated. The LAP polymer can potentially be synthesized on an industrial scale through a free radical polymerization reaction between acrylamide (AM), methyl acrylate (MAA), and the unsaturated surfactant monomer 2‐(acylamido)‐dodecane sulfonic acid (C12AMPS). The interfacial tension between 1000 mg L−1 LAP water solution and Bohai crude oil at 50 °C was reduced to a low value of around 0.2 mN m−1. Core flooding tests were also conducted to study the EOR potential and migration properties of LAP in porous media. The resistance and residual resistant factors of 1500 mg L−1 LAP solution were measured to be 51.0 ± 0.1 and 16.5 ± 0.1, respectively, suggesting LAP's great potential to be used for reservoir profile control. In addition, oil recovered from a three‐layer heterogeneous core by LAP solution was found to be comparable to that recovered using alkaline‐surfactant‐polymer (ASP) flooding. It is also worth mentioning that to accommodate different reservoir conditions, the molecular weight of LAP is adjustable by modifying the concentration of chain transfer agent, surfactant monomer, or initiator. [ABSTRACT FROM AUTHOR]

Perforated wells in ultra‐deep sandstone reservoirs are characterized by high reservoir temperature, high formation pressure, and high production, and sand production will cause severe safety hazards to these wells. Based on Drucker‐Prager (DP) rock failure criterion, a practical analytical model for predicting critical drawdown pressure (CDP) of sanding onset for perforated wells is established by comprehensively considering the influence of drag stress, formation water production, reservoir pressure depletion, temperature difference in the perforated wellbore. The proposed model is verified by field sanding onset monitoring data. The calculation results show that CDP changes with well inclination, and it decreases with the increase in wellbore temperature difference, reservoir pressure depletion, and water saturation. However, the CDP increases with the number of perforations and the ratio of diameter to length. The optimization of perforation parameters has an important influence on sand control. This study can effectively guide the prediction of CDP and provides basis for efficient and safe development of similar ultra‐deep and high yield sandstone reservoirs. [ABSTRACT FROM AUTHOR]

Under the impact of various uncertainties, the potential operation risk of the distribution network is gradually gaining more and more attention in both security and economy. To comprehensively determine the risk level, an operational risk assessment method considering multiple risk factors is proposed. Firstly, probabilistic models are established including temporal distributions of electric vehicles and uncertainties of renewable energy. Secondly, a time-sequential security risk assessment method with several security indicators including overvoltage risk, undervoltage risk, line-overload risk and load-loss risk is established using probabilistic load flow and dynamical sensitivity weight analysis method. Thirdly, conditional value at risk model is presented for time-varying economic risk considering line-loss risk and operational profit or loss risk of distributed generations. Finally, a risk early warning standard is proposed to realise the visualisation of risk warning by defining the risk level and risk area. Simulations of different scenarios are conducted on the modified IEEE 34-bus radial test system and the results reveal that the proposed strategy is effective and practical. [ABSTRACT FROM AUTHOR]

Electronics allowing for visible light to pass through are attractive, where a key challenge is to make the core functional units transparent. Here, it is shown that transparent electronics can be constructed by epitaxial growth of metal–organic frameworks (MOFs) on single‐layer graphene (SLG) to give a desirable transparency of 95.7% to 550 nm visible light and an electrical conductivity of 4.0 × 104 S m−1. Through lattice and symmetry match, collective alignment of MOF pores and dense packing of MOFs vertically on SLG are achieved, as directly visualized by electron microscopy. These MOF‐on‐SLG constructs are capable of room‐temperature recognition of gas molecules at the ppb level with a linear range from 10 to 108 ppb, providing real‐time gas monitoring function in transparent electronics. The corresponding devices can be fabricated on flexible substrates with large size, 3 × 5 cm, and afford continuous folding for more than 200 times without losing conductivity or transparency. [ABSTRACT FROM AUTHOR]

Acephalic spermatozoa, characterized by the headless sperm in the ejaculate, is a rare type of teratozoospermia. Here, we recruited two infertile patients with an acephalic spermatozoa phenotype to investigate the genetic pathology of acephalic spermatozoa. Whole‐exome sequencing analysis was performed and found mutations in CEP112 in the two patients: homozygous mutation c.496C > T:p.(Arg166X) in exon 5 from P1; and the biallelic mutations c.2074C > T:p.(Arg692Trp) in exon 20 and c.2104C > T:p.(Arg702Cys) in exon 20 from P2. Sanger sequencing confirmed the CEP112 mutations in the two patients. In silico analysis revealed that these CEP112 mutations are deleterious and rare, and all the mutations impact the coiled‐coil domain of CEP112, which may affect the protein function. The c.496C > T:p.Arg166X resulted in a truncated CEP112, which was verified by the mutation expression plasmid. The CEP112 expression was significantly reduced in the P2, suggesting the biallelic mutations c.2074C > T and c.2104C > T may affect the function and stability of CEP112. Therefore, we speculate that the loss‐of‐function mutations in CEP112 may be account for the human acephalic spermatozoa phenotype. [ABSTRACT FROM AUTHOR]

The majority of men with defects in spermatogenesis remain undiagnosed. Acephalic spermatozoa is one of the diseases causing primary infertility. However, the causes underlying over half of affected cases remain unclear. Here, we report by whole‐exome sequencing the identification of homozygous and compound heterozygous truncating mutations in PMFBP1 of two unrelated individuals with acephalic spermatozoa. PMFBP1 was highly and specifically expressed in human and mouse testis. Furthermore, immunofluorescence staining in sperm from a normal control showed that PMFBP1 localizes to the head‐flagella junction region, and the absence of PMFBP1 was confirmed in patients harboring PMFBP1 mutations. In addition, we generated Pmfbp1 knock‐out (KO) mice, which we found recapitulate the acephalic sperm phenotype. Label‐free quantitative proteomic analysis of testicular sperm from Pmfbp1 KO and control mice showed 124 and 35 proteins, respectively, increased or decreased in sperm from KO mice compared to that found in control mice. Gene ontology analysis indicates that the biological process of Golgi vesicle transport was the most highly enriched in differentially expressed proteins, indicating process defects related to Golgi complex function may disturb formation of the head‐neck junction. Collectively, our data indicate that PMFBP1 is necessary for sperm morphology in both humans and mice, and that biallelic truncating mutations in PMFBP1 cause acephalic spermatozoa. [ABSTRACT FROM AUTHOR]

Primary malignant melanoma of the lung is an extremely rare pulmonary carcinoma. Only 45 cases have been reported in the literature. Herein, we report a case of a 46‐year‐old male patient with an O Rh negative blood type who presented with pulmonary bronchial symptoms and underwent lobectomy. Genetic testing was also performed but no targetable mutations were found, and the patient's PD‐L1 RNA level was low. He developed brain metastasis four months after surgery and received radiotherapy but died 21 months after diagnosis. We review the published cases of this rare pulmonary lesion. [ABSTRACT FROM AUTHOR]

Aim To determine the absolute oral bioavailability ( Fp.o.) of saxagliptin and dapagliflozin using simultaneous intravenous 14C-microdose/therapeutic oral dosing (i.v.micro + oraltherap). Methods The Fp.o. values of saxagliptin and dapagliflozin were determined in healthy subjects ( n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively. Results The geometric mean point estimates (90% confidence interval) Fp.o. values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap. Conclusions Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability. [ABSTRACT FROM AUTHOR]

Abstract: Syntabulin is a microtubule-associated protein that mediates anterograde transport of vesicles to neuronal processes. Here, we found that syntabulin was expressed in mouse pancreas and insulin-secreting β-cells, and that it partially co-localized with microtubule and insulin-containing granules. The association of syntabulin with these organelles increased upon glucose stimulation. Knock-down of syntabulin by shRNA reduced both basal and glucose-stimulated insulin secretion, and diminished cAMP-Epac2 and cAMP-PKA potentiated insulin secretion. Additionally, syntabulin was preferentially phosphorylated by the Epac2 agonist 8-pCPT-2′-O-Me-cAMP, suggesting that syntabulin could be a novel effector of Epac2 and play a critical role in cAMP-enhanced insulin secretion. [Copyright &y& Elsevier]

Dethiobiotin synthetase (DTBS) is involved in the biosynthesis of biotin in bacteria, fungi, and plants. As humans lack this pathway, DTBS is a promising antimicrobial drug target. We determined structures of DTBS from Helicobacter pylori (hpDTBS) bound with cofactors and a substrate analog, and described its unique characteristics relative to other DTBS proteins. Comparison with bacterial DTBS orthologs revealed considerable structural differences in nucleotide recognition. The C-terminal region of DTBS proteins, which contains two nucleotide-recognition motifs, differs greatly among DTBS proteins from different species. The structure of hpDTBS revealed that this protein is unique and does not contain a C-terminal region containing one of the motifs. The single nucleotide-binding motif in hpDTBS is similar to its counterpart in GTPases; however, isothermal titration calorimetry binding studies showed that hpDTBS has a strong preference for ATP. The structural determinants of ATP specificity were assessed with X-ray crystallographic studies of hpDTBS·ATP and hpDTBS·GTP complexes. The unique mode of nucleotide recognition in hpDTBS makes this protein a good target for H. pylori-specific inhibitors of the biotin synthesis pathway. Database Coordinates and structure factors for structures presented in this article have been deposited in the Protein Data Bank under the following accession codes: - apo-form; - hpDTBS·8-ac·ADP· in P212121 form; - hpDTBS·ATP; - hpDTBS·8-ac:ADP· in C2 form; - hpDTBS·GTP; - hpDTBS·ANP; - 8-ac·GDP·; and - hpDTBS·GDP·. Structured digital abstract [ABSTRACT FROM AUTHOR]

Two firms with asymmetric costs engage in a Stackelberg game under multiple levels of uncertainty with information updating. A product life cycle perspective is employed to reveal when and why a second-mover may have an advantage. At early stages in the product life cycle, when uncertainty is the dominating factor, the impact of uncertainty may be either positive or negative. As a result, the Stackelberg leader faces the possibility of either overshooting or losing its market leadership position to the second-mover. In later market stages, when cost is more important, a process-innovating second-mover may accrue higher profits. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The structure of the Atu1476 protein from Agrobacterium tumefaciens was determined at 2 Å resolution. The crystal structure and biochemical characterization of this enzyme support the conclusion that this protein is an S-formylglutathione hydrolase ( AtuSFGH). The three-dimensional structure of AtuSFGH contains the α/β hydrolase fold topology and exists as a homo-dimer. Contacts between the two monomers in the dimer are formed both by hydrogen bonds and salt bridges. Biochemical characterization reveals that AtuSFGH hydrolyzes CO bonds with high affinity toward short to medium chain esters, unlike the other known SFGHs which have greater affinity toward shorter chained esters. A potential role for Cys54 in regulation of enzyme activity through S-glutathionylation is also proposed. [ABSTRACT FROM AUTHOR]

The structure of the PA1607 protein from Pseudomonas aureginosa was determined at 1.85 Å resolution using the Se-Met multiwavelength anomalous diffraction (MAD) technique. PA1607 forms a dimer and adopts a winged-helix motif similar to the MarR family of transcription regulators, though it has an unusual dimerization profile. The DNA-binding regions and a putative metal-binding site are not conserved in PA1607. [ABSTRACT FROM AUTHOR]

The S-adenosyl-L-methionine (SAM)-dependent methyltransferases represent a diverse and biologically important class of enzymes. These enzymes utilize the ubiquitous methyl donor SAM as a cofactor to methylate proteins, small molecules, lipids, and nucleic acids. Here we present the crystal structure of PH1915 from Pyrococcus horikoshii OT3, a predicted SAM-dependent methyltransferase. This protein belongs to the Cluster of Orthologous Group 1092, and the presented crystal structure is the first representative structure of this protein family. Based on sequence and 3D structure analysis, we have made valuable functional insights that will facilitate further studies for characterizing this group of proteins. Specifically, we propose that PH1915 and its orthologs are rRNA- or tRNA-specific methyltransferases. [ABSTRACT FROM AUTHOR]

As part of our structural proteomics initiative, we have determined the crystal structure of MTH1491, a previously uncharacterized hypothetical protein from Methanobacterium thermoautotrophicum. MTH1491 is one of numerous structural genomics targets selected in a genome-wide survey of uncharacterized proteins. It belongs to a family of proteins whose biological function is not known. The crystal structure of MTH1491, the first structure for this family of proteins, consists of an overall five-stranded parallel β-sheet with strand order 51234 and flanking helices. The oligomeric form of this molecule is a trimer as seen from both crystal contacts and gel filtration studies. Analysis revealed that the structure of MTH1491 is similar to that of dehydrogenases, amidohydrolases, and oxidoreductases. Using a combination of sequence and structural analyses, we showed that MTH1491 does not belong to either the dehydrogenase or the amidohydrolase superfamilies of proteins. [ABSTRACT FROM AUTHOR]

In the meiotic prophase, programmed SPO11‐linked DNA double‐strand breaks (DSBs) are repaired by homologous recombination (HR). The MRE11‐RAD50‐NBS1 (MRN) complex is essential for initiating DNA end resection, the first step of HR. However, residual DNA end resection still occurs in Nbs1 knockout (KO) spermatocytes for unknown reasons. Here, we show that DNA end resection is completely abolished in Mre11 KO spermatocytes. In addition, Mre11 KO, but not Nbs1 KO, undifferentiated spermatogonia are rapidly exhausted due to DSB accumulation, proliferation defects, and elevated apoptosis. Cellular studies reveal that a small amount of MRE11 retained in the nucleus of Nbs1 KO cells likely underlies the differences between Mre11 and Nbs1 KO cells. Taken together, our study not only demonstrates an irreplaceable role of the MRE11 in DNA end resection at SPO11‐linked DSBs but also unveils a unique function of MRE11 in maintaining the long‐term viability of undifferentiated spermatogonia. [ABSTRACT FROM AUTHOR]

The genome of the thermophilic fungus Scytalidium thermophilum (strain CBS 625.91) harbours a wide range of genes involved in carbohydrate degradation, including three genes, abf62A, abf62B and abf62C, predicted to encode glycoside hydrolase family 62 (GH62) enzymes. Transcriptome analysis showed that only abf62A and abf62C are actively expressed during growth on diverse substrates including straws from barley, alfalfa, triticale and canola. The abf62A and abf62C genes were expressed in Escherichia coli and the resulting recombinant proteins were characterized. Calcium-free crystal structures of Abf62C in apo and xylotriose bound forms were determined to 1.23 and 1.48 Å resolution respectively. Site-directed mutagenesis confirmed Asp55, Asp171 and Glu230 as catalytic triad residues, and revealed the critical role of non-catalytic residues Asp194, Trp229 and Tyr338 in positioning the scissile α-L-arabinofuranoside bond at the catalytic site. Further, the +2R substrate-binding site residues Tyr168 and Asn339, as well as the +2NR residue Tyr226, are involved in accommodating long-chain xylan polymers. Overall, our structural and functional analysis highlights characteristic differences between Abf62A and Abf62C, which represent divergent subgroups in the GH62 family., (© 2014 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.)

Aim: To determine the absolute oral bioavailability (F(p.o.) ) of saxagliptin and dapagliflozin using simultaneous intravenous ¹⁴C-microdose/therapeutic oral dosing (i.v.micro + oraltherap)., Methods: The F(p.o.) values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively., Results: The geometric mean point estimates (90% confidence interval) F(p.o) . values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap., Conclusions: Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability., (© 2012 Bristol-Myers Squibb, Co.. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)