bluuebunny/crossref_metadata_2025_split huggingface dataset:
Schedule and magnitude of reproductive investment under immune trade-offs explains sex differences in immunity
Authors: Metcalf C. Jessica E. , Graham Andrea L. 
Published: October 2018

AbstractSex differences in immunity are found in many species. Known immune mechanisms in birds and mammals suggest that pathogen detection may be amplified in females, whereas in males, pathogen killing is amplified. We show that these immunological profiles emerge as distinct peaks on a fitness landscape defined by sensitivity-specificity and infection-immunopathology immune tradeoffs. What selection pressures might drive males and females towards separate peaks? Surprisingly, modeling immune trade-offs alone results in a pattern of sex differences that is the reverse of what is observed. By integrating these trade-offs into a life-history framework, where the schedule and magnitude of reproductive investment differs between the sexes, we find that increased age-specific infection and mortality risks during parental investment can push females towards the peak that aligns with empirical observations. Overall, our model suggests enhanced pathogen detection (in females) versus enhanced pathogen killing (in males) is best explained if shared immune tradeoffs interact with sex-specific reproductive schedules and risks. We suggest ways to test this framework empirically.
Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II
Authors: Li Yujing , Liu Yunhua , Xu Hanchen , Jiang Guanglong , Van der Jeught Kevin , Fang Yuanzhang , Zhou Zhuolong , Zhang Lu , Frieden Michael , Wang Lifei , Luo Zhenhua , Radovich Milan , Schneider Bryan P. , Deng Yibin , Liu Yunlong , Huang Kun , He Bin , Wang Jin , He Xiaoming , Zhang Xinna , Ji Guang , Lu Xiongbin 
Published: October 2018

AbstractHeterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.
Defluorosilylation of fluoroarenes and fluoroalkanes
Authors: Cui Benqiang , Jia Shichong , Tokunaga Etsuko , Shibata Norio 
Published: October 2018

AbstractDirect activation of carbon–fluorine bonds (C–F) to introduce the silyl or boryl groups and generate valuable carbon–silicon (C–Si) or carbon–boron (C–B) bonds is important in the development of synthetically useful reactions, owing to the unique opportunities for further derivatization to achieve more complex molecules. Despite considerable progress of C–F bond activation to construct carbon–carbon (C–C) and carbon–heteroatom (C–X) bond formation, the defluorosilylation via C–F cleavage has been rarely demonstrated. Here, we report an ipso-silylation of aryl fluorides via cleavage of unactivated C–F bonds by a Ni catalyst under mild conditions and without the addition of any external ligand. Alkyl fluorides are also directly converted into the corresponding alkyl silanes under similar conditions, even in the absence of the Ni catalyst. Applications of this protocol in late-stage defluorosilylation of potentially bioactive pharmaceuticals and in further derivatizations are also carried out.
Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1
Authors: Daou Salima , Barbour Haithem , Ahmed Oumaima , Masclef Louis , Baril Caroline , Sen Nkwe Nadine , Tchelougou Daméhan , Uriarte Maxime , Bonneil Eric , Ceccarelli Derek , Mashtalir Nazar , Tanji Mika , Masson Jean-Yves , Thibault Pierre , Sicheri Frank , Yang Haining , Carbone Michele , Therrien Marc , Affar El Bachir 
Published: October 2018

AbstractThe tumor suppressor and deubiquitinase (DUB) BAP1 and its Drosophila ortholog Calypso assemble DUB complexes with the transcription regulators Additional sex combs-like (ASXL1, ASXL2, ASXL3) and Asx respectively. ASXLs and Asx use their DEUBiquitinase ADaptor (DEUBAD) domain to stimulate BAP1/Calypso DUB activity. Here we report that monoubiquitination of the DEUBAD is a general feature of ASXLs and Asx. BAP1 promotes DEUBAD monoubiquitination resulting in an increased stability of ASXL2, which in turn stimulates BAP1 DUB activity. ASXL2 monoubiquitination is directly catalyzed by UBE2E family of Ubiquitin-conjugating enzymes and regulates mammalian cell proliferation. Remarkably, Calypso also regulates Asx monoubiquitination and transgenic flies expressing monoubiquitination-defective Asx mutant exhibit developmental defects. Finally, the protein levels of ASXL2, BAP1 and UBE2E enzymes are highly correlated in mesothelioma tumors suggesting the importance of this signaling axis for tumor suppression. We propose that monoubiquitination orchestrates a molecular symbiosis relationship between ASXLs and BAP1.
Probing flow-induced nanostructure of complex fluids in arbitrary 2D flows using a fluidic four-roll mill (FFoRM)
Authors: Corona Patrick T. , Ruocco Nino , Weigandt Kathleen M. , Leal L. Gary , Helgeson Matthew E. 
Published: October 2018

AbstractEngineering flow processes to direct the microscopic structure of soft materials represents a growing area of materials research. In situ small-angle neutron scattering under flow (flow-SANS) is an attractive probe of fluid microstructure under simulated processing conditions, but current capabilities require many different sample environments to fully interrogate the deformations a fluid experiences in a realistic processing flow. Inspired by recent advances in microfluidics, we present a fluidic four-roll mill (FFoRM) capable of producing tunable 2D flow fields for in situ SANS measurements, that is intended to allow characterization of complex fluid nanostructure under arbitrary complex flows within a single sample environment. Computational fluid dynamics simulations are used to design a FFoRM that produces spatially homogeneous and sufficiently strong deformation fields. Particle tracking velocimetry experiments are then used to characterize the flows produced in the FFoRM for several classes of non-Newtonian fluids. Finally, a putative FFoRM-SANS workflow is demonstrated and validated through the characterization of flow-induced orientation in a semi-dilute cellulose nanocrystal dispersion under a range of 2D deformations. These novel experiments confirm that, for steady state straining flows at moderate strain rates, the nanocrystals orient along the principal strain-rate axis, in agreement with theories for rigid, rod-like Brownian particles in a homogeneous flow.
Hydrodynamic Clustering of Human Sperm in Viscoelastic Fluids
Authors: Ishimoto Kenta , Gaffney Eamonn A. 
Published: October 2018

AbstractWe have numerically investigated sperm clustering behaviours, modelling cells as superpositions of regularised flow singularities, coarse-grained from experimentally obtained digital microscopy of human sperm, both in watery medium and a highly viscous–weakly elastic, methylcellulose medium. We find that the cell yaw and cell pulling dynamics inhibit clustering in low viscosity media. In contrast clustering is readily visible in simulations modelling sperm within a methylcellulose medium, in line with previous observations that bovine sperm clustering is much more prominent in a rheological polyacrylamide medium. Furthermore, the fine-scale details of sperm flagellar movement substantially impact large-scale collective behaviours, further motivating the need for the digital microscopy and characterization of sperm to understand their dynamics.
A novel mechanobiological model can predict how physiologically relevant dynamic loading causes proteoglycan loss in mechanically injured articular cartilage
Authors: Orozco Gustavo A. , Tanska Petri , Florea Cristina , Grodzinsky Alan J. , Korhonen Rami K. 
Published: October 2018

AbstractCartilage provides low-friction properties and plays an essential role in diarthrodial joints. A hydrated ground substance composed mainly of proteoglycans (PGs) and a fibrillar collagen network are the main constituents of cartilage. Unfortunately, traumatic joint loading can destroy this complex structure and produce lesions in tissue, leading later to changes in tissue composition and, ultimately, to post-traumatic osteoarthritis (PTOA). Consequently, the fixed charge density (FCD) of PGs may decrease near the lesion. However, the underlying mechanisms leading to these tissue changes are unknown. Here, knee cartilage disks from bovine calves were injuriously compressed, followed by a physiologically relevant dynamic compression for twelve days. FCD content at different follow-up time points was assessed using digital densitometry. A novel cartilage degeneration model was developed by implementing deviatoric and maximum shear strain, as well as fluid velocity controlled algorithms to simulate the FCD loss as a function of time. Predicted loss of FCD was quite uniform around the cartilage lesions when the degeneration algorithm was driven by the fluid velocity, while the deviatoric and shear strain driven mechanisms exhibited slightly discontinuous FCD loss around cracks. Our degeneration algorithm predictions fitted well with the FCD content measured from the experiments. The developed model could subsequently be applied for prediction of FCD depletion around different cartilage lesions and for suggesting optimal rehabilitation protocols.
Functions of CsGPA1 on the hypocotyl elongation and root growth of cucumbers
Authors: Yan Yan , Zhang Wenna , Li Yansu , He Chaoxing , Gao Lihong , Yu Xianchang 
Published: October 2018

AbstractG proteins regulate shoot, root, and epidermis development, as well as biotic stress tolerance in plants; however, most studies have examined model plants and less attention has been paid to the function of G proteins in horticultural plants. Here, we identified a G protein, CsGPA1, from cucumber and studied its function in seedling development of cucumbers. CsGPA1 is a peptide of 392 amino acids with a predicted molecular mass of 44.6 kDa. Spatiotemporal expression analysis found that endogenous CsGPA1 was highly expressed in roots and young leaves. Immunohistochemical assay revealed that functional CsGPA1 was present in the plasma membranes of the epidermis and cortex, and in the cytosol of the endodermis, parenchyma, and vasculature of root meristematic cells. In comparison with wild-type seedlings, CsGPA1-overexpressing transgenic lines exhibited enhanced seed germination and earlier seedling development including hypocotyl elongation and root growth. In contrast, RNAi silencing of the CsGPA1 gene inhibited seedling growth and development. Further study showed that CsGPA1 controled hypocotyl elongation and root growth via promoting cell size and the meristem of hypocotyl and root tip cells of cucumber plants. Our study expands the roles of G proteins in plants and helps to elucidate the mechanism by which cucumber regulates early seedling development.
Changes of Arterial Pulse Waveform Characteristics with Gestational Age during Normal Pregnancy
Authors: Li Kunyan , Zhang Song , Yang Lin , Jiang Hongqing , Chi Zhenyu , Wang Anran , Yang Yimin , Li Xuwen , Hao Dongmei , Zhang Lei , Zheng Dingchang 
Published: October 2018

AbstractArterial pulse waveform analysis has been widely used to reflect physiological changes in the cardiovascular system. This study aimed to comprehensively investigate the changes of waveform characteristics of both photoplethysmographic (PPG) and radial pulses with gestational age during normal pregnancy. PPG and radial pulses were simultaneously recorded from 130 healthy pregnant women at seven gestational time points. After normalizing the arterial pulse waveforms, the abscissa of notch point, the total pulse area and the reflection index were extracted and compared between different measurement points and between the PPG and radial pulses using post-hoc multiple comparisons with Bonferrioni correction. The results showed that the effect of gestational age on all the three waveform characteristics was significant (all p < 0.001) after adjusting for maternal age, heart rate and blood pressures. All the three waveform characteristics demonstrated similar changing trends with gestational age, and they were all significantly different between the measurements from gestational week 12–15 and the others (all p < 0.05, except for the PPG total pulse area between the first and second measurement points). In conclusion, this study has comprehensively quantified similar changes of both PPG and radial pulse waveform characteristics with gestational age.
Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice
Authors: Kuno Atsushi , Hosoda Ryusuke , Sebori Rio , Hayashi Takashi , Sakuragi Hiromi , Tanabe Mika , Horio Yoshiyuki 
Published: October 2018

AbstractAutophagy activation improves the phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, although the underlying mechanisms are obscure. We previously found that resveratrol, a strong inducer of autophagy, ameliorates the cardiac pathology of mdx mice. Autophagy could eliminate damaged mitochondria, a major source of intracellular reactive oxygen species (ROS), although there is no evidence for mitochondriopathy in dystrophic cardiomyopathy. To elucidate resveratrol’s function, we investigated the deletion of mitochondrial DNA (mtDNA), autophagy of damaged mitochondria (mitophagy), and ROS accumulation in the mdx mouse heart. Low levels of normal mtDNA and abnormal accumulations of mitochondria-containing autophagosomes were found in the mdx mouse heart. Administering resveratrol to mdx mice for 56 weeks ameliorated the cardiomyopathy, with significant reductions in the amount of mtDNA deletion, the number of mitochondria-containing autophagosomes, and the ROS levels. Resveratrol induced nuclear FoxO3a accumulation and the expression of autophagy-related genes, which are targets of FoxOs. The most effective dose in mdx mice was 0.4 g resveratrol/kg food. In conclusion, resveratrol improved cardiomyopathy by promoting mitophagy in the mdx mouse heart. We propose that acquired mitochondriopathy worsens the pathology of DMD and is a potential therapeutic target for the cardiomyopathy in DMD patients.
Effect of Pufa Substrates on Fatty Acid Profile of Bifidobacterium breve Ncimb 702258 and CLA/CLNA Production in Commercial Semi-Skimmed Milk
Authors: Fontes Ana Luiza , Pimentel Lígia , Rodríguez-Alcalá Luis Miguel , Gomes Ana 
Published: October 2018

AbstractCurrent research on lipids is highlighting their relevant role in metabolic/signaling pathways. Conjugated fatty acids (CFA), namely isomers of linoleic and linolenic acid (i.e. CLA and CLNA, respectively) can positively modulate inflammation processes and energy metabolism, promoting anti-carcinogenic and antioxidant effects, improved lipid profiles and insulin resistance, among others. Bioactive doses have been indicated to be above 1 g/d, yet these cannot be achieved through a moderate intake (i.e. 1–2 servings) of natural sources, and certain CLA-containing products have limited commercial availability. Such handicaps have fueled research interest in finding alternative fortification strategies. In recent years, screening of dairy products for CFA-producing bacteria has attracted much attention and has led to the identification of some promising strains, including Bifidobacterium breve NCIMB 702258. This strain has shown interesting producing capabilities in model systems as well as positive modulation of lipid metabolism activities in animal studies. Accordingly, the aim of this research work was to assay B. breve NCIMB 702258 in semi-skimmed milk to produce a probiotic fermented dairy product enriched in bioactive CLA and CLNA. The effect of substrates (LA, α-LNA and γ-LNA) on growth performance and membrane fatty acids profile was also studied, as these potential modifications have been associated to stress response. When tested in cys-MRS culture medium, LA, α-LNA and γ-LNA impaired the fatty acid synthesis by B. breve since membrane concentrations for stearic and oleic acids decreased. Variations in the C18:1 c11 and lactobacillic acid concentrations, may suggest that these substrates are also affecting the membrane fluidity. Bifidobacterium breve CFA production capacity was first assessed in cys-MRS with LA, α-LNA, γ-LNA or all substrates together at 0.5 mg/mL each. This strain did not produce CFA from γ-LNA, but converted 31.12% of LA and 68.20% of α-LNA into CLA and CLNA, respectively, after incubation for 24 h at 37 °C. In a second phase, B. breve was inoculated in a commercial semi-skimmed milk with LA, α-LNA or both at 0.5 mg/mL each. Bifidobacterium breve revealed a limited capacity to synthesize CLA isomers, but was able to produce 0.062–0.115 mg/mL CLNA after 24 h at 37 °C. However, organoleptic problems were reported which need to be addressed in future studies. These results show that although CFA were produced at too low concentrations to be able to achieve solely the bioactive dose in one daily portion size, fermented dairy products are a suitable vector to deliver B. breve NCIMB 702258.
Predicting the need for a reduced drug dose, at first prescription
Authors: Coulet Adrien , Shah Nigam H. , Wack Maxime , Chawki Mohammad B. , Jay Nicolas , Dumontier Michel 
Published: October 2018

AbstractPrescribing the right drug with the right dose is a central tenet of precision medicine. We examined the use of patients’ prior Electronic Health Records to predict a reduction in drug dosage. We focus on drugs that interact with the P450 enzyme family, because their dosage is known to be sensitive and variable. We extracted diagnostic codes, conditions reported in clinical notes, and laboratory orders from Stanford’s clinical data warehouse to construct cohorts of patients that either did or did not need a dose change. After feature selection, we trained models to predict the patients who will (or will not) require a dose change after being prescribed one of 34 drugs across 23 drug classes. Overall, we can predict (AUC ≥ 0.70–0.95) a dose reduction for 23 drugs and 22 drug classes. Several of these drugs are associated with clinical guidelines that recommend dose reduction exclusively in the case of adverse reaction. For these cases, a reduction in dosage may be considered as a surrogate for an adverse reaction, which our system could indirectly help predict and prevent. Our study illustrates the role machine learning may take in providing guidance in setting the starting dose for drugs associated with response variability.
A Team Approach to Response to Intervention for Speech Sound Errors in the School Setting
Authors: Bruce Laurel , Lynde Sue , Weinhold Juliet , Peter Beate 
Published: October 2018

Purpose
Response to intervention (RTI) has been used within the school setting to support students at risk for a variety of communication disorders. Through RTI, these students can receive services prior to determining eligibility for special education, allowing students with speech sound errors (SSEs) to receive support from a speech-language pathologist speech-language pathologist support while still in the stage of speech sound development.

Method
This article discusses the implementation of a team-based RTI model spanning 6 years, which targeted three hundred eighty-nine 7- to 8.5-year-old students with SSEs.

Results
One hundred seventy-two students completed treatment through the RTI process, requiring an average of 6 therapy hours. One hundred eight RTI students needed an Individualized Education Program (IEP) to complete their treatment. Of these students, a subset of 32 who started treatment through RTI and finished through an IEP required an average of 53 therapy hours. This is significantly less than the average of 82 hours found through chart reviews of our own district IEPs.

Conclusion
An RTI process using individual therapy has the potential to reduce the overall treatment time needed for speech sound remediation. Advantages and drawbacks in using an RTI team model for SSEs and providing therapy through individual sessions are discussed.
Fast velocity trajectory planning and control algorithm of intelligent 4WD electric vehicle for energy saving using time‐based MPC
Authors: Wu Dong‐mei , Li Yue , Du Chang‐qing , Ding Hai‐tao , Li Yang , Yang Xiao‐bo , Lu Xin‐yue 
Published: October 2018

For intelligent four‐wheel‐drive (4WD) electric vehicle (EV), the vehicle speed can be planned and controlled for energy saving based on the slope information of road ahead. To reduce the calculation load of the optimisation algorithm, the model predictive control (MPC) method is formulated based on the time horizon in this study. Furthermore, a fast gradient method based control tool‐GARMPC is used to solve the optimisation problem. First, the longitudinal dynamics model of 4WD EV based on time horizon and distance horizon is established based on the road slope information, respectively. Second, the MPC problem based on the time‐discrete model is formulated and solved by GARMPC tool. For comparison, a dynamic program (DP) control method is introduced based on the distance‐discrete model. Finally, the simulation is conducted under a designed road condition and a real measured road condition. The results show that the time‐horizon based MPC method can significantly reduce the energy consumption compared with the proportion integration differentiation control method, which is similar to the driver's operation. Compared with the DP optimisation method, the time‐based MPC method reduces the calculation time to smaller than 1 ms, which is essential for real‐time application in a road vehicle.