bluuebunny/crossref_metadata_2025 huggingface dataset:
Sunlit, controlled‐environment chambers are essential for comparing plant responses to various climates
Authors: Allen L.H. , Boote K.J. , Jones J.W. , Jones P.H. , Pickering N.B. , Baker J.T. , Vu J.C.V. , Gesch R.W. , Thomas J.M.G. , Prasad P.V.V.
Published: August 2020

Unique capabilities of various systems for studying the impacts of rising atmospheric CO2 concentration and other environmental factors on growth and yield of plants are presented. These systems include soil–plant–atmosphere research (SPAR) chambers, free‐air carbon dioxide enrichment (FACE) facilities, temperature‐gradient greenhouses (TGG), and open top chambers (OTC). The SPAR chambers have several advantages compared to FACE and other facilities, including: (a) constant CO2 concentration and stabile setpoints; (b) CO2 concentration controlled to any range of sub‐ambient through supra‐ambient levels, providing comparison of plant responses to past and future climates; (c) precise air and dewpoint temperature setpoints; (d) calculation of whole‐canopy photosynthesis and evapotranspiration rates at short time intervals; (e) calculation of whole‐canopy respiration rates during the night; (f) determination of plant responses to temperature alone or including other factors; (g) multiple chambers for simultaneous comparison of plant responses to varying environments, providing data for plant growth modeling; (h) low operating expense for CO2 concentration; and (i) capability of measuring N2 fixation rates in the rooting zone of legumes or methane emissions from rice (Oryza sativa L.). SPAR systems were better suited than FACE systems for more than half of the attributes of enrichment systems identified in this paper. Limitations of plant responses due to fluctuating elevated CO2 concentration and limitations of range of elevated CO2 concentration exist for FACE systems. Controlled environments are needed for developing mathematical growth response functions under a wide range of conditions. Finally, we identified a use of portable SPAR chambers within FACE experiments for confirmation of diminished plant photosynthesis in fluctuating CO2 concentration.
Follicular Lymphoma Evaluation Index (FLEX): A new clinical prognostic model that is superior to existing risk scores for predicting progression‐free survival and early treatment failure after frontline immunochemotherapy
Authors: Mir Farheen , Mattiello Federico , Grigg Andrew , Herold Michael , Hiddemann Wolfgang , Marcus Robert , Seymour John F. , Bolen Christopher R. , Knapp Andrea , Nielsen Tina , Casulo Carla
Published: August 2020

Patients with advanced‐stage follicular lymphoma (FL) who progress early after receiving first‐line therapy have poor overall survival (OS). Currently applied clinical prognostic models such as FL International Prognostic Index [FLIPI], FLIPI‐2 and PRIMA‐Prognostic Index [PRIMA‐PI] have suboptimal sensitivity and specificity to predict this poor prognosis subgroup. The primary objective was to develop a novel prognostic model, the FL Evaluation Index (FLEX) score, to identify high‐risk patients and compare its performance with FLIPI, FLIPI‐2 and PRIMA‐PI. Progression‐free survival (PFS) after first‐line immunochemotherapy was the key endpoint, while OS and progression of disease within 24 months (POD24) were also assessed. The model, which includes nine clinical variables, was developed using a cohort of patients with previously untreated advanced‐stage FL from the phase 3 GALLIUM trial (NCT01332968). The performance of the model was validated using data from the SABRINA trial (NCT01200758). In GALLIUM (n = 1004; 127 with and 877 without POD24), FLEX increased the intergroup (low‐risk/high‐risk) difference in 2‐year and 3‐year PFS rates and demonstrated superior intergroup differences in 2‐year and 3‐year OS rates compared with FLIPI, FLIPI‐2 and PRIMA‐PI. Sensitivity for a high‐risk score to predict POD24 was 60% using FLEX compared with 53% for FLIPI and FLIPI‐2, and 69% for PRIMA‐PI, while specificity was 68% for FLEX compared with 58% for FLIPI, 59% for FLIPI‐2 and 48% for PRIMA‐PI. The prognostic value of FLEX in SABRINA was similar to FLIPI. Therefore, FLEX appears to perform better than existing prognostic models in previously untreated FL, in particular for the newer treatment regimens.
Genotype–phenotype correlation of 33 patients with maple syrup urine disease
Authors: Khalifa Ola A. , Imtiaz Faiqa , Ramzan Khushnooda , Zaki Osama , Gamal Radwa , Elbaik Lina , Rihan Shaimaa , Salam Ehab , Abdul‐Mawgoud Rehab , Hassan Magdy , Hassan Nahla , Saleh Eman , Seoudi Dina , Moustafa Amr S.
Published: August 2020

Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder due to defects in the branched‐chain α‐ketoacid dehydrogenase complex (BCKDC). MSUD varies in severity and its clinical spectrum is quite broad, ranging from mild to severe phenotypes. Thirty‐three MSUD patients were recruited into this study for molecular genetic variant profiling and genotype–phenotype correlation. Except for one patient, all other patients presented with the classic neonatal form of the disease. Seventeen different variants were detected where nine were novel. The detected variants spanned across the entire BCKDHA, BCKDHB and DBT genes. All variants were in homozygous forms. The commonest alterations were nonsense and frameshift variants, followed by missense variants. For the prediction of variant's pathogenicity, we used molecular modeling and several in silico tools including SIFT, Polyphen2, Condel, and Provean. In addition, six other tools were used for the prediction of the conservation of the variants' sites including Eigen‐PC, GERP++, SiPhy, PhastCons vertebrates and primates, and PhyloP100 rank scores. Herein, we presented a comprehensive characterization of a large cohort of patients with MSUD. The clinical severity of the variants' phenotypes was well correlated with the genotypes. The study underscores the importance of the use of in silico analysis of MSUD genotypes for the prediction of the clinical outcomes in patients with MSUD.
Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients
Authors: Sallum Juliana Maria Ferraz , Motta Fabiana Louise , Arno Gavin , Porto Fernanda Belga Ottoni , Resende Rosane Guazi , Belfort Rubens
Published: August 2020

Leber congenital amaurosis (LCA) and early‐onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10‐18 deletion.
Genetic testing for inherited retinal degenerations: Triumphs and tribulations
Authors: Branham Kari , Schlegel Dana , Fahim Abigail T. , Jayasundera K. Thiran
Published: August 2020

Inherited retinal degenerations (IRDs) are a genotypically and phenotypically diverse group of conditions. Great strides have been made toward identifying the genetic basis for these conditions over the last 30 years—more than 270 different genes involved in syndromic and nonsyndromic forms of retinal dystrophies have now been identified. The identification of these genes and the improvement of clinical laboratory techniques have led to the identification of the genetic basis of disease in 56–76% of patients with IRDs through next generation sequencing and copy number variant analysis. Genetic testing is an essential part of clinical care for patients affected with IRDs and is required to confirm the diagnosis, understand the inheritance of the condition, and determine eligibility for gene‐specific treatments or clinical trials. Despite the success achieved in determining the genetic cause of these conditions, several challenges remain, which must be considered when providing genetic testing and genetic counseling to patients. For this reason, an integrated team of ophthalmic and genetic clinicians who are familiar with these challenges is necessary to provide optimal comprehensive care to these patients.
Synthesis of Novel Triazole Incorporated Thiazolone Motifs Having Promising Antityrosinase Activity through Green Nanocatalyst CuI‐Fe3O4@SiO2 (TMS‐EDTA)
Authors: Darroudi Mahdieh , Ranjbar Sara , Esfandiar Mohammad , Khoshneviszadeh Mahsima , Hamzehloueian Mahshid , Khoshneviszadeh Mehdi , Sarrafi Yaghoub
Published: August 2020

In the present work, novel 5‐((1‐benzyl‐1,2,3‐triazol‐4‐yl)methoxybenzylidene)‐2‐(arylamino)thiazol‐4‐one thiazolone incorporated triazole derivatives have been designed as tyrosinase inhibitors. The compounds were synthesized through click reaction in good yield. Moreover, the antityrosinas activity of the synthesized derivatives was evaluated. In the search for establishing a click copper‐catalyzed azide/alkyne cycloaddition (CuAAC) reaction under strict conditions, in terms of a novel air‐stable, a recyclable and efficient magnetic catalyst was planned for new triazole derivatives as a well‐organized copper iodide supported on the functionalized Fe3O4@SiO2 core‐shell (CuI/Fe3O4@SiO2(TMS‐EDTA) nanoparticles). The engineered nanocatalyst synthesized for the first time and characterized by different methods, including FT‐IR spectroscopy, XRD, FESEM, EDX, TEM, TGA, and BET analysis. The excellent catalytic performance in ethanol with high surface area (351.7 m2g−1) and short reaction time for diverse functional groups (120–200 min), no use of toxic solvents, reusability of the catalyst, and using eco‐friendly conditions are the advantageous of this work. Moreover,the nanocatalyst can be used at least five times without any significant decrease in the yield of the reaction. The thiazolidine‐triazole derivatives 9a, 9c, 9e, and 9 g showed promising tyrosinase inhibitory activity with IC50 values in the range of 5.90–9.81 μM. The compounds were found to be considerably more potent tyrosinase inhibitors than the reference inhibitor kojic acid (IC50 = 18.36 μM).
Linear segmented polyurethanes. III. Mathematical model for a two‐steps polymerization
Authors: Polo Mara L. , Spontón Marisa E. , Huespe Alfredo , Estenoz Diana A. , Meira Gregorio R.
Published: August 2020

In the first article of this sequel (J. Appl. Polym. Sci., 2018, 135, 45747), an experimental and theoretical investigation was developed on the two‐steps synthesis of linear segmented thermoplastic polyurethanes. The reactions were carried out at 60°C, with methylene diphenyl diisocyanate (MDI), two poly(tetramethylene oxide) macrodiols, and 1,4‐butanediol (BD) as chain extender. In our second article (J. Appl. Polym. Sci., 2019, 136, 46946), a mathematical model for the prepolymerization was developed, that involved integrating a differential equation for each generated polymer species. The present article extends such model, and predicts the molecular structure along the finishing stage. In each stage, the new model first solves the molar balances at polymer topologies level (i.e.,: Disregarding the molar mass distribution [MMD] of the reacted macrodiol chains), and then calculates the MMD of the evolving polymer and its main subsets through an algebraic convolution procedure. The model reproduces the prepolymerization predictions of our previous article, but is three orders of magnitude faster. In the finishing stage, up to 156,000 polymer topologies and 4.53 × 108 polymer species were calculated; and the rate constant was readjusted to (k2 = 0.00129 L mol−1 s−1), in order to fit the measured MMDs.
Thermo‐responsive block copolymer micelle‐supported (S)‐α,α‐diphenylprolinol trimethylsilyl ether for asymmetric Michael addition of nitroalkenes and aldehydes in water
Authors: Li Tao , Wang Weilin , Wang Songmeng , Liu Lingyan , Chang Weixing , Li Jing
Published: August 2020

An amphiphilic block copolymer PNIPAM53‐b‐(PS30‐co‐P4AMS10) was facilely prepared by reversible addition‐fragmentation chain transfer (RAFT) polymerization. The immobilization of (S)‐α,α‐diphenylprolinol trimethylsilyl ether onto the block copolymers was then performed through using copper‐catalyzed alkyne‐azide cycloaddition (CuAAC), and the generating amphiphilic diblock copolymer supported chiral catalyst PNIPAM53‐b‐(PS30‐co‐P4AMS10)/proTMS was self‐assembled into micelles with regular diameters about 50 nm in aqueous solution. The micellar catalyst was further used for the asymmetric Michael reaction between propanal and trans‐β‐nitrostyrene in water. Using only 1 mol% micellar catalyst, the corresponding Michael addition products could be obtained in good yields and high enantioselectivities as well as good diastereoselectivities. In addition, this micellar catalyst could be reused at least for four times. Moreover, the micellar catalyst could be applied for the asymmetric addition reaction of 4‐chlorocinnamyl aldehyde and nitromethane, and thus constructing the baclofen pharmaceutical intermediate.
Fabrication of co‐PVDF/modacrylic/SiO2 nanofibrous membrane: Composite separator for safe and high performance lithium‐ion batteries
Authors: Al Rai Adel , Stojanovska Elena , Akgul Yasin , Khan Mohammad Mansoob , Kilic Ali , Yilmaz Safak
Published: August 2020

Highly porous free‐standing co‐poly(vinylidene fluoride)/modacrylic/SiO2 nanofibrous membrane was developed using electrically‐assisted solution blow spinning method. The performance and the potential of the membrane as a lithium‐ion battery separator were investigated. The addition of modacrylic enhanced the solution spinnability that resulted in defect‐free membranes. Moreover, the presence of modacrylic enhanced the dimensional and thermal stabilities, while the addition of hydrophilic SiO2 nanoparticle enhanced both mechanical property and ionic conductivity. Combustion test results illustrated that the presence of modacrylic provide flame retarding property over a set of different polymeric‐based membranes. Electrochemical performance results showed that the developed membrane can increase the battery capacity compared with the commercial separator.
Evaluation of the removal of n‐butanol vapor by the poly(lactic acid)‐zeolite‐TiO2 composite and formation of by‐products
Authors: Miranda Luciana Gampert , Peglow Carolina Pereira , Deorristt Victória Cardoso , Sales Neto Geórgia Campos , Cardoso Ariela Milbrath , Ferrarini Suzana Frighetto , Pires Marçal José Rodrigues
Published: August 2020

The use of polymeric films incorporated with zeolite‐TiO2 composites associated with UV radiation can be an alternative in the removal of volatile organic compounds (VOCs) through the adsorption and photodegradation processes. This study produced poly(lactic acid) (PLA) films incorporated with 13× zeolite, TiO2, and 13×‐TiO2 zeolite composite to remove n‐butanol and evaluate the by‐products generated in the process. The results showed that 13× zeolite and TiO2 added individually or as a composite to PLA, gave the polymer matrix a significant increase in the removal capacity of n‐butanol. The best performance was presented by the zeolite‐TiO2, composite, confirming a synergistic effect. However, the formation of CO and CO2 exceeded the expected values, with the verification that the polymeric matrix underwent photodegradation action by TiO2. The polymeric film only containing zeolite is the most suitable for the removal of VOCs, as it did not present degradation of the PLA, generating a lower concentration of by‐products.
Image analysis of flame behavior for polyolefins and polystyrene in vertical flame test
Authors: Hosokawa Yoshifumi , Nakashima Erika , Ueno Tomonaga
Published: August 2020

Although the UL‐94 vertical flame test is often used to evaluate the flammability of polymers based on ignition time and combustion duration parameters, a significant amount of information regarding the time course of combustion is difficult to analyze in detail. Herein, image analysis of the time course of the upper and lower end heights, total area, and color division of flame was performed for polyolefins and polystyrene with different molecular weights in the vertical flame test. The combustion process was classified into two stages: before and after the first drip. In the first stage, the upward spread velocity, oscillation, and color of flame were analyzed. It was assumed that the difference in the fuel production rates or thermal decomposition products depends on the molecular structure. In the second stage, the melt flowability, flame position, and combustion continuity differed vastly depending on the molecular structure or molecular weight.
Increased energy expenditure and activated β3‐AR‐cAMP‐PKA signaling pathway in the interscapular brown adipose tissue of 6‐OHDA‐induced Parkinson's disease model rats
Authors: Lian Hui , Zhou Li , Zhang Yang , Song Yan‐Hai , Zhang Yi‐Min , Cao Zheng‐Hao , Wang Zhi‐Yong
Published: August 2020

To explore the possible mechanism of weight loss in Parkinson's disease (PD). Bilateral injections of 6‐hydroxydopamine (6‐OHDA) into substantia nigra (SN) were performed to induce the PD model rats. The rotarod test, food intake, body weight, and interscapular brown adipose tissue (IBAT) weight were recorded 6 weeks postoperation. HE staining was performed to observe the morphology of multilocular adipose cells in IBAT. Immunohistochemistry and western blot were used to determine the protein levels of tyrosine hydroxylase (TH) in the SN, and the levels of uncoupling protein 1 (UCP1), peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α), phosphorylated‐hormone sensitive lipase (p‐HSL), HSL, TH, β3‐adrenergic receptor (β3‐AR), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) in IBAT. After treatment with 6‐OHDA for 6 weeks, 6‐OHDA rats exhibited decreased TH expression in SN accompanied with shortened staying time on the rotating rod. This motor impairment paralleled with no significant alteration in body mass, IBAT weight, and food intake until the end of the experimental protocol. However, the decreasing diameter of the single fat vesicle in IBAT was observed in the 6‐OHDA group. Meanwhile, compared with the control group, the protein expression of UCP1, PGC‐1α, p‐HSL, TH, β3‐AR, cAMP, and PKA in IBAT were increased significantly in the 6‐OHDA group, whereas no obvious change in the expression of HSL. The present study suggested an increased energy expenditure and activation of the β3‐AR‐cAMP‐PKA signaling pathway in the IBAT after the destruction of the dopamine system in the SN of the rat.
The Role of Executive Functioning in Predicting Social Competence in Children with and without Autism Spectrum Disorder
Authors: Fong Vanessa Clarisse , Iarocci Grace
Published: August 2020

All children with autism spectrum disorder (ASD) experience social difficulties but they differ with regard to the type and severity of their challenges. Potentially powerful interventions targeting social skills in children with ASD may have limited effectiveness if they are not tailored to the child's specific needs. One factor that may influence social competence is executive functioning (EF). EF may impact social competence by facilitating higher‐order strategies such as emotional and cognitive regulation which are necessary for social interactions. Participants included 132 children and adolescents, aged 7–13, including 77 with ASD (M = 10.11, SD = 1.94), and 55 without ASD (M = 9.54, SD = 1.67). Caregivers completed the Behavior Rating Inventory of Executive Functioning, Version 2 (BRIEF‐2) Parent Form, assessing everyday EF skills, and the Multidimensional Social Competence Scale (MSCS). Hierarchical multiple regression analyses were conducted separately for the group without ASD and the group with ASD, with MSCS entered as the dependent variables and EF indices and scales of the BRIEF‐2 as the main predictor variables. EF deficits in emotional control predicted poor emotion regulation for both children with and without ASD. For the group without ASD, better emotional control and initiation skills predicted empathic concern and social knowledge, respectively. Challenges in self‐monitoring significantly predicted difficulties with social inferencing and social knowledge for children with ASD. The findings highlight the importance of targeting specific EF skills that contribute to various aspects of social competence to increase the effectiveness of interventions for children with ASD. Autism Res 2020, 13: 1856‐1866. © 2020 International Society for Autism Research and Wiley Periodicals LLC

Lay Summary

We examined whether parents' ratings of their children's higher‐order thinking skills (e.g., paying attention, organizing and planning, initiating tasks, regulating emotions, self‐monitoring) predicted social competence among children with and without autism spectrum disorder (ASD). For children without ASD, emotional control and initiation skills were strongly linked to their displays of empathy and social knowledge, respectively. For children with ASD, their abilities to be aware of their own behaviors and its impact on others were strongly related to their ability to interpret social cues and their social knowledge. For both groups, the ability to regulate their emotions were important predictors of their ability to modulate their emotions in social contexts.
Nickel Metaphosphate as a Conversion Positive Electrode for Lithium‐Ion Batteries
Authors: Xia Qingbo , Avdeev Maxim , Schmid Siegbert , Liu Hongwei , Johannessen Bernt , Ling Chris D.
Published: August 2020

Lithium storage schemes based on conversion chemistry have been used in a large variety of negative electrodes achieving capacities 2–3 times higher than graphite. However, to date, relatively few positive electrode examples have been reported. Here, we report a new conversion positive electrode, Ni(PO3)2, and systematic studies on its working and degradation mechanisms. Crystalline Ni(PO3)2 undergoes an electrochemistry‐driven amorphization process in the first discharge to form a fine microstructure, consisting of Ni domains ∼2 nm wide that form a percolating electron‐conducting network, embedded in a glassy LiPO3 matrix. P does not participate electrochemically, remaining as P5+ in [PO3]− throughout. The electrode does not recrystallise in the following first charge process, remaining amorphous over all subsequent cycles. The low ionicity of the Ni−[PO3] bond and the high Li+ conductivity of the LiPO3 glass lead to high intrinsic electrochemical activity, allowing the micro‐sized Ni(PO3)2 to achieve its theoretical capacity of 247 mAh/g. The performance of the Ni(PO3)2 electrode ultimately degrades due to the growth of larger and more isolated Ni grains. While the theoretical capacity of Ni(PO3)2 is itself limited, this study sheds new light on the underlying chemical mechanisms of conversion positive electrodes, an important new class of electrode for solid‐state batteries.
Inhibition of microRNA‐27b‐3p relieves osteoarthritis pain via regulation of KDM4B‐dependent DLX5
Authors: Zhang Guixiang , Zhou Yang , Su Manman , Yang Xucheng , Zeng Biyun
Published: August 2020

Osteoarthritis (OA) represents a progressive degenerative disorder that predominantly affects the synovial membranes of joints. Recent studies have highlighted the significant role played by microRNAs (miRNAs) in OA development. The current study aimed to elucidate the underlying modulatory role of miR‐27b‐3p in the development of OA. The expression of miR‐27b‐3p in the OA patients and rat models post anterior cruciate ligament transection operation was measured using reverse transcription quantitative polymerase chain reaction, through which overexpressed miR‐27b‐3p was found in both of the samples. To further explore the miR‐27b‐3p functions in OA, western blot analysis, enzyme‐linked immunosorbent assay, and β‐galactosidase activity assay were conducted with the results showing that knockdown of miR‐27b‐3p promoted expression of the osteogenic differentiation markers while inhibiting expression of the adipogenic differentiation markers, inflammatory factors, and cellular senescence of bone marrow mesenchymal stem cells (BMSCs). After that, the interactions between miR‐27b‐3p, lysine Demethylase 4B (KDM4B), and Distal‐Less Homeobox 5 (DLX5) identified using dual‐luciferase reporter gene assay and ChIP assay revealed that miR‐27b‐3p inhibited KDM4B and further reduced expression of DLX5. Finally, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were assessed in rat models, and increased PWT and PWL were detected after miR‐27b‐3p silencing. In conclusion, suppression of miR‐27b‐3p could enhance KDM4B and DLX5 to alleviate OA pain, shedding light on a new potential therapeutic target for OA.
Determination of dopamine, noradrenaline, and adrenaline in Krebs–Henseleit solution by liquid chromatography coupled with tandem mass spectrometry and measurement of their basal release from Chelonoidis carbonaria aortae in vitro
Authors: Britto‐Júnior José , Antunes Natalícia J. , Campos Rafael , Sucupira Mauro , Mendes Gustavo Duarte , Fernandes Fernanda , Moraes Manoel Odorico , Moraes Maria Elisabete A. , De Nucci Gilberto
Published: August 2020

This study presented for the first time the development and validation of a sensitive method for quantification of dopamine, noradrenaline, and adrenaline in Krebs–Henseleit solution by LC–tandem mass spectrometry. Aliquots of 2.0 mL calibrators, quality controls, and samples of Krebs–Henseleit solution incubated with tortoise's aortic ring for 30 min were extracted by solid‐phase extraction. Catecholamine separation was achieved on a 100 × 4.6 mm LiChrospher RP‐8 column and the quantification was performed by a mass spectrometer equipped with an electrospray interface operating in positive ion mode. The run time was 4 min and the calibration curve was linear over the range of 0.1–20.0 ng/mL. The method was applied to the measurement of basal release of dopamine, noradrenaline, and adrenaline from the tortoise Chelonoidis carbonaria aortae in vitro. One aortic ring (30 mm) per tortoise (n = 5) was incubated for 30 min in a 5 mL organ bath filled with Krebs–Henseleit solution. The method demonstrated sensitivity, precision, and accuracy enough for its application in the measurement of basal release of these catecholamines from C. carbonaria aortic rings in vitro. The mean (standard deviation) concentrations of dopamine, noradrenaline, and adrenaline were 3.48 (2.55) ng/mL, 1.40 (0.57) ng/mL, and 1.87 (1.09) ng/mL, respectively.
Bridging “Big Data” and Mechanistic Insight To Enable Precision Medicine
Authors: Douglass Eugene F.
Published: August 2020

Realizing the promise of precision medicine will require breaking down communication barriers between genomic, screening and literature “big data.” We discuss the opportunities and challenges of reconciling data science approaches with the scientific method and the critical role of chemical biologists as a bridge between data and mechanism. Finally we propose next steps on the road to precision medicine and give examples of new tools designed to catalyze these steps.
Comparison of clinical results between percutaneous closure and surgical repair of ruptured sinus of Valsalva aneurysm
Authors: Yang Kai , Luo Xiaokang , Tang Yue , Hu Haibo , Sun Hansong
Published: August 2020

Objectives

This study was conducted to investigate whether percutaneous closure of ruptured sinus of Valsalva aneurysm (SVA) is as safe and effective as surgery repair.

Background

Percutaneous closure of ruptured SVA has been becoming an alternative to the traditional surgical repair recently. The reports regarding direct comparison of these two treatment options are scarce.

Methods

The medical records from the institutional database were retrospectively analyzed. A total of 134 patients were reviewed, including 26 patients undergoing percutaneous closure and 108 patients being treated surgically. To reduce the potential bias, 32 patients from Surgical Repair group were selected by propensity score matching.

Results

All the ruptured SVAs were successfully closed in each group. No severe procedure‐related complications were found in the perioperative period. After matching, there were no significant differences in the baseline clinical characteristics. The median postoperative hospital stays of Matched group were significantly longer than that of Percutaneous Closure group (7 days vs. 1 day, p < .001). Aortic regurgitation, residual shunt and recurrence of SVAs were common complications in both Percutaneous Closure group and Surgical Repair group.

Conclusions

The appropriately selected patients with ruptured SVA could be treated by percutaneous closure with an acceptable risk of short‐term complications. Though surgical repair remains the main treatment option for ruptured SVAs, percutaneous closure could be considered in patients with a small‐size rupture and no associated cardiac abnormalities.
Ileocecal knotting in a young man: A very rare and unique cause of intestinal obstruction
Authors: Gebresellassie Hailu Wondimu
Published: August 2020

Ileocecal knitting should be considered as a differential diagnosis of small intestinal obstruction. Aggressive resuscitation and early surgery will be life‐saving. One should anticipate finding extensive bowel gangrene which requires aggressive resection.
Stereoselective Copper‐Catalyzed Direct Aldol Reaction of β, γ‐Unsaturated α‐Ketoesters with Coumaran‐3‐Ones
Authors: Li Kuiliang , Sun Xiang , Li Linge , Zha Zhenggen , Zhang Feng‐Lian , Wang Zhiyong
Published: August 2020

An efficient direct aldol reaction between coumaran‐3‐ones and β, γ‐unsaturated α‐ketoesters by virtue of a chiral copper complex is developed. A series of coumaran‐3‐one derivatives containing chiral tertiary alcohol structures are obtained in excellent yields and stereoselectivities.
AAV Production Everywhere: A Simple, Fast, and Reliable Protocol for In‐house AAV Vector Production Based on Chloroform Extraction
Authors: Negrini Matilde , Wang Gang , Heuer Andreas , Björklund Tomas , Davidsson Marcus
Published: August 2020

Recombinant adeno‐associated virus (rAAV) is a mammalian virus that has been altered to be used as a gene delivery vehicle. Several changes to the viral genome have made them replication deficient so that this aspect of the viral infection cycle is under full control of the experimenter, while maintaining gene expression machinery. Over the last decades, rAAVs have become the gold standard for studying in vivo gene function and are especially favorable for gene transfer in the central nervous system. AAVs have been proven safe and provide stable gene expression over a long period of time. They are extensively used in preclinical experiments and show great potential for clinical applications. However, the use of AAVs in preclinical settings are often held back due to availability. Waiting lines are long at commercial production facilities, and in‐lab production is hindered due to lack of specific laboratory equipment needed. Here we present a novel production method that can be carried out in any molecular biology laboratory using standard laboratory equipment. We provide a simple, fast, and streamlined protocol for production that can result in titers comparable with the more time‐consuming iodixanol gradient ultracentrifugation method. The yield using this protocol is high enough for any type of study where AAV is the vector of choice. © 2020 The Authors.
Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach
Authors: Li Jerry , Nikanjam Mina , Cunningham Coleen K. , McFarland Elizabeth J. , Coates Emily E. , Houser Katherine V. , Lin Bob C. , McDermott Adrian B. , Flach Britta , Gama Lucio , Koup Richard A. , Graham Barney S. , Mascola John R. , Ledgerwood Julie E. , Capparelli Edmund V.
Published: August 2020

VRC01 is a first‐in‐class, potent, broadly neutralizing antibody that targets the CD4 binding site of gp120 on HIV‐1 viruses, and is under development as a novel HIV therapeutic. This study utilized population pharmacokinetic (PK) modeling to characterize VRC01 PK to guide dosing selection for ongoing phase II clinical trials in pediatric patients. Combining VRC01 PK data from 3 adult and 1 infant clinical trials, a total of 1,475 VRC01 serum concentrations from 100 participants were used in the analysis (40 infants and 60 adults). VRC01 was administered either i.v. or s.c. (1–40 mg/kg). All infants received s.c. doses as compared with 13% s.c. and 87% i.v. in adults. The data were well‐described by a two‐compartment model. Clearance was 37% higher in adults with HIV infection and 83% lower in infants than adults. Subcutaneous bioavailability was 55% in adults. Rapid absorption was seen in infants indicating therapeutic levels could be achieved quickly. Monte Carlo simulations were used to determine optimal dosing and demonstrated 40 mg/kg s.c. at weeks 0, 2, 6, and 10 would maintain VRC01 levels at the suppressive target concentration of 50 μg/mL for the first 14 weeks of life in infants. The current analysis provides new insight into differences in monoclonal antibody PK between infants and adults and demonstrates the utility of a population PK approach in informing drug development for infant populations.
Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective
Authors: Vargas Hugo M. , Rolf Michael G. , Wisialowski Todd A. , Achanzar William , Bahinski Anthony , Bass Alan , Benson Charles T , Chaudhary Khuram W. , Couvreur Nicolas , Dota Corina , Engwall Michael J , Michael Foley C. , Gallacher David , Greiter‐Wilke Andrea , Guillon Jean‐Michel , Guth Brian , Himmel Herbert M. , Hegele‐Hartung Christa , Ito Maki , Jenkinson Stephen , Chiba Katsuyoshi , Lagrutta Armando , Levesque Paul , Martel Eric , Okai Yoshiko , Peri Ravikumar , Pointon Amy , Qu Yusheng , Teisman Ard , Traebert Martin , Yoshinaga Takashi , Gintant Gary A. , Leishman Derek J. , Valentin Jean‐Pierre
Published: August 2020

Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based “double‐negative” nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.
Evaluation of durum wheat lines derived from interspecific crosses under drought and heat stress
Authors: Aberkane Hafid , Amri Ahmed , Belkadi Bouchra , Filali‐Maltouf Abdelkarim , Kehel Zakaria , Tahir Izzat S. A. , Meheesi Sara , Tsivelikas Athanasios
Published: August 2020

The productivity of durum wheat [Triticum turgidum subsp. durum (Desf.) van Slageren] is affected by drought and/or high temperatures, challenges to be amplified by climate change. Pre‐breeding using wild relatives can supply useful traits for durum wheat improvement to adapt to major abiotic and biotic stresses. Sixty‐seven lines issued from backcrosses of Cham5 and Haurani durum wheat varieties with accessions of Triticum aegilopoides (Link) Bal. ex Koern., T. dicoccoides Koern. ex Schweinf., T. urartu Thumanian ex Gandilyan, and Aegilops speltoides Tausch were evaluated for drought and heat tolerance. The trials were conducted during two seasons (2016−2017 and 2017–2018) at Tessaout, Morocco, under full irrigation (optimal conditions) and rainfed conditions (drought stressed) and at Wed Medani, Sudan, under full irrigation combined with heat stress. The recurrent parents, along with eight best cultivars and elite breeding lines, were used as checks. Drought reduced the grain yield by 62%. Grain yield and drought tolerance index were used to identify lines to be used by breeding programs to enhance drought and heat tolerance. The derivatives lines 142014 (Cham5*3/T. aegilopoides), 142074 (Cham5*3/T. dicoccoides), and 142015 along with the checks Icarachaz and Gidara 2 ranked among the best under heat stress. Under drought stress, the lines 141972 (Haurani*2/T. urartu) and 141973 (Cham5*2/T. dicoccoides) yielded 196 and 142% of their recurrent parents’ yield, respectively. High variation was found for agronomic and phenology traits, with heading time explaining 16% of grain yield under drought, while thousand kernel weight accounted for 18% of the yield under heat. We conclude that gene introgression from wild relatives pays off and can increase wheat resilience to cope with climate change effects.
Phase I safety, tolerability, and pharmacokinetic studies of tetramethylpyrazine nitrone in healthy Chinese volunteers
Authors: Zhao Caiyun , Lv Yuan , Cui Hong , Zhu Yan , Wei Minji , Xia Yahong , Tian Jihong , Ma Yan , Liu Yan , Zhang Pu , Wang Xi , Wu Jing , Wang Yatai
Published: August 2020

Background

The purpose of this study was to investigate the safety, tolerability and pharmacokinetics of tetramethylpyrazine nitrone (TBN) in healthy Chinese volunteers.

Methods

A single‐ascending‐dose (SAD) study where 68 subjects were randomized to a single dose of placebo or TBN (50, 100, 200, 400, 700, 1,000, 1,400, or 1,800 mg) through IV infusion over 30 min. A multiple‐ascending‐dose (MAD) study where 24 subjects received TBN twice daily (with 12 hr interval) for total 6.5 days at doses of either 700 or 1,400 mg. Adverse events were recorded and pharmacokinetic samples were collected during the whole study period.

Results

No serious adverse events were found in the study. All of the observed adverse events, including increased white blood cell (4.4% subjects) and neutrophil counts (4.4% subjects), and decreased hemoglobin levels (4.2% subjects), were laboratory test abnormalities. All the adverse events were mild and tolerable, and returned to normal without any intervention. In the SAD study, linear Cmax values were observed in the dose interval of 50–1,800 mg. In the MAD study, the average steady‐state concentrations (Cavg.ss) of TBN in the 700 and 1,400 mg dose group were 2,407 and 5,837 ng/ml, respectively. No drug accumulation was observed in this study.

Conclusions

TBN is well tolerated in healthy volunteers. Linear Cmax values were observed in the interval of 50–1,800 mg, and target exposures of TBN were achieved without accumulation after twice daily administration to subjects. (This study has been registered at ChiCTR.org.cn. Identifier: ChiCTR1800016225 and ChiCTR1800019627.)
Type II interferon signaling in the brain during a viral infection with age‐dependent pathogenesis
Authors: Creisher Patrick S. , Chandwani Manisha N. , Kamte Yashika S. , Covvey Jordan R. , Ganesan Priya , O'Donnell Lauren A.
Published: August 2020

Viral infections of the central nervous system (CNS) often cause disease in an age‐dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age‐dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)‐dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription‐1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ‐stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.
Development of the lamprey velum and implications for the evolution of the vertebrate jaw
Authors: Yokoyama Hiromasa , Yoshimura Miho , Suzuki Daichi G. , Higashiyama Hiroki , Wada Hiroshi
Published: August 2020

Background

The vertebrate jaw is thought to have evolved through developmental modification of the mandibular arch. An extant jawless vertebrate, the lamprey, possesses a structure called “velum”—a mandibular arch derivative—in addition to the oral apparatus. This leads us to assess the velum's possible contribution to the evolution of jaws.

Results

The velar muscles develop from progenitor cells distinct from those from which the oral muscles develop. In addition, the oral and velar regions originate from the different sub‐population of the trigeminal neural crest cells (NCCs): the former region receives NCCs from the midbrain, whereas the latter region receives NCCs from the anterior hindbrain. The expression of patterning genes (eg,DlxAandMsxA) is activated at a later developmental stage in the velum compared to the oral region,and more importantly, in different cells from those in the oral region.

Conclusion

The lamprey mandibular arch consists of two developmental units: the anterior oral unit and the posterior velar unit. Because structural elements of the lamprey velum may be homologous to the jaw, the evolution of vertebrate jaws may have occurred by the velum being released from its functional roles in feeding or respiration in jawless vertebrates.
Springs ecosystem classification
Authors: Stevens Lawrence E. , Schenk Edward R. , Springer Abraham E.
Published: August 2020

Springs ecosystems are globally abundant, geomorphologically diverse, and bio‐culturally productive, but are highly imperiled by anthropogenic activities. More than a century of scientific discussion about the wide array of ecohydrological factors influencing springs has been informative, but has yielded little agreement on their classification. This lack of agreement has contributed to the global neglect and degradation of springs ecosystems by the public, scientific, and management communities. Here we review the historical literature on springs classification variables, concluding that site‐specific source geomorphology remains the most diagnostic approach. We present a conceptual springs ecosystem model that clarifies the central role of geomorphology in springs ecosystem development, function, and typology. We present an illustrated dichotomous key to terrestrial (non‐marine) springs ecosystem types and subtypes, and describe those types. We identify representative reference sites, although data limitations presently preclude selection of continentally or globally representative reference springs of each type. We tested the classification key using data from 244 randomly selected springs of 13 types that were inventoried in western North America. The dichotomous key correctly identified springs type in 87.5% of the cases, with discrepancies primarily due to differentiation of primary vs. secondary typology, and insufficient inventory team training. Using that information, we identified sources of confusion and clarified the key. Among the types that required more detailed explanation were hypocrenes, springs in which groundwater is expressed through phreatophytic vegetation. Overall, springs biodiversity and ecosystem complexity are due, in part, to the co‐occurrence of multiple intra‐springs microhabitats. We describe microhabitats that are commonly associated with different springs types, reporting at least 13 microhabitats, each of which can support discrete biotic assemblages. Interdisciplinary agreement on basic classification is needed to enhance scientific understanding and stewardship of springs ecosystems, the loss and degradation of which constitute a global conservation crisis.
Incorporating capture heterogeneity in the estimation of autoregressive coefficients of animal population dynamics using capture–recapture data
Authors: Nicolau Pedro G. , Sørbye Sigrunn H. , Yoccoz Nigel G.
Published: August 2020

Population dynamic models combine density dependence and environmental effects. Ignoring sampling uncertainty might lead to biased estimation of the strength of density dependence. This is typically addressed using state‐space model approaches, which integrate sampling error and population process estimates. Such models seldom include an explicit link between the sampling procedures and the true abundance, which is common in capture–recapture settings. However, many of the models proposed to estimate abundance in the presence of capture heterogeneity lead to incomplete likelihood functions and cannot be straightforwardly included in state‐space models. We assessed the importance of estimating sampling error explicitly by taking an intermediate approach between ignoring uncertainty in abundance estimates and fully specified state‐space models for density‐dependence estimation based on autoregressive processes. First, we estimated individual capture probabilities based on a heterogeneity model for a closed population, using a conditional multinomial likelihood, followed by a Horvitz–Thompson estimate for abundance. Second, we estimated coefficients of autoregressive models for the log abundance. Inference was performed using the methodology of integrated nested Laplace approximation (INLA). We performed an extensive simulation study to compare our approach with estimates disregarding capture history information, and using R‐package VGAM, for different parameter specifications. The methods were then applied to a real data set of gray‐sided volesMyodes rufocanusfrom Northern Norway. We found that density‐dependence estimation was improved when explicitly modeling sampling error in scenarios with low process variances, in which differences in coverage reached up to 8% in estimating the coefficients of the autoregressive processes. In this case, the bias also increased assuming a Poisson distribution in the observational model. For high process variances, the differences between methods were small and it appeared less important to model heterogeneity.