bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics
Authors: van der Ende Emma L. , Meeter Lieke H. , Stingl Christoph , van Rooij Jeroen G. J. , Stoop Marcel P. , Nijholt Diana A. T. , Sanchez‐Valle Raquel , Graff Caroline , Öijerstedt Linn , Grossman Murray , McMillan Corey , Pijnenburg Yolande A. L. , Laforce Robert , Binetti Giuliano , Benussi Luisa , Ghidoni Roberta , Luider Theo M. , Seelaar Harro , van Swieten John C.
Published: March 2019

Objective

To identify novel CSF biomarkers in GRN‐associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS).

Methods

Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high‐resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers.

Results

Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor‐type tyrosine‐protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin‐A (CHGA), and V‐set and transmembrane domain‐containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers.

Interpretation

We identified and validated five novel CSF biomarkers in GRN‐associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.
C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
Authors: Dias Andreia , Santos Diana , Coelho Teresa , Alves‐Ferreira Miguel , Sequeiros Jorge , Alonso Isabel , Sousa Alda , Lemos Carolina
Published: March 2019

Objectives

Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age‐at‐onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR‐FAP Val30Met Portuguese patients.

Methods

We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non‐independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions.

Results

Two variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later‐onset.

Interpretation

C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR‐FAP Val30Met.
Si/CuIn0.7Ga0.3Se2 Core–Shell Heterojunction for Sensitive and Self‐Driven UV–vis–NIR Broadband Photodetector
Authors: Chen Liang , Tian Wei , Min Liangliang , Cao Fengren , Li Liang
Published: March 2019

Designing Si nanowire‐based heterostructures provides a promising path to construct self‐driven and broadband photodetectors, which are the key components for optoelectronic systems. Herein, the first fabrication of a p‐CuIn0.7Ga0.3Se2 nanoparticles/n‐Si nanowire array core–shell structure through a simple two‐stage process—spin coating and selenization treatment—and its integration into a self‐driven photodetector are reported. The heterojunction photodetector is sensitive to broad wavelength range from UV light to visible and near‐infrared light, with high detectivity of up to 1.6 × 1013 Jones, large responsivity of 0.33 A W−1, and an ultrafast response speed of 823/356 µs at zero bias. Additionally, this core–shell nanostructure exhibits good air stability and strong ability to detect weak light sources such as fluorescent lamp and lighter. The superior performance can be attributed to the strong light absorption of both Si and CuIn0.7Ga0.3Se2, the unique vertically standing core–shell structure, and effective photogenerated carriers' separation and transportation at the heterojunction interface.
Poly(3,4‐ethylenedioxythiophene):Poly(styrene sulfonate)/Polyethylene Oxide Electrodes with Improved Electrical and Electrochemical Properties for Soft Microactuators and Microsensors
Authors: Rohtlaid Kätlin , Nguyen Giao T. M. , Soyer Caroline , Cattan Eric , Vidal Frédéric , Plesse Cédric
Published: March 2019

The development of microsystems is a rapidly evolving field which enables a wide range of applications for electroactive materials. Microelectromechanical actuators based on electronically conducting polymers are elaborated with an up‐scalable process. Commercial poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is chosen as an easily processable electrode to ensure the reproducibility for further technological production and practical applications. First, the improvement of electrical, electrochemical, and mechanical properties of the PEDOT:PSS electrodes is described by incorporating reactive additives, that is, glycol‐based monomers (mPEG) as polyethylene oxide (PEO) network precursors. Moreover, the custom fit layer‐by‐layer (LbL) process to integrate these PEDOT:PSS/PEO composite electrodes into trilayer microactuators is presented. The incorporation of PEO within PEDOT:PSS improves significantly the electromechanical performances of the resulting microactuators with significant strain (0.82%) and high output forces (472 µN) compared to similar PEDOT based or pristine PEDOT:PSS microactuators. This work provides also the first demonstration that mechanical strain sensing behavior, extensively studied at macroscale, still occurs at microscale for these trilayer systems. Additionally, to this proof of concept, it highlights that output signal is significantly enhanced by downsizing the devices compared to similar macroscale samples. These results open promising perspectives in the development of numerous applications for soft and scalable microactuators and microsensors.
More than Data Collectors: A Systematic Review of the Environmental Outcomes of Youth Inquiry Approaches in the United States
Authors: Kennedy Heather , DeChants Jonah , Bender Kimberly , Anyon Yolanda
Published: March 2019

Over the last twenty years, research on the impact of engaging children and adolescents in the generation of new knowledge about their lives, schools, and communities, has grown tremendously. This systematic review summarizes the findings from empirical studies of youth inquiry approaches in the United States, with a focus on their environmental outcomes. Searches of four interdisciplinary databases retrieved a total of 3,724 relevant articles published between 1995 and 2015. Sixty‐three distinct studies met the systematic review inclusion criteria, of which, 36 (57.1%) reported that the youth inquiry approach contributed to positive changes among adults, peers, organizations, and/or institutions. These environmental outcomes were qualitatively recorded, inductively categorized, and then organized into Bronfenbrenner's ecological framework. Youth inquiry approaches led to practitioner growth and changes in peer group norms at the micro‐system level, program development or improvement and research benefits at the meso‐system level, and school, city, and state level policy adoption at the exo‐system level. Qualitative methods, especially case studies, were most commonly used to evaluate the impact of youth inquiry approaches on environmental outcomes. Studies of approaches that utilized advocacy to create change, targeted decision‐makers as the audience for the youth's work and convened for a longer duration were more likely to report improved environmental outcomes. This systematic review suggests that youth inquiry approaches are a promising strategy for ecological systems change.
Photoconductive Curved‐Nanographene/Fullerene Supramolecular Heterojunctions
Authors: Huang Qiang , Zhuang Guilin , Jia Hongxing , Qian Manman , Cui Shengsheng , Yang Shangfeng , Du Pingwu
Published: March 2019

This study presents synthesis and characterizations of two novel curved nanographenes that strongly bind with fullerene C60 to form photoconductive heterojunctions. Films of the self‐assembled curved nanographene/fullerene complexes, which served as the photoconductive layer, generated a significant photocurrent under light irradiation. Gram‐scale quantities of these curved nanographenes (TCR and HCR) as the “crown” sidewalls can be incorporated into a carbon nanoring to form molecular crowns, and the molecular structure of C60@TCR is determined by single‐crystal X‐ray diffraction. The UV/Vis absorption and emission spectra, and theoretical studies revealed their unique structural features and photophysical properties. Time‐resolved spectroscopic results clearly suggest fast photoinduced electron transfer process in the supramolecular heterojunctions.
Heterochromatin Protein HP1α Gelation Dynamics Revealed by Solid‐State NMR Spectroscopy
Authors: Ackermann Bryce E. , Debelouchina Galia T.
Published: March 2019

Heterochromatin protein 1α (HP1α) undergoes liquid–liquid phase separation (LLPS) and forms liquid droplets and gels in vitro, properties that also appear to be central to its biological function in heterochromatin compaction and regulation. Here we use solid‐state NMR spectroscopy to track the conformational dynamics of phosphorylated HP1α during its transformation from the liquid to the gel state. Using experiments designed to probe distinct dynamic modes, we identify regions with varying mobilities within HP1α molecules and show that specific serine residues uniquely contribute to gel formation. The addition of chromatin disturbs the gelation process while preserving the conformational dynamics within individual bulk HP1α molecules. Our study provides a glimpse into the dynamic architecture of dense HP1α phases and showcases the potential of solid‐state NMR to detect an elusive biophysical regime of phase separating biomolecules.
Engineering of Nucleic Acids and Synthetic Cofactors as Holo Sensors for Probing Signaling Molecules in the Cellular Membrane Microenvironment
Authors: Feng Guangfu , Luo Xingyu , Lu Xu , Xie Shiyi , Deng Lu , Kang Wenyuan , He Fang , Zhang Jiaheng , Lei Chunyang , Lin Bin , Huang Yan , Nie Zhou , Yao Shouzhuo
Published: March 2019

The comprehensive understanding of the mechanisms underlying the interaction of cells with their membrane microenvironment is of great value for fundamental biological research; however, tracking biomolecules on cell surfaces with high temporal and spatial resolution remains a challenge. Herein, a modular strategy is presented for the construction of cell surface DNA‐based sensors by engineering DNA motifs and synthetic cofactors. In this strategy, a stimuli‐reactive organic molecule is employed as the cofactor for the DNA motif, and the self‐assembly of them forms a FRET‐based holo DNA‐based sensor. With the use of the DNA‐based sensors, the versatility of this modular strategy has been demonstrated in the ratiometric imaging of the cellular extrusion process of endogenous signaling molecules, including sulfur dioxide derivatives and nitric oxide.
Identification of Chemokine Ligands by Biochemical Fragmentation and Simulated Peptide Evolution
Authors: Fuchs Jens‐Alexander , Brunner Cyrill , Schineis Philipp , Hiss Jan A. , Schneider Gisbert
Published: March 2019

Short linear peptides can overcome certain limitations of small molecules for targeting protein–protein interactions (PPIs). Herein, the interaction between the human chemokine CCL19 with chemokine receptor CCR7 was investigated to obtain receptor‐derived CCL19‐binding peptides. After identifying a linear binding site of CCR7, five hexapeptides binding to CCL19 in the low micromolar to nanomolar range were designed, guided by pharmacophore and lipophilicity screening of computationally generated peptide libraries. The results corroborate the applicability of the computational approach and the chosen selection criteria to obtain short linear peptides mimicking a protein–protein interaction site.
Quality of Sunflower Oil Obtained in the Main Producing Region of Brazil: Adherence to the Codex Alimentarius
Authors: de Carvalho Claudio Guilherme Portela , Mazzola Luana Fernanda , Caldeira Andressa , Dalchiavon Flávio Carlos , Mandarino José Marcos Gontijo
Published: March 2019

The objective of this work was to evaluate the quality of the oil extracted from sunflower achenes grown in Campo Novo de Parecis, the main producing region of Brazil, to optimize its use by the processing and food industries. In addition, the fatty acid profiles of the oil were checked for their adherence to the CODEX STAN 210–1999. Traditional and high‐oleic genotypes were grown between 2014 and 2017 during trials with a randomized complete block experimental design with four replications. The contents of oleic, linoleic, palmitic, and stearic acids were determined using gas chromatography. The fatty acid profiles of traditional genotypes were observed to be outside the ranges established by the CODEX, with an oleic acid content above 39.4% and linoleic, palmitic, and stearic acid values lower than 48.3%, 2.7%, and 5.0%, respectively, as well as high‐oleic sunflower oil with a stearic acid content of less than 2.6%. The availability of this information can, on the one hand, positively impact industries and encourage the use of better quality raw materials that are more technologically and nutritionally adequate. On the other hand, the commercialization of sunflower oil with a fatty acid profile outside the ranges established by CODEX can be difficult, because the contents are out of specification due to the climatic conditions in the cropping region.
Fuel‐Free Micro‐/Nanomotors as Intelligent Therapeutic Agents
Authors: Liu Lu , Gao Junbin , Wilson Daniela A. , Tu Yingfeng , Peng Fei
Published: March 2019

There are many efficient biological motors in Nature that perform complex functions by converting chemical energy into mechanical motion. Inspired by this, the development of their synthetic counterparts has aroused tremendous research interest in the past decade. Among these man‐made motor systems, the fuel‐free (or light, magnet, ultrasound, or electric field driven) motors are advantageous in terms of controllability, lifespan, and biocompatibility concerning bioapplications, when compared with their chemically powered counterparts. Therefore, this review will highlight the latest biomedical applications in the versatile field of externally propelled micro‐/nanomotors, as well as elucidating their driving mechanisms. A perspective into the future of the micro‐/nanomotors field and a discussion of the challenges we need to face along the road towards practical clinical translation of external‐field‐propelled micro‐/nanomotors will be provided.
Optimal cue aggregation in the absence of criterion knowledge
Authors: Zhao Wenjia Joyce , Davis‐Stober Clintin P. , Bhatia Sudeep
Published: March 2019

The study of multi‐cue judgment investigates how decision makers aggregate cues to predict the value of a criterion variable. We consider a multi‐cue judgment task in which decision makers have prior knowledge of inter‐cue relationships but are ignorant of how the cues correlate with the criterion. In this setting, a naive judgment strategy prescribes weighting the cues equally. Although many participants are well described via an equal weighting scheme, we find that a substantial minority of participants make predictions consistent with a weighting scheme based on a low‐dimensional projection of the cue space that optimally takes into account inter‐cue correlations. The use of such a weighting scheme is consistent with minimizing maximal error in prediction when the cue‐criterion relationships are unknown.
Determination of Chemical and Enantiomeric Purity of α‐Amino Acids and their Methyl Esters as N‐Fluorenylmethoxycarbonyl Derivatives Using Amylose‐derived Chiral Stationary Phases
Authors: Islam Md. Fokhrul , Adhikari Suraj , Paik Man‐Jeong , Lee Wonjae
Published: March 2019

Liquid chromatographic enantiomer separation and simultaneous determination of chemical and enantiomeric purity of α‐amino acids and their methyl esters as N‐fluorenylmethoxycarbonyl (FMOC) derivatives was performed on three covalently bonded type chiral stationary phases (CSPs) derived from amylose derivatives. The enantiomer separation of α‐amino acid esters as N‐FMOC derivatives was better than that of the corresponding acids, especially for CSP 1 and 2. Chemical impurities as the corresponding racemic acids present in several commercially available racemic amino acid methyl esters were observed to be 0.49–17.50%. Enantiomeric impurities of several commercially available L‐amino acid methyl esters were found to be 0.03–0.58%, whereas chemical impurities as the corresponding racemic acids present in the same analytes were found to be 0.13–13.62%. This developed analytical method will be useful for the determination of chemical and enantiomeric purity of α‐amino acids and/or esters as N‐FMOC derivatives using amylose‐derived CSPs.
The effect of ketogenic diet on behaviors and synaptic functions of naive mice
Authors: Huang Jie , Li Yuan‐Quan , Wu Cui‐Hong , Zhang Yun‐Long , Zhao Shen‐Ting , Chen Yong‐Jun , Deng Yu‐Hong , Xuan Aiguo , Sun Xiang‐Dong
Published: March 2019

Introduction

Beyond its application as an epilepsy therapy, the ketogenic diet (KD) has been considered a potential treatment for a variety of other neurological and metabolic disorders. However, whether KD promotes functional restoration by reducing the pathological processes underlying individual diseases or through some independent mechanisms is not clear.

Methods

In this study, we evaluated the effect of KD on a series of behaviors and synaptic functions of young adult naive mice. Wild‐type C57BL/6J mice at age of 2–3 months were fed with control diet or KD for three months. Body weight and caloric intake were monitored throughout the experiments. We assessed behavioral performance with seizure induction, motor coordination and activity, anxiety level, spatial learning and memory, sociability, and depression. Synaptic transmission and long‐term potentiation were also recorded.

Results

KD‐fed mice performed equivalent to control‐diet‐fed mice in the behavioral tests and electrophysiological assays except exhibiting slower weight gain and increased seizure threshold.

Conclusions

Our results contribute to the better understanding of effects of the KD on physiological behaviors and synaptic functions.
From shame to fame: The improbable career of the great anatomist‐surgeon D. Hayes Agnew
Authors: Wright James R.
Published: March 2019

David Hayes Agnew began his career as a country doctor in rural Pennsylvania in 1838. After a 3‐year diversion as a partner in a large ironworks business that went bankrupt in 1846, Agnew, seriously in debt, returned to the medical profession in Cochranville, PA, hoping to focus on surgery. Recognizing that he needed to improve his knowledge of anatomy, he purchased cadavers from Philadelphia and dissected at home in his spare time. When he was finished dissecting, he covertly moved bodies to a nearby pond so he could later collect skeletons after eels had removed the remaining soft tissues. This worked well until Agnew and the townspeople found out that a local fisherman, known for selling the most delicious eels, fished exclusively from this pond. Agnew was asked to leave Cochranville and he moved to Philadelphia, where he purchased the Philadelphia School of Anatomy and worked as a surgeon at Blockley Hospital. During the Civil War, he became renowned for his ability to manage gunshot wounds. Agnew was upwardly mobile in Philadelphia, becoming one of America's most prominent 19th‐century academic surgeons. When President James Garfield was shot by an assassin, Agnew was called to care for him. When he retired from his position as the John Rhea Barton Professor of the Principles and Practice of Surgery at the University of Pennsylvania, the medical students hired the famous American realist painter, Thomas Eakins, to produce The Agnew Clinic, which became one of the artist's two most important paintings. Clin. Anat. 32:661–671, 2019. © 2019 Wiley Periodicals, Inc.
Identification of mNeonGreen as a pH‐Dependent, Turn‐On Fluorescent Protein Sensor for Chloride
Authors: Tutol Jasmine N. , Kam Hiu C. , Dodani Sheel C.
Published: March 2019

Chloride‐sensitive fluorescent proteins generated from laboratory evolution have a characteristic tyrosine residue that interacts with a chloride ion and π‐stacks with the chromophore. However, the engineered yellow‐green fluorescent protein mNeonGreen lacks this interaction but still binds chloride, as seen in a recently reported crystal structure. Based on its unique coordination sphere, we were curious if chloride could influence the optical properties of mNeonGreen. Here, we present the structure‐guided identification and spectroscopic characterization of mNeonGreen as a turn‐on fluorescent protein sensor for chloride. Our results show that chloride binding lowers the chromophore pKa and shifts the equilibrium away from the weakly fluorescent phenol form to the highly fluorescent phenolate form, resulting in a pH‐dependent, turn‐on fluorescence response. Moreover, through mutagenesis, we link this sensing mechanism to a non‐coordinating residue in the chloride binding pocket. This discovery sets the stage to further engineer mNeonGreen as a new fluorescent protein‐based tool for imaging cellular chloride.
Keep your eye on…
Authors: Knopf Alison
Published: March 2019

The increase in irritability as a risk factor for suicidality

Distinctions between psychosis and bipolar spectrum syndromes
[Co(TPP)]‐Catalyzed Formation of Substituted Piperidines
Authors: Lankelma Marianne , Olivares Astrid M. , de Bruin Bas
Published: March 2019

Radical cyclization via cobalt(III)‐carbene radical intermediates is a powerful method for the synthesis of (hetero)cyclic structures. Building on the recently reported synthesis of five‐membered N‐heterocyclic pyrrolidines catalyzed by CoII porphyrins, the [Co(TPP)]‐catalyzed formation of useful six‐membered N‐heterocyclic piperidines directly from linear aldehydes is presented herein. The piperidines were obtained in overall high yields, with linear alkenes being formed as side products in small amounts. A DFT study was performed to gain a deeper mechanistic understanding of the cobalt(II)‐porphyrin‐catalyzed formation of pyrrolidines, piperidines, and linear alkenes. The calculations showed that the alkenes are unlikely to be formed through an expected 1,2‐hydrogen‐atom transfer to the carbene carbon. Instead, the calculations were consistent with a pathway involving benzyl‐radical formation followed by radical‐rebound ring closure to form the piperidines. Competitive 1,5‐hydrogen‐atom transfer from the β‐position to the benzyl radical explained the formation of linear alkenes as side products.
A Neutral Germanium/Phosphorus Frustrated Lewis Pair and Its Contrasting Reactivity Compared to Its Silicon Analogue
Authors: Kinder Timo A. , Pior René , Blomeyer Sebastian , Neumann Beate , Stammler Hans‐Georg , Mitzel Norbert W.
Published: March 2019

Chlorogermane (C2F5)3GeCl with very electronegative pentafluoroethyl groups was converted with LiCH2P(tBu)2 to obtain the intramolecular frustrated Lewis pair (FLP) (C2F5)3GeCH2P(tBu)2, a neutral, germanium‐based FLP. Its reactivity was compared to its silicon homologue (C2F5)3SiCH2P(tBu)2. Both FLPs cleave NO but give cyclic (Si) and open‐chain oxides (Ge). In reactions with HCl both FLPs gave the same adduct type in the solid state, while the proton seems more mobile in solution in the germanium case. Reactions with PhCNO and Me3SiCHN2 result in ring‐type adducts. The structures of (C2F5)3GeCH2P(tBu)2 and of five adducts with substrates were elucidated by X‐ray diffraction. The study clearly showed the germanium compound to have a more moderate Lewis acidity compared to the silicon analogue.
Regioselective Oxidative Ring Cleavage of Antiaromatic Nickel(II) Norcorrole to Dialkoxybis(dipyrrin)s
Authors: Shafie Siham A. , Kawashima Hiroyuki , Miyake Yoshihiro , Shinokubo Hiroshi
Published: March 2019

The Ni(II) complex of meso‐dimesitylnorcorrole is a stable 16π antiaromatic porphyrinoid. We have previously reported that the reaction of the norcorrole Ni(II) complex with m‐chloroperbenzoic acid resulted in oxygen insertion to afford the corresponding 10‐ oxacorrole Ni(II) complex, which is an 18π aromatic porphyrinoid. In sharp contrast, we have found that treatment of the norcorrole Ni(II) complex with bis[(trifluoroacetoxy)iodo]benzene in the presence of a variety of alcohols induced a ring‐opening reaction to furnish the corresponding dialkoxybis(dipyrrin)s through regioselective oxidative C−C bond cleavage. Furthermore, dihydroxybis(dipyrrin) exhibited solvent‐dependent absorption and emission behavior through keto−enol tautomerization of the hydroxy groups.
Effects of prenatal alcohol exposure on social competence: Asymmetry in play partner preference among heterogeneous triads of male and female rats
Authors: Holman Parker J. , Baglot Samantha L. , Morgan Erin , Weinberg Joanne
Published: March 2019

Social behavior deficits associated with prenatal alcohol exposure (PAE) are frequently described in terms of impaired social competence, which can be defined as the effectiveness in social interaction and the ability to employ social skills successfully within different interpersonal contexts. Play behavior—which peaks during adolescence—is critical for developing social competence, as well as for motor, cognitive, and emotional development. Studies of play behavior typically utilize protocols where animals interact in dyads. However, less is understood about how the social environment may shape PAE‐related social behavior deficits, particularly in more complex social contexts. Here, we assess play partner preference utilizing a novel approach in which adolescent male and female animals interact within same‐sex triads comprised of animals from mixed prenatal treatments to determine how play partner identity and social group composition interact to shape behavior. When triads included one PAE animal and two control animals (i.e., control animals had the option to play either with a fellow control or a PAE playmate), we observed play target asymmetry whereby controls preferentially played with fellow controls. Notably, these results were consistent for triads of both males and females, with subtle differences in frequency of initiations versus reciprocations. We found no play target asymmetry, however, when triads included two PAE animals and one control animal or different configurations of control and pair‐fed animals. Taken together, play target asymmetry resulting from ineffective social interactions, including a failure to engage with, respond to, and/or solicit play from control play partners appropriately, suggests that PAE negatively impacts the development of social competence.
Kidney organoids in translational medicine: Disease modeling and regenerative medicine
Authors: Miyoshi Tomoya , Hiratsuka Ken , Saiz Edgar Garcia , Morizane Ryuji
Published: March 2019

The kidney is one of the most complex organs composed of multiple cell types, functioning to maintain homeostasis by means of the filtering of metabolic wastes, balancing of blood electrolytes, and adjustment of blood pressure. Recent advances in 3D culture technologies in vitro enabled the generation of “organoids” which mimic the structure and function of in vivo organs. Organoid technology has allowed for new insights into human organ development and human pathophysiology, with great potential for translational research. Increasing evidence shows that kidney organoids are a useful platform for disease modeling of genetic kidney diseases when derived from genetic patient iPSCs and/or CRISPR‐mutated stem cells. Although single cell RNA‐seq studies highlight the technical difficulties underlying kidney organoid generation reproducibility and variation in differentiation protocols, kidney organoids still hold great potential to understand kidney pathophysiology as applied to kidney injury and fibrosis. In this review, we summarize various studies of kidney organoids, disease modeling, genome‐editing, and bioengineering, and additionally discuss the potential of and current challenges to kidney organoid research.
LPA1, LPA2, LPA4, and LPA6 receptor expression during mouse brain development
Authors: Suckau Olga , Gross Isabel , Schrötter Sandra , Yang Fan , Luo Jiankai , Wree Andreas , Chun Jerold , Baska David , Baumgart Jan , Kano Kuniyuki , Aoki Junken , Bräuer Anja U.
Published: March 2019

Background

LPA is a small bioactive phospholipid that acts as an extracellular signaling molecule and is involved in cellular processes, including cell proliferation, migration, and differentiation. LPA acts by binding and activating at least six known G protein–coupled receptors: LPA1–6. In recent years, LPA has been suggested to play an important role both in normal neuronal development and under pathological conditions in the nervous system.

Results

We show the expression pattern of LPA receptors during mouse brain development by using qRT‐PCR, in situ hybridization, and immunocytochemistry. Only LPA
1, LPA
2, LPA
4, and LPA
6 mRNA transcripts were detected throughout development stages from embryonic day 16 until postnatal day 30 of hippocampus, neocortex, cerebellum, and bulbus olfactorius in our experiments, while expression of LPA
3 and LPA
5 genes was below detection level. In addition to our qRT‐PCR results, we also analyzed the cellular protein expression of endogenous LPA receptors, with focus on LPA1 and LPA2 within postnatal brain slices and primary neuron differentiation with and without cytoskeleton stabilization and destabilization.

Conclusions

The expression of LPA receptors changes depends on the developmental stage in mouse brain and in cultured hippocampal primary neurons. Interestingly, we found that commercially available antibodies for LPA receptors are largely unspecific.
Diet and macronutrient niche of Asiatic black bear (Ursus thibetanus) in two regions of Nepal during summer and autumn
Authors: Panthi Saroj , Aryal Achyut , Coogan Sean C. P.
Published: March 2019

Relatively little is known about the nutritional ecology of omnivorous Asiatic black bears (Ursus thibetanus) in Nepal. We characterized the diet of black bears in two seasons (June–July, “summer”; and October–November “autumn”) and two study areas (Dhorpatan Hunting Reserve [DHR]; and Kailash Sacred Landscape [KSL]). We then conducted nutritional analysis of species consumed by black bears in each study area, in combination with nutritional estimates from the literature, to estimate the proportions of macronutrients (i.e., protein [P], lipid [L], and carbohydrate [C]) in the seasonal bear foods and diets, as well as their macronutrient niche breadth. We found that bamboo (Arundinaria spp.) had the highest relative frequency in both study areas and seasons. Ants and termites were found in DHR diets, but not KSL diets. One anthropogenic crop was found in DHR summer diets (Zea mays) and two were found in KSL summer diets (Z. mays; and Kodo millet [Paspalum scrobiculatum]). Other than insects, no animal prey was found in either diet. The proportions of macronutrients in diets (i.e., realized macronutrient niches) were relatively high in carbohydrate for both study areas and seasons: DHRsummer 24.1P:8.7L:67.2C; KSLsummer 16.7P:8.2L:75.1C; DHRautumn 21.1P:10.5L:68.4C; KSHautumn 19.0P:11.0L:70.0C. Macronutrient niche breadth was 3.1 × greater in the DHR than KSL during summer, and 4.0 × greater in the autumn, primarily due to the higher proportion of lipid in ants and termites relative to plant foods. Within‐study area differences in niche breadth were greater during summer than autumn; in the KSH the macronutrient breadth was 1.4 × greater in summer, while in the DHR it was 1.1 × greater in summer. Similarity in dietary macronutrient proportions despite differences in foods consumed and niche breadth are suggestive of foraging to reach a preferred macronutrient balance.
Sampling related individuals within ponds biases estimates of population structure in a pond‐breeding amphibian
Authors: O'Connell Kyle A. , Mulder Kevin P. , Maldonado Jose , Currie Kathleen L. , Ferraro Dennis M.
Published: March 2019

Effective conservation and management of pond‐breeding amphibians depends on the accurate estimation of population structure, demographic parameters, and the influence of landscape features on breeding‐site connectivity. Population‐level studies of pond‐breeding amphibians typically sample larval life stages because they are easily captured and can be sampled nondestructively. These studies often identify high levels of relatedness between individuals from the same pond, which can be exacerbated by sampling the larval stage. Yet, the effect of these related individuals on population genetic studies using genomic data is not yet fully understood. Here, we assess the effect of within‐pond relatedness on population and landscape genetic analyses by focusing on the barred tiger salamanders (Ambystoma mavortium) from the Nebraska Sandhills. Utilizing genome‐wide SNPs generated using a double‐digest RADseq approach, we conducted standard population and landscape genetic analyses using datasets with and without siblings. We found that reduced sample sizes influenced parameter estimates more than the inclusion of siblings, but that within‐pond relatedness led to the inference of spurious population structure when analyses depended on allele frequencies. Our landscape genetic analyses also supported different models across datasets depending on the spatial resolution analyzed. We recommend that future studies not only test for relatedness among larval samples but also remove siblings before conducting population or landscape genetic analyses. We also recommend alternative sampling strategies to reduce sampling siblings before sequencing takes place. Biases introduced by unknowingly including siblings can have significant implications for population and landscape genetic analyses, and in turn, for species conservation strategies and outcomes.
Offspring mass variation in tree swallows: A case of bet‐hedging?
Authors: Gossieaux Philippine , Leclerc Martin , Van de Walle Joanie , Poisson Yoanna , Toni Pauline , Landes Julie , Bourret Audrey , Garant Dany , Pelletier Fanie , Bélisle Marc
Published: March 2019

The evolution of reproductive strategies is affected by the ability of organisms to deal with future environmental conditions. When environments are temporally unpredictable, however, it is difficult to anticipate optimal offspring phenotype. Diversification of offspring phenotypes, a strategy called diversified bet‐hedging, may allow parents to maximize their fitness by reducing between‐year variation in reproductive success. The link between diversification of offspring phenotypes and individual reproductive success, however, has rarely been documented empirically. We used an eight‐year dataset (1215 broods, 870 females) on individually marked tree swallows (Tachycineta bicolor) to assess whether intra‐brood mass variation was compatible with a diversified bet‐hedging strategy. Intra‐brood mass variation was weakly, but significantly repeatable within females, suggesting consistent individual differences. Greater intra‐brood mass variation, however, was not associated with reduced between‐year variation in reproductive success or increased female reproductive success. Moreover, contrary to diversified bet‐hedging expectations, fledging success of large broods was greater when hatchlings had similar rather than variable masses. Our results suggest that intra‐brood mass variation may not result from diversified bet‐hedging, but rather from complex interactions between environmental, brood, and maternal characteristics.
The novel butyrate derivative phenylalanine‐butyramide protects from doxorubicin‐induced cardiotoxicity
Authors: Russo Michele , Guida Fiorentina , Paparo Lorella , Trinchese Giovanna , Aitoro Rosita , Avagliano Carmen , Fiordelisi Antonella , Napolitano Fabiana , Mercurio Valentina , Sala Valentina , Li Mingchuan , Sorriento Daniela , Ciccarelli Michele , Ghigo Alessandra , Hirsch Emilio , Bianco Roberto , Iaccarino Guido , Abete Pasquale , Bonaduce Domenico , Calignano Antonio , Berni Canani Roberto , Tocchetti Carlo G.
Published: March 2019

Aims

Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine‐butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function.

Methods and results

In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co‐administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase‐2 mRNAs, which were not elevated on co‐treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre‐treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2O2, which were blunted by FBA pre‐treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour‐killing action of DOXO.

Conclusions

Phenylalanine‐butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
Impact of Alkyne Functionalization on Photophysical and Electrochemical Properties of 1,10‐Phenanthrolines and Their RuII Complexes
Authors: Wintergerst Pascal , Mengele Alexander K. , Nauroozi Djawed , Tschierlei Stefanie , Rau Sven
Published: March 2019

Three differently substituted alkyne phenanthrolines have been synthesized in high yields and the molecular structure in the solid state is confirmed by X‐ray diffraction. Synthesis of the corresponding ruthenium polypyridine complexes is feasible without metal carbonyl formation. The photophysical and electrochemical properties of the compounds reveal that substitution of the phenanthroline in the 5‐position leads to a pronounced effect in the absorption properties of the uncomplexed ligands as well as a significant shift of the redox potentials of the complexes. However, no effect on the energy of the MLCT transition and emission could be detected. This rather contradictory behavior is further analyzed by TD‐DFT calculations.
Strategies for Enzymatic Synthesis of Omega‐3 Structured Triacylglycerols from Camelina sativa Oil Enriched in EPA and DHA
Authors: Castejón Natalia , Señoráns Francisco J.
Published: March 2019

Enzymatic production of enriched eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) structured triacylglycerols (STAGs) is done in a two‐step reaction from a new source of omega‐3 α‐linolenic acid (ALA), Camelina sativa oil. A fast‐pressurized liquid extraction method with ethyl acetate as green solvent is used to produce camelina oil with a 39.3% yield in less than 20 min. In a first stage, camelina oil with a 29.7% of ALA is used to enzymatically produce 2‐monoacylglycerols (2‐MAGs) with high ALA composition in position sn‐2 (49.8% of ALA) using Lipozyme TL IM at 25 °C. For omega‐3 incorporation into STAGs, several lipases are studied, with 2‐MAG and omega‐3 FAEEs at different ratios (1:5, 1:10, and 1:20 (w/w)), 10% (w/w) of biocatalyst at 35 °C. STAGs yields reached with EPA ethyl esters are notably higher than using DHA‐EE. Lipase from Candida antarctica B (CAL‐B) and Thermomyces lanuginosus (TLL) incorporate EPA into STAGs in the same degree, 95.1 and 95.5%, respectively. However, for enriched DHA STAGs, maximum reaction yield is reached with CAL‐B (81.0%). The transesterification method of 2‐MAGs from vegetable omega‐3 sources like camelina oil, with marine EPA and DHA FAEEs, opens new approaches for developing VLC‐PUFA fortified functional foods.

Practical Applications: Results provided in this research not only demonstrate the efficiency of this enzymatic method for enriching camelina oil in EPA and DHA, but offer a very effective strategy for the development of omega‐3‐enriched products from other vegetable oil sources like chia or echium as ingredients for functional foods with recognized health claims for applications in nutraceutical and food industries. Camelina oil proved to be an excellent source to enzymatically produce 2‐MAGs enriched in omega‐3 ALA. Moreover, lipase screening with commercial biocatalysts establish the most appropriate strategy to reach maximum STAGs yields with direct application in industry. Tested lipases exhibit different degree of substrate specificity toward EPA and DHA, omega‐3 acids not present in natural seed oils. Thus, CAL‐B seems to be the most suitable lipase to produce high content EPA and DHA enriched STAGs from camelina oil as new food ingredients for nutraceutical applications.

Enzymatic production of structured TAGs enriched in EPA and DHA is done in a two‐step reaction from a natural source of omega‐3 ALA, camelina oil, studying reaction kinetics and characterizing isolated products.
Amrubicin is effective against small cell carcinoma of the prostate as a second‐line chemotherapeutic agent: A case report
Authors: Maesaka Fumisato , Nakai Yasushi , Tomizawa Mitsuru , Owari Takuya , Miyake Makito , Inoue Takeshi , Anai Satoshi , Tanaka Nobumichi , Fujimoto Kiyohide
Published: March 2019

Introduction

Small cell carcinoma of the prostate has a poor prognosis. Furthermore, treatments for small cell carcinoma of the prostate have not been established. We report a case where amrubicin was effective for second‐line chemotherapy.

Case presentation

A 50‐year‐old man complaining of painful micturition was referred to our hospital. Due to high prostate‐specific antigen level (16.57 ng/mL) and abnormal magnetic resonance imaging findings (cT2c), prostate biopsy was performed; mixed adenocarcinoma and small cell carcinoma of the prostate were observed. Radical prostatectomy was performed following a cT2cN0M0 diagnosis. One month after prostatectomy, fluorodeoxyglucose positron emission tomography/computed tomography showed metastatic lesions in the bone; the patient received androgen deprivation therapy and two cycles of cisplatin plus irinotecan. Due to new metastatic lesions and sustained abnormal pro‐gastrin‐releasing peptide levels, amrubicin was administered for second‐line chemotherapy. Pro‐gastrin‐releasing peptide was normalized and positron emission tomography/computed tomography showed a complete metabolic response after 15 cycles of amrubicin.

Conclusion

Amrubicin could serve as a second‐line chemotherapeutic agent against small cell carcinoma of the prostate.
IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma
Authors: Wang Yan , Yao Rongrong , Zhang Lan , Xie Xiaoying , Chen Rongxin , Ren Zhenggang
Published: March 2019

Background

Both Indole‐amine‐2,3‐dioxygenase (IDO) and neutrophils were proved to have pro‐tumor effect in some kinds of solid tumors by immune suppression. However, little is known about their effect on hepatocellular carcinoma (HCC) and the relationship between these two immune‐suppressive factors. The aim of this study was to evaluate the prognostic significance of IDO and intra‐tumoral neutrophils and their correlations in HCC.

Methods

Specimens’ tissue microarray (TMA) for 153 HCC patients was used in this study. We examined intra‐tumoral expression of IDO and CD66b in TMA. The Kaplan‐Meier method and Cox regression models were used to evaluate the prognostic value of IDO expression and CD66b.

Results

Multivariate analysis showed both IDO expression and intra‐tumoral neutrophils infiltration were independent prognostic factors for overall survival (OS). In high IDO expression group, the percentage of intra‐tumoral neutrophils infiltration was higher than that in low IDO expression group.

Conclusion

Both IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for HCC.
Renal effects of general anesthesia from old to recent studies
Authors: Alizadeh Reza , Fard Ziba A.
Published: March 2019

Various types of anesthesia are being utilized to maintain physiologically secured surgical conditions. Nearly all categories of general anesthesia are characterized by various perioperative and postoperative complications. These shortcomings are important aspects that need to be considered by the anesthesiologist and surgeon before administration of these compounds. The renal effects of anesthesia play an important role in understanding possible systemic changes due to the fact that the kidney has a direct or indirect impact on nearly all the systems of the body. Various studies have been conducted to find out changes in renal parameters and its systemic effects upon administration of the anesthesia and its postoperative repercussions. Besides that, the impaired renal function might have an impact on the excretion of anesthetic metabolites, which can lead to long‐term dysfunction. Patients with a previous history of disease ought to be brought under consideration because these chemicals can ameliorate pre‐existent symptoms. This review is intended to discuss the early and latest studies based on the effects of general anesthesia on the renal system.