bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence learning in a single trial: a spiking neurons model based on hippocampal circuitry
Authors: Coppolino S. , Migliore M.
Published: January 2020

In contrast with our everyday experience using brain circuits, it can take a prohibitively long time to train a computational system to produce the correct sequence of outputs in the presence of a series of inputs. This suggests that something important is missing in the way in which models are trying to reproduce basic cognitive functions. In this work, we introduce a new neuronal network architecture that is able to learn, in a single trial, an arbitrary long sequence of any known objects. The key point of the model is the explicit use of mechanisms and circuitry observed in the hippocampus, which allow the model to reach a level of efficiency and accuracy that, to the best of our knowledge, is not possible with abstract network implementations. By directly following the natural system’s layout and circuitry, this type of implementation has the additional advantage that the results can be more easily compared to experimental data, allowing a deeper and more direct understanding of the mechanisms underlying cognitive functions and dysfunctions, and opening the way to a new generation of learning architectures.
Required concentration index quantifies effective drug combinations against hepatitis C virus infection
Authors: Kakizoe Yusuke , Koizumi Yoshiki , Ikoma Yukino , Ohashi Hirofumi , Wakita Takaji , Iwami Shingo , Watashi Koichi
Published: January 2020

Successful clinical drug development requires rational design of combination treatments based on preclinical data. Anti-HCV drugs exhibit significant diversity in antiviral effect. Dose-response assessments can be used to determine parameters profiling the diverse antiviral effect during combination treatment. In the current study, a combined experimental and mathematical approaches were used to compare and score different combinations of anti-hepatitis C virus (HCV) treatments. A “required concentration index” was generated and used to rank the antiviral profile of possible double- and triple-drug combinations against HCV genotype 1 and 2. Rankings varied based on target HCV genotype. Interestingly, multidrug (double and triple) treatment not only augmented antiviral activity, but also reduced genotype-specific efficacy, suggesting another advantage of multidrug treatment. The current study provides a quantitative method for profiling drug combinations against viral genotypes, to better inform clinical drug development.
Hemoglobin Non-equilibrium Oxygen Dissociation Curve
Authors: Scrima Rosella , Fugetto Sabino , Capitanio Nazzareno , Gatti Domenico L.
Published: January 2020

Abnormal hemoglobins can have major consequences for tissue delivery of oxygen. Correct diagnosis of hemoglobinopathies with altered oxygen affinity requires a determination of hemoglobin oxygen dissociation curve (ODC), which relates the hemoglobin oxygen saturation to the partial pressure of oxygen in the blood. Determination of the ODC of human hemoglobin is typically carried out under conditions in which hemoglobin is in equilibrium with O2at each partial pressure. However, in the human body due to the fast transit of RBCs through tissues hemoglobin oxygen exchanges occur under non-equilibrium conditions. We describe the determination of non-equilibrium ODC, and show that under these conditions Hb cooperativity has two apparent components in the Adair, Perutz, and MWC models of Hb. The first component, which we callsequential cooperativity, accounts for ∼70% of Hb cooperativity, and emerges from the constraint of sequential binding that is shared by the three models. The second component, which we callconformational cooperativity, accounts for ∼30% of Hb cooperativity, and is due either to a conformational equilibrium between low affinity and high affinity tetramers (as in the MWC model), or to a conformational change from low to high affinity once two of the tetramer sites are occupied (Perutz model).
A flexible workflow for simulating transcranial electric stimulation in healthy and lesioned brains
Authors: Kalloch Benjamin , Bazin Pierre-Louis , Villringer Arno , Sehm Bernhard , Hlawitschka Mario
Published: January 2020

Simulating transcranial electric stimulation is actively researched as knowledge about the distribution of the electrical field is decisive for understanding the variability in the elicited stimulation effect. Several software pipelines comprehensively solve this task in an automated manner for standard use-cases. However, simulations for non-standard applications such as uncommon electrode shapes or the creation of head models from non-optimized T1-weighted imaging data and the inclusion of irregular structures are more difficult to accomplish.

We address these limitations and suggest a comprehensive workflow to simulate transcranial electric stimulation based on open-source tools. The workflow covers the head model creation from MRI data, the electrode modeling, the modeling of anisotropic conductivity behavior of the white matter, the numerical simulation and visualization.

Skin, skull, air cavities, cerebrospinal fluid, white matter, and gray matter are segmented semi-automatically from T1-weighted MR images. Electrodes of arbitrary number and shape can be modeled. The meshing of the head model is implemented in a way to preserve feature edges of the electrodes and is free of topological restrictions of the considered structures of the head model. White matter anisotropy can be computed from diffusion-tensor imaging data.

Our solver application was verified analytically and by contrasting tDCS simulation results with another simulation pipeline (SimNIBS 3.0). An agreement in both cases underlines the validity of our workflow.

Our suggested solutions facilitate investigations of irregular structures in patients (e.g. lesions, implants) or of new electrode types. For a coupled use of the described workflow, we provide documentation and disclose the full source code of the developed tools.
Rapid detection of Pecan Root-Knot Nematode,Meloidogyne partityla, in laboratory and field conditions using loop-mediated isothermal amplification
Authors: Waliullah Sumyya , Bell Jessica , Stackhouse Tammy , Jagdale Ganpati , Hajihassani Abolfazl , Brenneman Timothy , Ali Md Emran
Published: January 2020

Meloidogyne partitylais the dominant root-knot nematode (RKN) species parasitizing pecan in Georgia. This species is known to cause a reduction in root growth and a decline in yields from mature pecan trees. Rapid and accurate diagnosis of this RKN is required to control this nematode disease and reduce losses in pecan production. In this study, a loop-mediated isothermal amplification (LAMP) method was developed for simple, rapid and on-site detection ofM. partitylain infested plant roots and validated to detect the nematode in laboratory and field conditions. Specific primers were designed based on the sequence distinction of internal transcribed spacer (ITS)-18S/5.8S ribosomal RNA gene betweenM. partitylaand otherMeloidogynespp. The LAMP detection technique could detect the presence ofM. partitylagenomic DNA at a concentration as low as 1 pg, and no cross reactivity was found with DNA from other major RKN species such asM. javanica,M. incognitaandM. arenaria, andM. hapla. We also conducted a traditional morphology-based diagnostic assay and conventional polymerase chain reaction (PCR) assay to determine which of these techniques was less time consuming, more sensitive, and convenient to use in the field. The LAMP assay provided more rapid results, amplifying the target nematode species in less than 60 min at 65°C, with results 100 times more sensitive than conventional PCR (~2-3 hrs). Morphology-based, traditional diagnosis was highly time-consuming (2 days) and more laborious than conventional PCR and LAMP assays. These features greatly simplified the operating procedure and made the assay a powerful tool for rapid, on-site detection of pecan RKN,M. partityla. The LAMP assay will facilitate accurate pecan nematode diagnosis in the field and contribute to the management of the pathogen.
The effect of exercise on the protein profile of rat knee joint intra- and extra-articular ligaments
Authors: Kharaz Yalda A. , Birch Helen L. , Chester Alexandra , Alchorne Eleanor , Simpson Deborah , Clegg Peter , Comerford Eithne
Published: January 2020

Injuries to the intra-articular knee joint ligament (anterior cruciate ligament (ACL)) together with the extra-articular medial collateral ligament (MCL) result in significant joint instability, pain and immobility for the affected individual. Moderate endurance type exercise has been shown to increase ligament strength, however little is known on the effect of short-term high intensity exercise regimes such as treadmill training on the ACL and MCL and whether they may be beneficial to the extracellular matrix (ECM) structure of these ligaments. This study aimed to identify the effect of short-term high intensity exercise on the proteome of the rat ACL and MCL using mass spectrometry. Sprague Dawley male rats (n=12) were split into equal groups of control and exercise animals, which were subjected to high intensity training and followed by proteomic analysis of the ACL and MCL. Knee joint and ligament health was assessed using OARSI scoring or using a validated histological scoring system. Histopathological analyses demonstrated no significant changes in the ACL, MCL or cartilage of the knee joint, indicating that the exercise regime used in this study did not have substantial impact on tissue structure and health of several tissues within the rat knee joint. Some proteins were found to be significantly more abundant in the ACL in the exercised group than the control group. However, no proteins with a significantly different expression were identified between MCL control and MCL exercised groups. The majority of proteins expressed at higher levels in the ACL exercise group were cytoskeletal proteins, ribosomal proteins and enzymes. Several matrisomal proteins were also more abundant such as collagen proteins and proteoglycans in ACL exercise group. In conclusion, our results indicate that short-term high intensity exercise has an impact on ACL ECM protein expression, with the majority of differential expressed proteins being cellular proteins such as actins, ribosomal and heat shock proteins, indicative of metabolic and molecular responses. Further study is necessary to determine the impact of these short-term changes on ligament structure and function.
NOTCH inhibition promotes myoblast fusion by releasing HEYL repression onTMEM8Cregulatory regions in foetal skeletal muscles
Authors: Esteves de Lima Joana , Blavet Cédrine , Bonnin Marie-Ange , Hirsinger Estelle , Havis Emmanuelle , Duprez Delphine
Published: January 2020

Differentiation and fusion are two intricate processes involved in skeletal muscle development. The close association of differentiation and fusion makes it difficult to address the process of fusion independently of differentiation. Using the fusion markermyomaker, namedTMEM8Cin chicken, we found that bothTMEM8Ctranscripts and the differentiated and fusion-competent MYOG+ cells are preferentially regionalized in the central regions of limb foetal muscles in chicken embryos. Because the NOTCH signalling pathway is a potent inhibitor of muscle differentiation during developmental myogenesis, NOTCH function in myoblast fusion was not addressed so far. We analysed the consequences of NOTCH inhibition for myoblast fusion andTMEM8Cexpression during foetal myogenesis using in vitro and in vivo chicken systems. NOTCH inhibition following chicken embryo immobilisation or in myoblast cultures increasedTMEM8Cexpression and myoblast fusion. Moreover, we showed that NOTCH inhibition induced the un-binding of the HEYL transcriptional repressor from theTMEM8Cregulatory regions in limb muscles and myoblast cultures. These results identify a molecular mechanism underlying the fusion-promoting effect of NOTCH-inhibition during foetal myogenesis.
Full-length LINE-1s with functional ORFs are favoured by host-level selection in human genomes
Authors: zu Dohna Heinrich , Zhou Bo , Zhu Xiaowei , Urban Alexander E.
Published: January 2020

The effects of transposable elements, such as LINE-1, on host fitness are still poorly understood. Our analysis of the site frequency spectrum of LINE-1s and SNPs within LINE1s in human genomes shows that selection coefficients are higher for full-length than for fragment LINE-1s and on full-length LINE-1s, SNPs are significantly depleted on ORFs and non-synonymous sites within ORFs. These results suggest that host-level selection maintains transposition competent LINE-1s.
Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes
Authors: Fujimoto Noriki , He Yuliang , D’Addio Marco , Tacconi Carlotta , Detmar Michael , Dieterich Lothar C.
Published: January 2020

Lymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.
ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy
Authors: Lepelley Alice , Vaughn Lauren S. , Staniszewski Agnieszka , Zhang Hong , Du Fang , Koppensteiner Peter , Tomljanovic Zeljko , Carneiro Flávia R.G. , Teich Andrew F. , Ninan Ipe , Yan Shirley ShiDu , Postler Thomas S. , Hayden Matthew S. , Arancio Ottavio , Ghosh Sankar
Published: January 2020

Altered mitochondrial fitness is a potential triggering factor in Alzheimer’s disease (AD). Mitochondrial quality control pathways are dysfunctional and mitochondrially-derived reactive oxygen species (mROS) levels are increased in AD patient brains. However, the pathways responsible for dysregulated mROS accumulation have remained relatively unclear. In this study, we demonstrate that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains. Neuronal ECSIT downregulation increased mROS generation and impaired mitophagy of defective mitochondria. Consequently, decreasing neuronal ECSIT caused AD-like changes, including memory loss and neuropathology. In contrast, augmented neuronal expression of ECSIT protected against the development of an AD-like phenotype. Decreased levels of ECSIT in AD patient brains therefore likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.
Defective Function of α-Ketoglutarate Dehydrogenase Exacerbates Mitochondrial ATP Deficits during Complex I Deficiency
Authors: Piroli Gerardo G. , Manuel Allison M. , McCain Richard S. , Smith Holland H. , Ozohanics Oliver , Mellid Sara , Cotham William E. , Walla Michael D. , Cascón Alberto , Ambrus Attila , Frizzell Norma
Published: January 2020

TheNDUFS4knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of theNDUFS4KO brain affected by neurodegeneration, suggesting a mechanistic role in neurodegenerative decline. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in theNDUFS4KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
Altered polarization of PAR-2 signaling during airway epithelial remodeling
Authors: Carey Ryan M. , Freund Jenna R. , Hariri Benjamin M. , Adappa Nithin D. , Palmer James N. , Lee Robert J.
Published: January 2020

Background

Protease-activated receptor 2 (PAR-2) is activated by proteases involved in allergy and triggers airway epithelial secretion and inflammation. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells.

Objective

We tested if epithelial remodeling during diseases characterized by loss of cilia and squamous metaplasia may alter PAR-2 polarization.

Methods

Endogenous PAR-2 responses were measured by live cell calcium and cilia imaging, measurement of fluid secretion, and quantification of cytokines. We utilized airway squamous cell lines, primary differentiated air-liquid interface cultures, and tissue explants. Cells were exposed to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency. We used concentrations and exposure times that altered epithelial morphology without causing breakdown of the epithelial barrier, likely reflecting early disease states.

Results

PAR-2 signaling in airway squamous cells activated calcium and inflammatory responses. Squamous cells cultured at air liquid interface (ALI) responded to PAR-2 agonists applied both apically and basolaterally. Primary well-differentiated nasal epithelial ALI cultures responded only to basolateral PAR-2 stimulation. Primary cultures exposed to IL-13, cigarette smoke condensate, or reduced retinoic acid responded to both apical and basolateral PAR-2 stimulation. Nasal polyp tissue, but not control middle turbinate, exhibited apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyp and turbinate maintained basolateral PAR-2 polarization.

Conclusions

Squamous metaplasia and/or loss of cilia enhances apical PAR-2 responses. Altered PAR-2 polarization in dedifferentiated or remodeled epithelia may contribute to increased sensitivity to inhaled protease allergens in inflammatory airway diseases.
DNA Features Viewer, a sequence annotations formatting and plotting library for Python
Authors: Zulkower Valentin , Rosser Susan
Published: January 2020

Motivation

While the Python programming language counts many Bioinformatics and Computational Biology libraries, none offers customizable sequence annotations visualizations with layout optimization.

Results

DNA Features Viewer is a sequence annotations plotting library which optimizes plot readability while letting users tailor other visual aspects (colors, labels, highlights, etc.) to their particular use case.

Availability

Open-source code and documentation are available on Github under the MIT licence (https://github.com/Edinburgh-Genome-Foundry/DnaFeaturesViewer).

Contact

valentin.zulkower@ed.ac.uk

Supplementary information

attached.
Cell segmentation using deep learning: comparing label and label-free approaches using hyper-labeled image stacks
Authors: Cameron William D. , Bennett Alex M. , Bui Cindy V. , Chang Huntley H. , Rocheleau Jonathan V.
Published: January 2020

Deep learning provides an opportunity to automatically segment and extract cellular features from high-throughput microscopy images. Many labeling strategies have been developed for this purpose, ranging from the use of fluorescent markers to label-free approaches. However, differences in the channels available to each respective training dataset make it difficult to directly compare the effectiveness of these strategies across studies. Here we explore training models using subimage stacks composed of channels sampled from larger, ‘hyper-labeled’, image stacks. This allows us to directly compare a variety of labeling strategies and training approaches on identical cells. This approach revealed that fluorescence-based strategies generally provide higher segmentation accuracies but were less accurate than label-free models when labeling was inconsistent. The relative strengths of label and label-free techniques could be combined through the use of merging fluorescence channels and out-of-focus brightfield images. Beyond comparing labeling strategies, using subimage stacks for training was also found to provide a method of simulating a wide range of labeling conditions, increasing the ability of the final model to accommodate a greater range of experimental setups.
A role for theMEGF6gene in predisposition to osteoporosis
Authors: Teerlink Craig C. , Jurynec Michael J , Hernandez Rolando , Stevens Jeff , Hughes Dana C. , Brunker Cherie P. , Rowe Kerry , Grunwald David J. , Facelli Julio C. , Cannon-Albright Lisa A.
Published: January 2020

Osteoporosis is a common skeletal disorder characterized by deterioration of bone tissue in later life. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative-pairs, approximately cousins, from ten pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant inMEGF6(rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genesmegf6aandmegf6bin zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in-silico protein structure modeling, and functional assays support a role forMEGF6in predisposition to osteoporosis.
Mutation of the Galectin-3 Glycan Binding Domain (Lgals3-R200S) Enhances Cortical Bone Expansion in Male and Trabecular Bone Mass in Female Mice
Authors: Maupin Kevin A. , Dick Daniel , Vivarium VARI , Core Transgenics , Williams Bart O.
Published: January 2020

The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype inLgals3-R200S mutant mice at 36 weeks as we previously observed inLgals3-KO mice with slight variation. LikeLgals3-KO mice,Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only maleLgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and femaleLgals3-KO mice and only in female mice using a separateLgals3null allele (Lgals3). These results suggest that the trabecular bone phenotype ofLgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype ofLgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to theLgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
Design and demonstration in vitro of a mouse-specific Transcranial Magnetic Stimulation coil
Authors: Khokhar Farah A. , Voss Logan J. , Steyn-Ross D. Alistair , Wilson Marcus T.
Published: January 2020

Background

Transcranial Magnetic Stimulation (TMS) is a technique used to treat different neurological disorders non-invasively. A pulsed current to a coil generates a magnetic field (B-field) which induces an electric field (E-field). Underlying biophysical effects of TMS are unclear. Therefore, animal experiments are needed; however, making small TMS coils suitable for mice is difficult and their field strengths are typically much lower than for human sized coils.

Objectives/Hypothesis

We aimed to design and demonstrate a mouse-specific coil that can generate high and focused E-field.

Methods

We designed a tapered TMS coil of 50 turns of 0.2 mm diameter copper wire around a 5 mm diameter tapered powdered iron core and discharged a 220 μF capacitor at 50 V through it. We measured B-field with a Hall probe and induced E-field with a wire loop. We measured temperature rise with a thermocouple. We applied 1200 pulses of continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) to mouse brain slices and analysed how spontaneous electrical activity changed.

Results

The coil gave maximum B-field of 685 mT at the base of the coil and 340 mT at 2 mm below the coil, and maximum E-field 2 mm below the coil of approximately 10 V/m, at 50 V power supply, with a temperature increase of 20 degrees after 1200 pulses of cTBS. We observed no changes in B-field with heating. cTBS reduced frequency of spontaneous population events in mouse brain slices up to 20 minutes after stimulation and iTBS increased frequency up to 20 minutes after stimulation. No frequency changes occurred after 20 minutes. No changes in amplitude of spontaneous events were found.

Conclusion

The design generated fields strong enough to modulate brain activity in vitro.
Developmental hourglass and heterochronic shifts in fin and limb development
Authors: Onimaru Koh , Tatsumi Kaori , Tanegashima Chiharu , Kadota Mitsutaka , Nishimura Osamu , Kuraku Shigehiro
Published: January 2020

How genetic changes are linked to morphological novelties and developmental constraints remains elusive. Here we investigate genetic apparatuses that distinguish fish fins from tetrapod limbs by analyzing transcriptomes and open chromatin regions (OCRs). Specifically, we compare mouse forelimb buds with pectoral fin buds of a slowly evolving species, the brown-banded bamboo shark (Chiloscyllium punctatum). A transcriptomic comparison with an accurate orthology map reveals both a mass heterochrony and hourglass-shaped conservation of gene expression between fins and limbs. Furthermore, chromatin-accessibility data indicate that conserved regulatory sequences are most active during mid-stage limb development. During this stage, stage-specific and tissue-specific OCRs are also enriched. Together, early and late stages of fin/limb development are more permissive to mutations, which may have contributed to the major morphological changes during the fin-to-limb evolution. We also hypothesize that the middle stages are constrained by regulatory complexity that results from dynamic and tissue-specific transcriptional controls.
Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease
Authors: Ma Shi-Xun , Kim Donghoon , Xiong Yulan , Kwon Seung-Hwan , Brahmachari Saurav , Kim Sangjune , Kam Tae-In , Nirujogi Raja Sekhar , Kwon Sang Ho , Dawson Valina L. , Dawson Ted M. , Pandey Akhilesh , Na Chan Hyun , Ko Han Seok
Published: January 2020

Parkinson’s disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and eventually, cognitive impairment. α-Synuclein protein has been known to be the most culprit protein, but the underlying pathological mechanism still remains to be elucidated. As an effort to clarify the pathogenesis mechanism by α-synuclein, various PD mouse models with α-synuclein overexpression have been developed. However, the systemic analysis of protein abundance change by the overexpressed α-synuclein in the whole proteome level has been still lacking. To address this issue, we established two sophisticated mouse models of PD by injecting α-synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T α-synuclein to discover overlapping pathways, which could be altered in the two different types of PD mouse model. For more accurate quantification of mouse brain proteome, stable isotope labeling with amino acid in mammal-based quantification was implemented. As a result, we have successfully identified a total of 8,355 proteins from both of the mouse models; ∼6,800 and ∼7,200 proteins from α-synuclein PFF injected mice and human A53T α-synuclein transgenic mice, respectively. From the pathway analysis of the differentially expressed proteins in common, the complement and coagulation cascade pathway were determined as the most enriched ones. This is the first study that highlights the significance of the complement and coagulation pathway in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.
SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β-cells
Authors: Hu Li , He Fengli , Huang Meifeng , Zhao Qian , Cheng Lamei , Said Neveen , Zhou Zhiguang , Liu Feng , Dai Yan-Shan
Published: January 2020

SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we show that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of β-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets fromsparc-/- mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS insparc-/- mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic β cells.
Targeting Aryl Hydrocarbon Receptor with small molecule, 1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester blocked human glioma cell invasion via MYH9
Authors: Zhao Lijiao , Shu Qiuting , Sun Hui , Ma Yunlong , Kang Dandan , Zhao Yating , Lu Jing , Gong Pei , Yang Fan , Wan Fang
Published: January 2020

Aryl hydrocarbon receptor (AHR) was a master regulator of anti-tumor cell migration in various cell types. Whether and how AHR regulates glioma cell migration is largely unknown. We found that small molecule 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous AHR ligand, can significantly block glioma cell migration and invasionin vitro,ex vivoandin vivo. Knocking down AHR by siRNA abolished ITE’s migration-inhibiting effects. ITE increased the number of filopodia-like protrusion formation, but reduced protrusion attachment to the extracellular matrix, and inhibited the rear retraction of migrating glioma cells. Moreover, both mesenchymal and amoeboid migrating cells were observed in the DMSO control group while none of the cells display amoeboid migration in the ITE treated group. MYH9 was significantly reduced by ITE treatment in human glioma cells. Over-expression of MYH9 abrogated ITE’s migration-inhibiting effects, with the expression level of MYH9 correlated with cell migration ability. Since MYH9 is a component of non-muscle myosin IIA (NMIIA), which is essential for cell migration in 3D confined space, and not a discovered target of AHR, the fact that ITE affects MYH9 via AHR opens a new research and development avenue.
The OptoGenBox - a device for long-term optogenetics inC. elegans
Authors: Busack Inka , Jordan Florian , Sapir Peleg , Bringmann Henrik
Published: January 2020

Optogenetics controls neural activity and behavior in living organisms through genetically targetable actuators and light. This method has revolutionized biology and medicine as it allows controlling cells with high temporal and spatial precision. Optogenetics is typically applied only at short time scales, for instance to study specific behaviors. Optogenetically manipulating behavior also gives insights into physiology, as behavior controls systemic physiological processes. For example, arousal and sleep affect aging and health span. To study how behavior controls key physiological processes, behavioral manipulations need to occur at extended time scales. However, methods for long-term optogenetics are scarce and typically require expensive compound microscope setups. Optogenetic experiments can be conducted in many species. Small model animals such as the nematodeC. elegans, have been instrumental in solving the mechanistic basis of medically important biological processes. We developed OptoGenBox, an affordable stand-alone and simple-to-use device for long-term optogenetic manipulation ofC. elegans. OptoGenBox provides a controlled environment and is programmable to allow the execution of complex optogenetic manipulations over long experimental times of many days to weeks. To test our device, we investigated how optogenetically increased arousal and optogenetic sleep deprivation affect survival of arrested first larval stageC. elegans. We optogenetically activated the nociceptive ASH sensory neurons using ReaChR, thus triggering an escape response and increase in arousal. In addition, we optogenetically inhibited the sleep neuron RIS using ArchT, a condition known to impair sleep. Both optogenetic manipulations reduced survival. Thus, OptoGenBox presents an affordable system to study the long-term consequences of optogenetic manipulations of key biological processes inC. elegansand perhaps other small animals.
TQM for Greek SMEs: an alternative in facing crisis conditions
Authors: Sainis George , Haritos George , Kriemadis Thanos , Papasolomou Ioanna
Published: January 2020

Purpose

This study aims to bridge the gap left by earlier studies regarding the issue of whether the International Organization for Standardization (ISO) certification is a stepping stone that ultimately leads to instilling a total quality management (TQM) culture, or whether it is the end-point in their journey toward quality.

Design/methodology/approach

The study was primarily quantitative in nature supported from a qualitative survey following the triangulation approach, as the aim was to test a number of hypotheses related to TQM’s role in the operation of Greek ISO certified small and medium-sized enterprises (SMEs). A questionnaire was developed based on the critical success factors that were used in the self-assessment instrument developed by Hunt (1992) and Sashkin (1996) to assess the level of TQM implementation in approximately 400 Greek SMEs.

Findings

The study revealed that Greek ISO certified SMEs, emphasize performance appraisal, invest in quality elements that require minimum usage of their resources and prioritize their ISO certification.

Originality/value

TQM is one of the most powerful concepts available to businesses today. However, most of the literature focuses on the practice of TQM within large manufacturing organizations. This paper aims to readdress the situation by outlining a study on TQM in the SME sector in Greece.
Do types of strategic orientations make a difference?
Authors: Pehrsson Tobias
Published: January 2020

Purpose

The purpose of this paper is to create a new research direction within the domain of firms’ strategic orientations.

Design/methodology/approach

Based on data from Swedish multinational corporations (MNCs), this paper identifies types, i.e. configurations, of strategic orientations involving the components of entrepreneurial orientation and market orientation, and examines relationships with performance in foreign markets. Cluster analysis identifies types, and linear regression analysis examines relationships with performance in foreign markets.

Findings

Four types of orientations were found: conservative; entrepreneurial; maximizing; and irresolute. Furthermore, it was found that the relationship with performance in foreign markets is most positive for the maximizing followed by the conservative and irresolute.

Research limitations/implications

First, it is established that entrepreneurial orientation and market orientation do not operate in isolation but are mutually supportive. Second, by establishing that type of orientations makes a difference for performance, this paper goes beyond the predominant view saying that just degrees matter. Third, the findings contribute to resource-advantage theory by establishing that competitive advantage results from resources being complementary in nature.

Practical implications

Instead of solely relying only on entrepreneurial orientation, or market orientation, corporations are advised to carefully evaluate their configuration of orientations. The evaluation is decisive because it cites implications for performance.

Originality/value

The study contributes to the literature on strategic orientation in a unique way as it captures performance implications stemming from types of strategic orientations.
The role of home market context in business model change in internationalizing SMEs
Authors: Rissanen Tommi , Ermolaeva Liubov , Torkkeli Lasse , Ahi Ali , Saarenketo Sami
Published: January 2020

Purpose

This paper aims to explore the underlying reasons for business model change among internationalizing SMEs and illustrate how home market context affects that change.

Design/methodology/approach

This is a comparative case study of two companies with similar backgrounds from different countries of origin. In each case, the data were collected by means of in-depth interviews with key informants. For its theoretical background, the study draws on the business model innovation and international business literature.

Findings

The authors found that home market context has two kinds of effect on business model change in internationalizing SMEs. First, home market maturity has a strong effect on the timing of companies’ internationalization efforts. Second, the company’s home market can either be used to strengthen the value proposition or may be disguised, depending on how the country of origin is seen in international markets. This factor has a strong influence on how SMEs change their business model when internationalizing.

Research limitations/implications

The study’s limitations relate to its qualitative and exploratory nature. Future research should further assess the generalizability of these findings across different cultural contexts and countries of origin by quantifying the central concepts and examining how they relate to larger-scale cross-national and cross-sectional panel data.

Practical implications

As internationalization increasingly poses both threats and opportunities, companies must be able to experiment with business models when necessary to adapt to the host market. In so doing, it is also important to consider how a company’s home market affects business model change.

Originality/value

This is one of the first studies to illustrate how the process of internationalization drives SMEs to change their business models. As such, the paper enhances existing understanding of business model change in the context of internationalization. To our knowledge, no previous study has described these dynamics in a comparative context that takes account of SME country of origin.
The mediating role of entrepreneurial ambition in the relationship between entrepreneurial efficacy and entrepreneurial drive for female nascent entrepreneurs
Authors: Sims Randi L. , Chinta Ravi
Published: January 2020

Purpose

Using Vroom’s expectancy theory of motivation as a theoretical basis, this study aims to test the relationship between female entrepreneurial efficacy, entrepreneurial ambition and nascent entrepreneurial drive, accounting for the potential barriers of race and minority disadvantage.

Design/methodology/approach

The sample included 950 respondents comprising 213 Black women and 737 White women living in the state of Alabama, USA, who expressed an intention to starting their own business.

Findings

The results indicate that race and perceptions of minority disadvantage are perceived barriers in the mediated relationship between female entrepreneurial efficacy, entrepreneurial ambition and entrepreneurial drive. However, the findings suggest that, unlike race, minority disadvantage is not perceived as a significant factor in the mediated relationship between entrepreneurial confidence, entrepreneurial ambition and entrepreneurial drive.

Research limitations/implications

Limitations of this study include the lack of an experimental design and the use of cross-sectional data.

Practical implications

Results are discussed in terms of the context of the history of racial and gender discrimination within the state of Alabama, USA.

Social implications

The results show that the direct effects of minority disadvantage on entrepreneurial ambition are significantly higher for the Black women compared with the White women in our sample.

Originality/value

The results of this study show that the direct effects of minority disadvantage on entrepreneurial ambition are significantly higher for the Black women compared with the White women. For the subgroup of Black women, the greater the perception of minority disadvantage, the greater the entrepreneurial ambition reported.
Viral marketing content for Universal Health Coverage campaign in Indonesia
Authors: Putri Nuzulul Kusuma , Ernawaty Ernawaty
Published: January 2020

Purpose

Today, viral marketing is popular as a highly effective marketing strategy with a low cost for mass targeting. This is suitable for the Universal Health Coverage campaign which seeks to attract the whole nation’s population to voluntarily register with social health insurance. It uses the target market itself as a weapon and the marketing content as a bullet. This study aims to determine the exact viral marketing content for the Universal Health Coverage campaign in Indonesia.

Design/methodology/approach

Viral marketing content is formulated based on the feelings of the target market toward social health insurance. Qualitative content analysis was conducted to identify the media framing and the audience’s response. Two of the biggest online news websites were analysed to determine the media framing. The audience’s response was identified through a Facebook group discussion.

Findings

This study shows that negative media framing makes people question the benefit of participating in social health insurance. Considering the local wisdom of Indonesia, helping poor people through social health insurance would be the best viral marketing content.

Research limitations/implications

Because of the limited number of sources focused on the audience’s responses that have been analysed, the variations in the audience response could not be captured completely. Researchers should also analyse other audience channels (social media and messenger application) besides Facebook.

Practical implications

The paper includes implications for the future marketing agenda of insurance providers in relation to engaging the community.

Originality/value

This study operationally introduced how to use the media channel selected and audience framing in designing an effective viral marketing content in health-care marketing.
The joint effects of lead time, information sharing, and the accounts receivable period on reverse factoring
Authors: Huang Qiuping , Zhao Xiande , Zhang Min , Yeung KwanHo , Ma Lijun , Yeung Jeff Hoi-yan
Published: January 2020

Purpose

The purpose of this paper is to empirically investigate the joint effects of lead time, information sharing and the accounts receivable period on reverse factoring (RF) adoption from the suppliers’ perspective.

Design/methodology/approach

Supported by one of the largest commercial banks in China, survey data are collected from 424 Chinese manufacturing firms and analyzed using regression methods.

Findings

The results suggest that lead time positively affects suppliers’ RF adoption directly and indirectly through the accounts receivable period. Meanwhile, information sharing has a positive, direct and a negative, indirect influence on suppliers’ RF adoption.

Originality/value

The findings give suppliers and financial institutions a better understanding of how to leverage the benefits of RF.