bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice
Authors: Haigh Jessica L. , Adhikari Anna , Copping Nycole A. , Stradleigh Tyler , Wade A. Ayanna , Catta-Preta Rinaldo , Su-Feher Linda , Zdilar Iva , Morse Sarah , Fenton Timothy A , Nguyen Anh , Quintero Diana , Agezew Samrawit , Sramek Michael , Kreun Ellie J , Carter Jasmine , Gompers Andrea , Lambert Jason , Canales Cesar P. , Pennacchio Len A. , Visel Axel , Dickel Diane E. , Silverman Jill L. , Nord Alex S.
Published: September 2019

Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. Mice harboring a deletion of the extended evolutionarily-conserved 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression in brain with accompanying electroencephalographic seizures and behavioral deficits. This work identified the 1b region as a critical disease-relevant regulatory element and provides evidence that non-canonical and seemingly redundant promoters can have essential function.
Linked optical and gene expression profiling of single cells at high throughput
Authors: Zhang Jesse Q. , Siltanen Christian A. , Liu Leqian , Chang Kai-Chun , Gartner Zev J. , Abate Adam R.
Published: September 2019

Single cell RNA sequencing has emerged as a powerful tool for characterizing cells, but not all phenotypes of interest can be observed through gene expression alone. Linking sequencing with optical analysis has provided insight into the molecular basis behind cellular function, but current approaches have limited throughput. Here, we present a high throughput platform for linked optical and gene expression profiling of single cells. We demonstrate accurate fluorescence and gene expression measurements from thousands of cells in a single experiment and use the platform to characterize DNA and RNA changes in Jurkat cells through the cell cycle. In addition to its scalability, our integration of microfluidics and array-based molecular biology holds promise for comprehensive multi-omics profiling of single cells.
A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families
Authors: Bronstein Revital , Capowski Elizabeth E. , Mehrotra Sudeep , Jansen Alex D. , Navarro-Gomez Daniel , Maher Mathew , Place Emily , Sangermano Riccardo , Bujakowska Kinga M. , Gamm David M. , Pierce Eric A.
Published: September 2019

Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient induced pluripotent stem cell (iPSC) derived retinal organoids (ROs) transcriptome analysis. With this approach we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.
E. coliTraR allosterically regulates transcription initiation by altering RNA polymerase conformation and dynamics
Authors: Chen James , Gopalkrishnan Saumya , Chiu Courtney , Chen Albert Y. , Campbell Elizabeth A. , Gourse Richard L. , Ross Wilma , Darst Seth A.
Published: September 2019

TraR and its homolog DksA are bacterial proteins that regulate transcription initiation by binding directly to RNA polymerase (RNAP) rather than to promoter DNA. Effects of TraR mimic the combined effects of DksA and its cofactor ppGpp. How TraR and its homologs regulate transcription is unclear. Here, we use cryo-electron microscopy to determine structures ofEscherichia coliRNAP, with or without TraR, and of an RNAP-promoter complex. TraR binding induced RNAP conformational changes not seen in previous crystallographic analyses, and a quantitative analysis of RNAP conformational heterogeneity revealed TraR-induced changes in RNAP dynamics. These changes involve mobile regions of RNAP affecting promoter DNA interactions, including the βlobe, the clamp, the bridge helix, and several lineage-specific insertions. Using mutational approaches, we show that these structural changes, as well as effects on σ70region 1.1, are critical for transcription activation or inhibition, depending on the kinetic features of regulated promoters.
Learning long temporal sequences in spiking networks by multiplexing neural oscillations
Authors: Vincent-Lamarre Philippe , Calderini Matias , Thivierge Jean-Philippe
Published: September 2019

Many cognitive and behavioral tasks – such as interval timing, spatial navigation, motor control and speech – require the execution of precisely-timed sequences of neural activation that cannot be fully explained by a succession of external stimuli. We show how repeatable and reliable patterns of spatiotemporal activity can be generated in chaotic and noisy spiking recurrent neural networks. We propose a general solution for networks to autonomously produce rich patterns of activity by providing a multi-periodic oscillatory signal as input. We show that the model accurately learns a variety of tasks, including speech generation, motor control and spatial navigation. Further, the model performs temporal rescaling of natural spoken words and exhibits sequential neural activity commonly found in experimental data involving temporal processing. In the context of spatial navigation, the model learns and replays compressed sequences of place cells and captures features of neural activity such as the emergence of ripples and theta phase precession. Together, our findings suggest that combining oscillatory neuronal inputs with different frequencies provides a key mechanism to generate precisely timed sequences of activity in recurrent circuits of the brain.
Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets
Authors: Wangzhou Andi , McIlvried Lisa A. , Paige Candler , Barragan-Iglesias Paulino , Guzman Carolyn A. , Dussor Gregory , Ray Pradipta R. , Gereau Robert W. , Price Theodore J.
Published: September 2019

Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing. They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to our knowledge, no study has ever directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro, or between different labs and culturing protocols. We extracted bilateral lumbar DRG from C57BL6/J mice and human organ donors, and acutely froze one side and processed the other side as a dissociated cell culture, which was then maintained in vitro for 4 days. RNA was extracted and sequenced using the NextSeq Illumina platform. Comparing native to cultured human or mouse DRG, we found that the overall expression level of many ion channels and GPCRs specifically expressed in neurons is markedly lower in culture, but still expressed. This suggests that most pharmacological targets expressed in vivo are present in culture conditions. However, there are changes in expression levels for these genes. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with the mitotic status of many cells in these cultures. We did find a subset of genes that are typically neuronally expressed, increased in human and mouse DRG cultures, including genes associated with nerve injury and/or inflammation in preclinical models such as BDNF, MMP9, GAL, and ATF3. We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery.
Alzheimer’s genetic risk factorFERMT2(Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner
Authors: Eysert Fanny , Coulon Audrey , Boscher Emmanuelle , Vreulx Anaїs-Camille , Flaig Amandine , Mendes Tiago , Hughes Sandrine , Grenier-Boley Benjamin , Hanoulle Xavier , Demiautte Florie , Bauer Charlotte , Marttinen Mikael , Takalo Mari , Amouyel Philippe , Desai Shruti , Pike Ian , Hiltunen Mikko , Chécler Frédéric , Farinelli Mélissa , Delay Charlotte , Malmanche Nicolas , Hébert Sébastien , Dumont Julie , Kilinc Devrim , Lambert Jean-Charles , Chapuis Julien
Published: September 2019

Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement ofFERMT2(or Kindlin-2), a genetic risk factor of Alzheimer’s disease (AD), as a potential key modulator of axon guidance; a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3’UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.
Interhemispheric connections between olfactory bulbs improve odor detection
Authors: Kermen Florence , Yaksi Emre
Published: September 2019

Interhemispheric connections enable interaction and integration of sensory information in bilaterian nervous systems and are thought to optimize sensory computations. However, the cellular and spatial organization of interhemispheric networks as well as the computational properties they mediate in vertebrates are still poorly understood. Thus, it remains unclear to which extent the connectivity between left and right brain hemispheres participates in sensory processing. Here, we show that the zebrafish olfactory bulbs (OBs) receive direct interhemispheric projections from their contralateral counterparts in addition to top-down inputs from the contralateral zebrafish homolog of olfactory cortex. The direct interhemispheric projections between the OBs reach peripheral layers of the contralateral OB and retain a fine-grained topographic organization, which directly connects similarly tuned olfactory glomeruli across hemispheres. In contrast, interhemispheric top-down inputs consist of diffuse projections that broadly innervate the inhibitory granule cell layer. Jointly, these interhemispheric connections elicit a balance of topographically organized excitation and non-topographic inhibition on the contralateral OB and modulate odor responses. We show that the interhemispheric connections in the olfactory system enable the modulation of odor response and improve the detection of a reproductive pheromone, when presented together with competing complex olfactory cues, by boosting the response of the pheromone selective neurons. Taken together, our data shows a previously unknown function for an interhemispheric connection between chemosensory maps of the olfactory system.
TGFβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration
Authors: Kaji Deepak A. , Howell Kristen L. , Huang Alice H.
Published: September 2019

Tendon injuries are common with poor healing potential. The paucity of therapies for tendon is due to our limited understanding of the cells and molecules that drive tendon regeneration. Using a model of neonatal mouse tendon regeneration, we determined the molecular basis for regeneration and identify TGFβ signaling as a major pathway. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and –independent mechanisms underyling tendon regeneration. Importantly, functional recovery depended on TGFβ signaling and loss of function is due to impaired tenogenic cell recruitment from bothScxlinand non-Scxlinsources. We show that TGFβ signaling is required directly in neonatal tenocytes for recruitment and that TGFβ is positively regulated in tendons. Collectively, these results are the first to show a functional role for TGFβ signaling in tendon regeneration and offer new insights toward the divergent cellular activities that may lead to regenerative vs fibrotic healing.
Peptide-based quorum sensing systems inPaenibacillus polymyxa
Authors: Voichek Maya , Maaß Sandra , Kroniger Tobias , Becher Dörte , Sorek Rotem
Published: September 2019

Paenibacillus polymyxais an agriculturally important plant growth-promoting rhizobacterium. ManyPaenibacillusspecies are known to be engaged in complex bacteria-bacteria and bacteria-host interactions, which in other species were shown to necessitate quorum sensing communication. However, to date no quorum sensing systems have been described inPaenibacillus. Here we show that the type strainP. polymyxaATCC 842 encodes at least 16 peptide-based communication systems. Each of these systems is comprised of a pro-peptide that is secreted to the growth medium and processed to generate a mature short peptide. Each peptide has a cognate intracellular receptor of the RRNPP family, and we show that external addition ofP. polymyxacommunication peptides leads to reprogramming of the transcriptional response. We found that these quorum sensing systems are conserved across hundreds of species belonging to thePaenibacillaceaefamily, with some species encoding more than 25 different peptide-receptor pairs, representing a record number of quorum sensing systems encoded in a single genome.
Atoh1 is repurposed from neuronal to hair cell determinant by Gfi1 acting as a coactivator without redistribution of its genomic binding sites
Authors: Costa Aida , Powell Lynn M. , Soufi Abdenour , Lowell Sally , Jarman Andrew P.
Published: September 2019

Although the lineage-determining ability of transcription factors is often modulated according to cellular context, the mechanisms by which such switching occurs are not well known. Using a transcriptional programming model, we found that Atoh1 is repurposed from a neuronal to an inner ear hair cell (HC) determinant by the combined activities of Gfi1 and Pou4f3. In this process, Atoh1 maintains its regulation of neuronal genes but gains ability to regulate HC genes. Pou4f3 enables Atoh1 access to genomic locations controlling the expression of sensory (including HC) genes, but Atoh1+Pou4f3 are not sufficient for HC differentiation. Gfi1 is key to the Atoh1-induced lineage switch, but surprisingly does not alter Atoh1’s binding profile. Gfi1 acts in two divergent ways. It represses the induction by Atoh1 of genes that antagonise HC differentiation, a function in keeping with its well-known repressor role in haematopoiesis. Remarkably, we find that Gfi1 also acts as a co-activator: it binds directly to Atoh1 at existing target genes to enhance its activity. These findings highlight the diversity of mechanisms by which one TF can redirect the activity of another to enable combinatorial control of cell identity.
Mapping Cell Membrane Organization and Dynamics Using Soft Nano-Imprint Lithography
Authors: Sansen T. , Sanchez-Fuentes D. , Rathar R. , Colom-Diego A. , El Alaoui F. , Viaud J. , Macchione M. , de Rossi S. , Matile S. , Gaudin R. , Bäcker V. , Carretero-Genevrier A. , Picas L.
Published: September 2019

Membrane shape is a key feature of many cellular processes, including cell differentiation, division, migration, and trafficking. The development of nanostructured surfaces allowing for the in situ manipulation of membranes in living cells is crucial to understand these processes, but this requires complicated and limited-access technologies. Here, we investigate the self-organization of cellular membranes by using a customizable and bench top method allowing to engineer 1D SiO2 nanopillar arrays of defined sizes and shapes on high-performance glass compatible with advanced microscopies. As a result of this original combination, we provide a mapping of the morphology-induced modulation of the cell membrane mechanics, dynamics and steady-state organization of key protein complexes implicated in cellular trafficking and signal transduction.
High Resolution Structural Insights into Heliorhodopsin Family
Authors: Kovalev K. , Volkov D. , Astashkin R. , Alekseev A. , Gushchin I. , Haro-Moreno J. M. , Rogachev A. , Balandin T. , Borshchevskiy V. , Popov A. , Bourenkov G. , Bamberg E. , Rodriguez-Valera F. , Bueldt G. , Gordeliy V.
Published: September 2019

Rhodopsins are the most abundant light-harvesting proteins. A new family of rhodopsins, heliorhodopsins (HeRs), was recently discovered. In opposite to the known rhodopsins their N-termini face the cytoplasm. HeRs structure and function remain unknown. We present structures of two HeR-48C12 states at 1.5 Å showing its remarkable difference from all known rhodopsins. Its internal extracellular part is completely hydrophobic, while the cytoplasmic part comprises a cavity (’active site’), surrounded by charged amino acids and containing a cluster of water molecules, presumably being a primary proton acceptor from the Schiff base. At acidic pH a planar triangle molecule (acetate) is present in the ‘active site’ which demonstrated its ability to maintain such anions as carbonate or nitrate. Structure-based bioinformatic analysis identified 10 subfamilies of HeRs suggesting their diverse biological functions. The structures and available data suggest an enzymatic activity of HeR-48C12 subfamily and their possible involvement into fundamental redox biological processes.
Coordination of humoral immune factors dictates compatibility betweenSchistosoma mansoniandBiomphalaria glabrata
Authors: Li Hongyu , Hambrook Jacob R. , Pila Emmanuel A. , Gharamah Abdullah A. , Fang Jing , Wu Xinzhong , Hanington Patrick C.
Published: September 2019

Immune factors in snails of the genusBiomphalariaare critical for combatingSchistosoma mansoni, the predominant cause of human intestinal schistosomiasis. Independently, many of these factors are known to play an important role in, but not fully define, the compatibility between the model snailB. glabrata,andS. mansoni. Here, we demonstrate association between four, previously characterized humoral immune molecules;BgFREP3,BgTEP1,BgFREP2 and Biomphalysin. We also identify unique immune determinants in the plasma ofS. mansoni-resistantB. glabratathat explain the incompatible phenotype. These factors coordinate to initiate haemocyte-mediated deestruction ofS. mansonisporocysts via production of reactive oxygen species. The inclusion ofBgFREP2 in aBgFREP3-initiated complex that also includesBgTEP1 almost completely explains resistance toS. mansoniin this model. Our study unifies many independent lines of investigation to provide a more comprehensive understanding of the snail immune system in the context of infection by this important human parasite.
Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets
Authors: Curran DM , Grote A , Nursimulu N , Geber A , Voronin D , Jones Drew , Ghedin E , Parkinson J
Published: September 2019

The filarial nematodeBrugia malayirepresents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteriaWolbachia—present in many filariae—which is vital to the worm.

Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but only recently have been applied to eukaryotic organisms. Here, we presentiDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 99 reactions essential to the survival ofB. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.
Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Authors: Garcia-Gomez Antonio , Li Tianlu , Rodríguez-Ubreva Javier , Ciudad Laura , Català-Moll Francesc , Martín-Sánchez Montserrat , San-Segundo Laura , Morales Xabier , Ortiz de Solórzano Carlos , Oyarzabal Julen , San José-Enériz Edurne , Agirre Xabier , Prosper Felipe , Garayoa Mercedes , Ballestar Esteban
Published: September 2019

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on the bone marrow (BM) microenvironment, in particular on mesenchymal stromal cells (MSCs). MSCs from MM patients exhibit an abnormal transcriptional profile, suggesting that epigenetic alterations could be governing the tumor-promoting functions of MSCs and their prolonged osteoblast (OB) suppression in MM. In this study, we analyzed the DNA methylome of BM-derived MSCs from patients with monoclonal gammopathy of undetermined significance, smoldering myeloma and symptomatic MM at diagnosis in comparison with their normal counterparts. DNA methylation alterations were found at each of the myeloma stage in association with deregulated expression levels of Homeobox genes involved in osteogenic differentiation. Moreover, these DNA methylation changes were recapitulatedin vitroby exposing MSCs from healthy individuals to MM plasma cells. Pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, reverted the expression of aberrantly methylated osteogenic regulators and promoted OB differentiation of MSCs from myeloma patients. Most importantly, in a mouse model of bone marrow-disseminated MM, administration of CM-272 prevented tumor-associated bone loss and reduced tumor burden. Our results demonstrated that not only was aberrant DNA methylation a main contributor to bone formation impairment found in MM patients, but also its targeting by CM-272 was able to reverse MM-associated bone loss.

KEY POINTS

- Bone marrow-derived mesenchymal stromal cells (MSCs) from monoclonal gammopathy of undetermined significance, smoldering myeloma and myeloma patients exhibit an aberrant DNA methylome compared to their healthy counterparts.

- These DNA methylation changes are associated with an altered expression of genes of the Homeobox loci that orchestrate osteogenic differentiation of mesenchymal precursors.

- MM plasma cell-exposed healthy MSCs recapitulate the DNA methylation alterations observed in MSCs isolated from myeloma patients.

- Dual targeting of DNMTs and the histone methyltransferase G9a with CM-272 not only controls MM tumor burden but also prevents myeloma-associated bone loss.
Increase in egg resistance to desiccation in springtails correlates with blastodermal cuticle formation: eco-evolutionary implications for insect terrestrialization
Authors: Vargas Helena Carolina Martins , Panfilio Kristen A. , Roelofs Dick , Rezende Gustavo Lazzaro
Published: September 2019

Land colonization was a major event in the history of life. Among animals, insects exerted a staggering terrestrialization success, due to traits usually associated with post-embryonic life stages, while the egg stage has been largely overlooked in comparative studies. In many insects, after blastoderm differentiation, the extraembryonic serosal tissue wraps the embryo and synthesizes the serosal cuticle, an extracellular matrix that lies beneath the eggshell and protects the egg against water loss. In contrast, in non-insect hexapods such as springtails (Collembola) the early blastodermal cells synthesize a blastodermal cuticle. Here, we investigate the relationship between blastodermal cuticle formation and egg resistance to desiccation in the springtailsOrchesella cinctaandFolsomia candida, two species with different oviposition environments and developmental rates. The blastodermal cuticle becomes externally visible inO. cinctaandF. candidaat 22 and 29% of embryogenesis, respectively. To contextualize, we describe the stages of springtail embryogenesis, exemplified byF. candida. Our physiological assays then showed that blastodermal cuticle formation coincides with an increase in egg viability in a dry environment, significantly contributing to hatching success. However, protection differs between species: whileO. cinctaeggs survive at least 2 hours outside a humid environment, the survival period recorded forF. candidaeggs is only 15 minutes, which correlates with this species’ requirement for humid microhabitats. We suggest that the formation of this cuticle protects the eggs, constituting an ancestral trait among hexapods that predated and facilitated the process of terrestrialization that occurred during insect evolution.

Research Highlights

The formation of the blastodermal cuticle produced during early embryogenesis coincides with a higher protection against water loss in springtail (Collembola) eggs.

Orchesella cinctaeggs are more resistant to drought thanFolsomia candidaones.

The formation of a protective egg cuticle would be an ancestral trait among hexapods that facilitated their process of terrestrialization.

Graphical Abstract

Graphical Abstract legend:Eggs when laid uptake water but are also prone to water loss. Late eggs acquire some protection against water loss, but at different levels, depending on the species.
A VPS13D spastic ataxia mutation disrupts the conserved adaptor binding site in yeast Vps13
Authors: Dziurdzik Samantha K. , Bean Björn D. M. , Davey Michael , Conibear Elizabeth
Published: September 2019

Mutations in each of the four human VPS13 (VPS13A-D) proteins are associated with distinct neurological disorders: chorea-acanthocytosis, Cohen syndrome, early-onset Parkinson’s disease and spastic ataxia. Recent evidence suggests that the different VPS13 paralogs transport lipids between organelles at different membrane contact sites. How each VPS13 isoform is targeted to organelles is not known. We have shown that the localization of yeast Vps13 protein to membranes requires a conserved six-repeat region, the Vps13 Adaptor Binding (VAB) domain, which binds to organelle-specific adaptors. Here, we use a systematic mutagenesis strategy to determine the role of each repeat in recognizing each known adaptor. Our results show that mutation of invariant asparagines in repeats 1 and 6 strongly impact the binding all adaptors and block Vps13 membrane recruitment. However, we find that repeats 5 to 6 are sufficient for localization and interaction with adaptors. This supports a model where a single adaptor binding site is found in the last two repeats of the VAB domain, while VAB domain repeat 1 may help maintain domain conformation. Importantly, a disease-causing mutation in VPS13D, which maps to the highly conserved asparagine residue in repeat 6, blocks adaptor binding and Vps13 membrane recruitment when modeled in yeast. Our findings are consistent with a conserved adaptor binding role for the VAB domain and suggests the presence of as-yet-unidentified adaptors in both yeast and humans.
Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma
Authors: Wrzeszczynski Kazimierz O. , Rahman Sadia , Frank Mayu O. , Arora Kanika , Shah Minita , Geiger Heather , Felice Vanessa , Manaa Dina , Dikoglu Esra , Khaira Depinder , Chimpiri A. Rao , Michelini Vanessa V. , Jobanputra Vaidehi , Darnell Robert B. , Powers Scott , Choi Minsig
Published: September 2019

The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4. The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual.
Honor the old, welcome the new: an account of unlearning and forgetting in NPD teams
Authors: Klammer Adrian , Gueldenberg Stefan
Published: September 2019

Purpose

The purpose of this paper is to empirically investigate the antecedents, levers of control and outcomes of organizational unlearning and forgetting in new product development (NPD) teams.

Design/methodology/approach

This paper employs a holistic multiple-case study design. This paper gathered data from 30 individual semi-structured interviews in 10 different NPD teams as well as additional data to triangulate the findings.

Findings

The authors propose a model of unlearning and forgetting elements occurring in NPD teams. The two most prominent factors that hamper innovation are the inability to unlearn and involuntary forgetting. Failure to manage these antecedents results in the loss of crucial resources, missing innovations or intra-team tensions. Managing knowledge loss by promoting unlearning and reducing forgetting leads to enhanced creativity and flexibility, a higher chance of exceeding innovation goals, increased conversion efficiency and augmentation of existing knowledge.

Research limitations/implications

This paper contributes empirical evidence to the field of unlearning and forgetting. The model illustrates the NPD process from the perspective of organizational unlearning and forgetting. The authors examined the NPD process from an unlearning and forgetting perspective and proposed new categories of antecedents, consequences and managing unlearning and forgetting. This generates a more profound theoretical understanding of underlying knowledge loss processes in NPD teams.

Practical implications

Companies should promote unlearning and specify spatial and temporal freedom. In doing so, team members can identify outdated and obsolete knowledge. Being attentive to unlearning and forgetting processes allows teams to achieve increased creativity and flexibility.

Originality/value

This paper provides empirical evidence to generate a more profound understanding of the underlying mechanisms of knowledge loss in NPD teams. First, the authors propose a holistic model of antecedents, levers of control and consequences of both unlearning and forgetting. Second, the authors suggest that organizations can use these levers of control to successfully manage unlearning and forgetting in NPD teams.
Discrimination against gays and lesbians in hiring decisions: a meta-analysis
Authors: Flage Alexandre
Published: September 2019

Purpose

The purpose of this paper is to evaluate the true level of discrimination against openly gay and lesbian applicants in hiring decisions in OECD countries as well as on its determinants.

Design/methodology/approach

The author presents an overview of all studies conducted in order to test for discrimination against homosexual applicants in the labor market by the correspondence testing method. Moreover, the author performs a meta-analysis of correspondence tests from 18 separate studies conducted in OECD countries to test sexual orientation discrimination, containing more than 70 estimates of effects and representing a total of more than 50,000 resumes sent to employers. In addition to presenting overall results, the author focus on subgroups of specific correspondence tests in order to highlight the differences across gender, type of jobs, procedure, continent and type of information provided in applications.

Findings

The author provides evidence that sexual orientation discrimination occurs in the labor market in OECD countries, such that openly homosexual applicants face similar discrimination as ethnic minority applicants. Discrimination is significantly greater in the selection process for low-skilled than for high-skilled jobs. In the selection process for low-skilled jobs, lesbian candidates face significantly lower discrimination than gays (except in jobs that are considered “women’s” jobs). Discrimination is significantly higher in Europe than in North America. Moreover, the way sexual orientation is signaled may influence the level of discrimination found. Finally, discrimination against homosexual applicants is not only a matter of preferences: providing more positive information in applications significantly reduces the level of discrimination.

Originality/value

This paper offers the first quantitative analysis of sexual orientation discrimination in OECD countries through meta-analyses.
Rules versus relationships and campus sexual misconduct
Authors: Pappas Brian
Published: September 2019

Purpose

How do university compliance administrators implement the rules prohibiting campus sexual misconduct? Title IX Coordinators’ authority is legal–rational and derives from the power to enforce Title IX and university rules. The paper aims to discuss this issue.

Design/methodology/approach

Analyzing narratives collected from administrators at 22 large institutions of higher education, this paper distinguishes rules from relationship-oriented Coordinators and develops an understanding of how and why Title IX Coordinators utilize relational authority as they implement Title IX.

Findings

The key finding is that relational administrators exhibit less institutional authority than their rules-based counterparts and focus on their relationships with complainants and respondents over university leaders and administrators.

Originality/value

While other researchers have focused on rules, this research demonstrates how Title IX Coordinators draw heavily on relational strategies.
Earnings management in local governments: the role of political factors
Authors: Cohen Sandra , Bisogno Marco , Malkogianni Ioanna
Published: September 2019

Purpose

The purpose of this paper is to examine earnings management practices in local governments (LGs). The implementation of accrual accounting in LGs opens the way for empirical research on the topic, as reporting high surpluses or high deficits can be negatively interpreted by the central government, monitoring authorities, citizens and political opponents. According to public choice theory, the conflicting interests between politicians, who pursue re-election, and voters, who observe politicians’ actions to assess their alignment with social welfare, create fertile ground for earnings management practices.

Design/methodology/approach

The study calculates discretionary accruals, by using the Jones (1991) model, and relates them to several political variables. It employs a large sample of Greek and Italian LGs. The Greek database covers the period from 2002 to 2015 with about 4,300 observations, and the Italian database includes the period from 2008 to 2015 with about 1,130 observations.

Findings

The findings from the analysis give evidence that LGs engage in earnings management. The principal factor is the electoral cycle, as earnings management seems to be greater when the mayor is re-elected than when the mayor is elected for the first time. Furthermore, the period before elections create conditions that cultivate earnings management attitudes.

Research limitations/implications

Previous studies have principally investigated earnings management in the private sector. Considering that many public-sector entities have implemented accrual accounting systems, this study intends to examine earnings management behaviour at the LG level, providing interesting findings for researchers and policy makers.

Practical implications

A better understanding of the political factors and the financial conditions, which act as obstacles or facilitators, should work hand in hand with the accounting reforms. The usefulness of financial statements for decision making and control presupposes that they are of high quality, an attribute that can be impaired by earnings management.

Originality/value

This study investigates the influence of political factors on earnings management behaviour in public-sector contexts where self-interest and accountability pressures coexist.
Arousing a positive climate for knowledge sharing through moral lens: the mediating roles of knowledge-centered and collaborative culture
Authors: Lei Hui , Do Nguyen Khoi , Le Phong Ba
Published: September 2019

Purpose

The purpose of this paper is to investigate the correlation between ethical leadership (EL), collaborative culture (CC), knowledge-centered culture and employees’ behaviors toward knowledge sharing (KS) in Chinese firms.

Design/methodology/approach

The paper used structural equation modeling to examine the level of how EL, CC and knowledge-centered culture impact on tacit and explicit KS of employees via the data collected from 319 participants in 51 Chinese firms.

Findings

The research findings show collaborative and knowledge-centered culture mediates the relationship between EL and employees’ KS behaviors. It highlights the necessity of practicing EL style to develop a positive climate aimed at positively improving tacit and explicit KS of employees.

Research limitations/implications

Future studies should focus on investigating the relationship between EL, CC and knowledge management process or the other variables to explore and maximize their potential and benefits toward key organizational outcomes.

Practical implications

This paper offers leaders a deeper understanding of the effective pathways to build positive climates for fostering employees’ tacit and explicit KS.

Originality/value

This paper is unique in the attempts to increase the understanding of moral lens by which EL might successfully arouse a positive organizational culture and foster KS behaviors in their firms.
Knowledge transfer and boundary conditions
Authors: Du Juana , Wang Rong
Published: September 2019

Purpose

The purpose of this paper is to examine innovative practices and emphasize the mechanism of knowledge transfer across knowledge boundaries. By comparing and discussing the emerging boundary issues in knowledge transfer among small- and medium-sized enterprises (SMEs) registered in the incubation centers in China, this paper identified the main knowledge transfer approach and several contextual and organizational factors impacting knowledge transfer.

Design/methodology/approach

The authors conduct 39 semi-structured in-depth interviews with employees working within business incubation centers in China. The study uses thematic analysis for data analysis.

Findings

Our results contribute to the literature of knowledge transfer and in particular to our understanding of boundary conditions and knowledge transfer approaches in emerging economies. The results also highlight several contextual and organizational factors which impact knowledge transformation across the pragmatic boundary in the context of China.

Practical implications

First, organizations need to establish an effective process with tools to accommodate novelty; second, organizations should be aware of the impact of entrepreneurial orientation on innovative performance; and third, it will help organizations if they adopt and integrate information-rich media in managing innovative practices.

Originality/value

This research highlights the impact of contextual and organizational factors of SMEs on knowledge transfer in emerging markets and chooses incubation centers as study subjects, which is an organizational context that has not been thoroughly studied due to its unique nature and emerging complexity.
Proposing researcher brand equity index in hospitality and tourism
Authors: Köseoglu Mehmet Ali , Okumus Fevzi , Rahimi Roya
Published: September 2019

Purpose

This study aims to propose a holistic model to rank and evaluate researchers’ performance. This holistic model is developed by focusing on brand equity, which includes three components of perceived quality, brand image and brand loyalty.

Design/methodology/approach

To show how the model works, two pseudo cases are presented.

Findings

This model encourages researchers to conduct more interdisciplinary research and collaborate with researchers from diverse backgrounds. Because the model includes publication attributes identified by researchers in the publication processes, it allows researchers to strengthen their brand equity score or performance.

Practical implications

The model is applicable not only to the fields of hospitality and tourism but also to other disciplines.

Originality/value

As one of the first studies in the field, this research introduces a holistic model to rank and evaluate researchers’ performance.
Culture and tourism: natural partners or reluctant bedfellows? A perspective paper
Authors: Richards Greg
Published: September 2019

Purpose

This paper aims to review the development of the relationship between culture and tourism over the past 75 years and outline some future developments over the coming 75 years.

Design/methodology/approach

This paper is based on a review of previous major work on cultural tourism.

Findings

Tourism and culture have been drawn inexorably closer over the years as culture has become one of the major content providers for tourism experiences, and tourism has become one of the most important income streams for cultural institutions. In the future, this is likely to change, as cultural institutions find it increasingly difficult to maintain their authority as the dominant producers of local, regional and national culture and as tourism becomes increasingly integrated into the everyday culture of the destination.

Practical implications

Cultural institutions will need to change their relationship with tourism as flows of tourists become more prevalent and fragmented.

Social implications

The authority of high cultural institutions will be eroded as tourists increasingly seek authenticity in the culture of everyday life and the ‘local’.

Originality/value

This study reviews the dynamics of the cultural field and sketches the long-term future development of the relationship between tourism and culture.
Business travel: a perspective paper
Authors: Lubbe Berendien
Published: September 2019

Purpose

The purpose of this paper is to provide a brief perspective on the growth of business travel over the past 60 years and how it may unfold in the future, highlighting certain themes and noting limitations in the research.

Design/methodology/approach

This paper is based on selected academic literature and industry sources on business travel which briefly reviews its growth and directions of research in this field.

Practical implications

The paper distinguishes between different types of business travel and provides a bird's eye view of the future.

Originality/value

The review distinguishes between different forms of business travel and concludes that greater clarity of the business travel concept will enable research to be conducted within a properly defined theoretical framework.
Flow-based destination management and marketing: a perspective article
Authors: Reinhold Stephan , Laesser Christian , Beritelli Pietro
Published: September 2019

Purpose

This paper aims to provide a selective review of sectoral and academic developments that have led to the flow-based view of destination management and marketing and inspires future work.

Design/methodology/approach

A review of the relevant literature serves as a foundation for the discussion of the flow-based view of destination management and marketing. From the results of this review, future prospects for practice and research are derived.

Findings

Destination management and marketing has undergone many changes in the past and is subject for some major overhauls in the future.

Originality/value

The paper inspires in terms of rather asking questions for the future than finding answers from the past.
Image of Poland as perceived by German and British medical tourists
Authors: Dryglas Diana , Lubowiecki-Vikuk Adrian
Published: September 2019

Purpose

The purpose of this paper is to identify Poland’s image as a medical tourism destination (MTD).

Design/methodology/approach

Survey data were collected from 282 German and British medical tourists, using a self-administered questionnaire. The Computer-Assisted Web Interviewing method was used to conduct the survey. Subsequently, the responses were analysed using advanced statistical tools (McNemar’s exact test, Cochran’s Q test and Chi-square test).

Findings

Before visiting Poland, the respondents perceived the country through the prism of medical attributes, whereas after the visit, they perceived it through the prism of non-medical attributes.

Research limitations/implications

Identification of a set of MTD image characteristics has important implications for scholars, allowing them to understand attributes which shape projected and perceived MTD image. Such construct can also be a useful tool for marketing planners, destination managers and marketers to create an effective marketing policy and projected image of MTDs based on these features.

Originality/value

The study fills an important gap regarding the lack of conceptual and empirical content allowing for exploration of MTD image.