bluuebunny/crossref_metadata_2025 huggingface dataset:
Transition From Pediatric to Adult Services: Challenges for Family Caregivers of Young Adults With Traumatic Brain Injury
Authors: Shankar Janki , Nicholas David , Mrazik Martin , Waugh Earle , Tan Shawn , Zulla Rossalyn , Urichuk Liana , Paranica Sue
Published: October 2018

Family caregivers are the main source of support for survivors of traumatic brain injury (TBI) while they transition from pediatric to adult care service and support systems. Yet there is little research that examines the needs of these caregivers during the transition phase. The aim of this qualitative phenomenological study was to examine the lived experiences of family caregivers of young adults with TBI who had recently transitioned from services for children and adolescents to adult care service and supports. The study sample comprised 15 family caregivers of young adult TBI survivors who had transitioned to adult services in the last 5 years. They were recruited from two large hospitals and a caregiver support center in a city in Western Canada. Semistructured interviews were conducted with the caregivers and the data were analyzed using Colaizzi’s approach in developing an essential structure of the phenomenon of caregiving. Fifteen themes emerged from the analysis and these are discussed under two broad domains: (a) caregivers’ experiences and challenges with their relative at the time of transition; (b) caregivers’ challenges with services and supports systems during transition. Findings suggest that there is a wide gap between what caregivers need and what is available to them to support their young adult relative through the transition process and beyond. Most caregivers reported that the transition phase is overwhelming and has a profound and pervasive impact on their lives. Implications of the findings and recommendations for policy and practice are discussed.
Occupation Exploration: Using O*NET in the Management Classroom
Authors: Chauhan Rahul S.
Published: October 2018

In this article, I discuss the potential uses of the Department of Labor–sponsored Occupational Information Network (O*NET) in the classroom context. O*NET is a free, publicly available resource that provides an array of occupation-specific information, such as relevant tasks, knowledge, skills, abilities, and salary information. Tools such as the Interest Profiler are also available and are designed to help individuals find an occupation that best fits their preferences and interests. I discuss my use of O*NET to assign a variety of well-received and original assignments to my students, varying at both the undergraduate and graduate levels. I further discuss how O*NET can be used to teach specific topics in a variety of management-related courses, such as recruitment and selection, and conclude with how O*NET is an overall valuable and easy-to-implement resource for instructors in the field of management.
A Systematic Review of Artificial Intelligence and Robots in Value Co-creation: Current Status and Future Research Avenues
Authors: Kaartemo Valtteri , Helkkula Anu
Published: October 2018

As artificial intelligence (AI) and robots are increasingly taking place in practical service solutions, it is necessary to understand technology in value co-creation. We conducted a systematic literature review on the topic to advance theoretical analysis of AI and robots in value co-creation. By systematically reviewing 61 AI and robotics articles, which have been published in top marketing and service research journals, we identified four themes in literature, namely, generic field advancement, supporting service providers, enabling resource integration between service providers and beneficiaries, and supporting beneficiaries’ well-being. With the identification of the first set of literature on AI and robots in value co-creation, we push forward an important sub-field of value co-creation literature. In addition, to advance the field, we suggest building on actor–network theory and science and technology studies to understand the agency of technology in value co-creation. Considering that technology has agency, it opens new interesting research avenues around shopping bots and human-to-non-human frontline interaction that are likely to influence resource integration, customer engagement and value co-creation in the future. We also encourage our colleagues to conduct postphenomenological research to be better geared for analysing how technology (including AI and robots) mediates the individual experience of value.
How I treat the blast phase of Philadelphia chromosome–negative myeloproliferative neoplasms
Authors: Odenike Olatoyosi
Published: October 2018

The classic Philadelphia chromosome (Ph)–negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem-cell diseases, characterized by activated JAK/STAT signaling and significant phenotypic mimicry, including a propensity for evolution to myeloid blast phase disease. Effective therapeutic options are limited for patients with Ph− MPNs in the blast phase (MPN-BP), and allogeneic stem-cell transplantation is the only known cure. Our increasing understanding of the molecular pathogenesis of this group of diseases, coupled with the increasing availability of targeted agents, has the potential to inform new subset-specific therapeutic approaches. Ultimately, progress in MPN-BP will hinge on prospective clinical and translational investigations with the goal of generating more effective treatment interventions. This case-based review highlights the molecular and clinical heterogeneities of MPN-BP and incorporates a treatment algorithm that underscores the importance of a personalized approach to this challenging group of diseases.
Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells
Authors: Humblet-Baron Stéphanie , Barber John S. , Roca Carlos P. , Lenaerts Aurelie , Koni Pandelakis A. , Liston Adrian
Published: October 2018

Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital deficiency in DCs caused by mutations in GATA2 or IRF8. The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here, we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice whose DCs are deficient in antigen presentation, we find spontaneous MPD that is characterized by splenomegaly, neutrophilia, and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II (MHCII) antigen-presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking MHCII and CD4 T cells did not develop disease. Thus, MPD was paradoxically contingent on the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naive Flt3 ligand–expressing state. These results identify a novel requirement for intercellular collaboration between DCs and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.
The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase
Authors: Vogel Sebastian , Arora Taruna , Wang Xunde , Mendelsohn Laurel , Nichols James , Allen Darlene , Shet Arun S. , Combs Christian A. , Quezado Zenaide M. N. , Thein Swee Lay
Published: October 2018

A key inflammatory mechanism recently identified in platelets involves the Nod-like receptor nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK), which control activation of caspase-1 within inflammasome complexes. We investigated platelet caspase-1 activity in the context of sickle cell disease (SCD) directly in platelets isolated from SCD patients (n = 24) and indirectly by incubating platelets from healthy subjects with plasma obtained from SCD patients (n = 20), both in steady state and during an acute pain crisis (paired samples). The platelet NLRP3 inflammasome was upregulated in SCD patients under steady state conditions compared with healthy controls, and it was further upregulated when patients experienced an acute pain crisis. The results were consistent with indirect platelet assays, in which SCD plasma increased caspase-1 activity of platelets from healthy subjects in an NLRP3-dependent fashion. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) was elevated in plasma of SCD subjects compared with healthy controls and correlated with caspase-1 activity in platelets. Pharmacological or antibody-mediated inhibition of HMGB1, Toll-like receptor 4, and BTK interfered with sickle plasma–induced platelet caspase-1 activation. In Townes SCD mice, caspase-1 activity and aggregation of circulating platelets were elevated, which was suppressed by IV injection of an NLRP3 inhibitor and the BTK inhibitor ibrutinib. Activation of the platelet NLRP3 inflammasome in SCD may have diagnostic and therapeutic implications.
Formal and computational modeling of anticipation mechanisms of resilience in the complex sociotechnical air transport system
Authors: Blok Anne-Nynke , Sharpanskykh Alexei , Vert Matthieu
Published: October 2018

With ever-growing numbers of passengers and complexity of the air transport system, it becomes more and more of a challenge to manage the system in an effective, safe, and resilient manner. This is especially evident when disruptions occur. Understanding and improving resilience of the air transport system and its adaptive capacity to disruptions is essential for the system’s uninterrupted successful performance. Using theoretical findings from behavioral sciences, this paper makes the first steps towards formalization of the adaptive capacity of resilience of the air transport system with a particular focus on its ability to anticipate. To this end, an expressive logic-based language called Temporal Trace Language is used. The proposed approach is illustrated by a case study, in which anticipatory mechanisms are implemented in an agent-based airport terminal operations model, to deal with a disruptive scenario of unplanned and challenging passenger demand at the security checkpoint. Results showed that the timing of an adaptive action could have a significant influence on reducing the risk of saturation of the system, where saturation implies performance loss. Additionally, trade-off relations were obtained between cost, corresponding to the extra resources mobilized, and the benefits, such as a decrease in risk of saturation of the passenger queue.
Making up symptoms: psychic indeterminacy and the construction of psychotic phenomena
Authors: Green Huw
Published: October 2018

Psychotic phenomena include a far wider range of experiences than is captured by the brief descriptions offered in contemporary diagnostic guides. Given the richness of historical clinical phenomenology, what can account for the recent ascendancy of relatively impoverished descriptions of psychosis? One possible explanation is provided by Hacking's notion of dynamic nominalism, where human categories change over time in tandem with those who they classify. But although dynamic nominalism makes sense of changes in behaviour, it fails to account for change at the level of subjective experience. In this paper, psychotic symptoms are addressed in the light of the indeterminacy of subjective mental content. A naïve-introspectionist approach to mental symptoms assumes that, notwithstanding practical difficulties, such symptoms are reliably describable in principle. Contemporary philosophy of mind challenges this assumption. Lighting upon a verbal description for ineffable phenomena changes their nature, resolving them into new forms.

Declaration of interest

None.
Single-Cell RNA Sequencing Reveals Novel Markers of Male Pituitary Stem Cells and Hormone-Producing Cell Types
Authors: Cheung Leonard Y M , George Akima S , McGee Stacey R , Daly Alexandre Z , Brinkmeier Michelle L , Ellsworth Buffy S , Camper Sally A
Published: October 2018

Transcription factors and signaling pathways that regulate stem cells and specialized hormone-producing cells in the pituitary gland have been the subject of intense study and have yielded a mechanistic understanding of pituitary organogenesis and disease. However, the regulation of stem cell proliferation and differentiation, the heterogeneity among specialized hormone-producing cells, and the role of nonendocrine cells in the gland remain important, unanswered questions. Recent advances in single-cell RNA sequencing (scRNAseq) technologies provide new avenues to address these questions. We performed scRNAseq on ∼13,663 cells pooled from six whole pituitary glands of 7-week-old C57BL/6 male mice. We identified pituitary endocrine and stem cells in silico, as well as other support cell types such as endothelia, connective tissue, and red and white blood cells. Differential gene expression analyses identify known and novel markers of pituitary endocrine and stem cell populations. We demonstrate the value of scRNAseq by in vivo validation of a novel gonadotrope-enriched marker, Foxp2. We present novel scRNAseq data of in vivo pituitary tissue, including data from agnostic clustering algorithms that suggest the presence of a somatotrope subpopulation enriched in sterol/cholesterol synthesis genes. Additionally, we show that incomplete transcriptome annotation can cause false negatives on some scRNAseq platforms that only generate 3′ transcript end sequences, and we use in vivo data to recover reads of the pituitary transcription factor Prop1. Ultimately, scRNAseq technologies represent a significant opportunity to address long-standing questions regarding the development and function of the different populations of the pituitary gland throughout life.
Secret Signals from Another World
Authors: Charles Matthew
Published: October 2018

Walter Benjamin refers to the “idea of revolution as an innervation of the technical organs of the collective” as one article of his politics. Drawing on some of the debates and tensions generated by the work of Miriam Bratu Hansen, the article analyzes lesser-known intellectual sources that influenced Benjamin’s theory of innervation. Rather than reconcile or integrate these sources with dominant philosophical reconstructions of what is sometimes characterized as Benjamin’s “Western Marxism” and elaborated, in the more familiar context of surrealist innervation, as a synthesis of Sigmund Freud and Karl Marx, the article attempts to reveal an alternative constellation of Soviet biomechanics and reactionary anticapitalist Lebensphilosophie, united in their shared rejection of Freudian psychoanalysis.
Heidegger in Hebrew
Authors: Herskowitz Daniel
Published: October 2018

This article deals with the largely neglected topic of Martin Heidegger’s Jewish reception by examining the translation of The Origin of the Work of Art into Hebrew by Shlomo Zemach in 1968. The various challenges confronting the coming-into-being of this translation are outlined by drawing on previously unknown archival material, including correspondence between Zemach and Vittorio Klostermann (Heidegger’s German publisher), as well as between Zemach and Heidegger himself. With a look at Heidegger’s reception in post-Holocaust Israel as reflected in the debates over his work provoked by Zemach’s translation, the article examines the question of the implied ties between translation and reconciliation and the particular political, moral, and religious challenges raised by putting Heidegger’s philosophy into Hebrew, the holy language.
Anticapitalist Affect
Authors: Norberg Jakob
Published: October 2018

In his writings on satire, the Marxist literary critic Georg Lukács argued that hatred could function as an anticapitalist affect. Hatred, he believed, equips the committed author with a set of traits—certainty, lucidity, endurance, and pitilessness—that are eminently useful for exposing and destroying a fundamentally criminal socioeconomic system. Contrary to the contemporary anxiety about hatred (hate speech, hate crimes), Lukács wanted to mobilize the affect for revolutionary ends. Yet he also admitted that hatred tends to grow in conditions of powerlessness, dependence, and frustration. As a consequence, Lukács could not unite the cool passion of hatred with the position of a confident revolutionary.
Spectator and Society
Authors: Westerman Richard
Published: October 2018

Interpretations of Georg Lukács’s theory of reification and consciousness have typically assumed that Lukács relies on an essentialized notion of subjectivity that can be restored by dereification. This article argues instead that he treats subjectivity as a formally defined position within the totality of consciousness, an account of consciousness that closely parallels Alois Riegl’s theory of the spectator as a formally defined component of works of art. Both Lukács and Riegl incorporate notions of agency and active involvement in the forms of representation into these accounts of subjectivity: what Riegl finds in the Kunstwollen of different works of art, Lukács finds in the formal structures of social reality. The article thus reinterprets reification as the formal definition of the subject as an isolated individual playing no active part in the structure of social forms. Finally, the article draws on Riegl’s idea that Dutch group portraits incorporate spectators as active constitutors of artistic form to offer some suggestions about Lukács’s theory of the revolutionary party.
Distinct cis-acting elements mediate targeting and clustering of Drosophila polar granule mRNAs
Authors: Eagle Whitby V. I. , Yeboah-Kordieh Daniel K. , Niepielko Matthew G. , Gavis Elizabeth R.
Published: October 2018

Specification and development of Drosophila germ cells depend on molecular determinants within the germ plasm, a specialized cytoplasmic domain at the posterior of the embryo. Localization of numerous mRNAs to the germ plasm occurs by their incorporation, as single-transcript ribonucleoprotein (RNP) particles, into complex RNP granules called polar granules. Incorporation of mRNAs into polar granules is followed by recruitment of additional like-transcripts to form discrete homotypic clusters. The cis-acting localization signals that target mRNAs to polar granules and promote homotypic clustering remain largely uncharacterized. Here, we show that the polar granule component (pgc) and germ cell-less (gcl) 3' untranslated regions contain complex localization signals comprising multiple, independently weak and partially functionally redundant localization elements (LEs). We demonstrate that targeting of pgc to polar granules and self-assembly into homotypic clusters are functionally separable processes mediated by distinct classes of LEs. We identify a sequence motif shared by other polar granule mRNAs that contributes to homotypic clustering. Our results suggest that mRNA localization signal complexity may be a feature required by the targeting and self-recruitment mechanism that drives germ plasm mRNA localization.
Hedgehog signaling regulates cell motility and optic fissure and stalk formation during vertebrate eye morphogenesis
Authors: Gordon Hannah B. , Lusk Sarah , Carney Keith R. , Wirick Emily O. , Murray Brooke Froelich , Kwan Kristen M.
Published: October 2018

Establishment of precise 3-dimensional tissue structure is vital for organ function. In the visual system, optic fissure and stalk morphogenesis is a critical, yet poorly understood process, disruptions of which can lead to coloboma, a birth defect causing visual impairment. Here, we use 4-dimensional imaging, cell tracking, and molecular genetics in zebrafish to define cell movements underlying normal optic fissure and stalk formation. We determine how these events are disrupted in a coloboma model in which the Hedgehog receptor ptch2 is lost, resulting in overactive Hh signaling. In the ptch2 mutant, cells exhibit defective motile behaviors and morphology. Cells that should contribute to the fissure do not arrive at their correct position, and instead contribute to an ectopically large optic stalk. Our results suggest that overactive Hh signaling, through overexpression of downstream transcriptional targets, impairs cell motility underlying optic fissure and stalk formation, via non-cell autonomous and cell-autonomous mechanisms. More broadly, our cell motility and morphology analyses provide a new framework to study other coloboma-causing mutations disrupting optic fissure or stalk formation.
Neuromesodermal progenitors are a conserved source of spinal cord with divergent growth dynamics
Authors: Attardi Andrea , Fulton Timothy , Florescu Maria , Shah Gopi , Muresan Leila , Lenz Martin O. , Lancaster Courtney , Huisken Jan , van Oudenaarden Alexander , Steventon Benjamin
Published: October 2018

During gastrulation, embryonic cells become specified into distinct germ layers. In mouse, this continues throughout somitogenesis from a population of bipotent stem cells called neuromesodermal progenitors (NMps). However, the degree of self-renewal associated with NMps in the fast-developing zebrafish embryo is unclear. With a genetic clone tracing method, we labelled early embryonic progenitors and find a strong clonal similarity between spinal cord and mesoderm tissues. We followed individual cell lineages by light-sheet imaging, revealing a common neuromesodermal lineage contribution to a subset of spinal cord tissue across the anterior-posterior body axis. An initial population subdivides at mid gastrula stages and is directly allocated to neural and mesodermal compartments during gastrulation. A second population in the tailbud undergoes delayed allocation to contribute to the neural and mesodermal compartment only at late somitogenesis. Cell tracking and retrospective cell fate assignment at late somitogenesis stages reveal these cells to be a collection of mono-fated progenitors. Our results suggest that NMps are a conserved population of bipotential progenitors, whose lineage varies in a species-specific manner due to vastly different rates of differentiation and growth.
Basal epithelial tissue folding is mediated by differential regulation of microtubules
Authors: Visetsouk Mike R. , Falat Elizabeth J. , Garde Ryan J. , Wendlick Jennifer L. , Gutzman Jennifer H.
Published: October 2018

The folding of epithelial tissues is critical for development of three-dimensional structure and function. Understanding this process can assist in determining etiology of developmental disease and engineering of tissues for the future of regenerative medicine. Folding of epithelial tissues towards the apical surface has long been studied, while the molecular mechanisms that mediate epithelial folding towards the basal surface are just emerging. Here we utilize the zebrafish neuroepithelium to identify mechanisms that mediate basal tissue folding to form the highly conserved embryonic midbrain-hindbrain boundary. Live imaging revealed Wnt5b as a mediator of anisotropic epithelial cell shape, both apically and basally. In addition, we uncovered a Wnt5b mediated mechanism for specific regulation of basal anisotropic cell shape that is microtubule-dependent and likely to involve JNK signaling. We propose a model by which a single morphogen can differentially regulate apical versus basal cell shape during tissue morphogenesis.
Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis
Authors: Hernández Diego E. , Salvadores Natalia A. , Moya-Alvarado Guillermo , Catalán Romina J. , Bronfman Francisca C. , Court Felipe A.
Published: October 2018

Neuronal excitotoxicity induced by glutamate leads to cell death and functional impairment in a variety of central nervous system pathologies. Glutamate-mediated excitotoxicity triggers neuronal apoptosis in the cell soma as well as degeneration of axons and dendrites by a process associated with Ca2+ increase and mitochondrial dysfunction. Importantly, degeneration of axons initiated by diverse stimuli, including excitotoxicity, has been proposed as an important pathological event leading to functional impairment in neurodegenerative conditions. Here, we demonstrate that excitotoxicity-induced axonal degeneration proceeds by a mechanism dependent on the necroptotic kinases RIPK1 and RIPK3, and the necroptotic mediator MLKL. Inhibition of RIPK1, RIPK3 or MLKL prevents key steps in the axonal degeneration cascade, including mitochondrial depolarization, the opening of the permeability transition pore and Ca2+ dysregulation in the axon. Interestingly, the same excitotoxic stimuli lead to apoptosis in the cell soma, demonstrating the co-activation of two independent degenerative mechanisms in different compartments of the same cell. The identification of necroptosis as a key mechanism of axonal degeneration after excitotoxicity is an important initial step in the development of novel therapeutic strategies for nervous system disorders.
The topology of the lymphotoxin β receptor that accumulates upon endolysosomal dysfunction dictates the NF-κB signaling outcome
Authors: Banach-Orłowska Magdalena , Jastrzębski Kamil , Cendrowski Jarosław , Maksymowicz Małgorzata , Wojciechowska Karolina , Korostyński Michał , Moreau Dimitri , Gruenberg Jean , Miaczynska Marta
Published: October 2018

Cytokine receptors, such as tumor necrosis factor receptor I (TNFRI, also known as TNFRSF1A) and lymphotoxin β receptor (LTβR), activate inflammatory nuclear factor (NF)-κB signaling upon stimulation. We have previously demonstrated that depletion of ESCRT components leads to endosomal accumulation of TNFRI and LTβR, and their ligand-independent signaling to NF-κB. Here, we studied whether other perturbations of the endolysosomal system could trigger intracellular accumulation and signaling of ligand-free LTβR. While depletion of the CORVET components had no effect, knockdown of Rab7a or HOPS components, or pharmacological inhibition of lysosomal degradation, caused endosomal accumulation of LTβR and increased its interaction with the TRAF2 and TRAF3 signaling adaptors. However, the NF-κB pathway was not activated under these conditions. We found that knockdown of Rab7a or HOPS components led to sequestration of LTβR in intraluminal vesicles of endosomes, thus precluding NF-κB signaling. This was in contrast to the LTβR localization on the outer endosomal membrane that was seen after ESCRT depletion and was permissive for signaling. We propose that the inflammatory response induced by intracellular accumulation of endocytosed cytokine receptors critically depends on the precise receptor topology within endosomal compartments.
Nuclear entry and export of FIH are mediated by HIF1α and exportin1, respectively
Authors: Wang Yihua , Zhong Shan , Schofield Christopher J. , Ratcliffe Peter J. , Lu Xin
Published: October 2018

Hypoxia plays a crucial role at cellular and physiological levels in all animals. The responses to chronic hypoxia are, at least substantially, orchestrated by activation of the hypoxia inducible transcription factors (HIFs), whose stability and subsequent transcriptional activation are regulated by HIF hydroxylases. Factor inhibiting HIF (FIH), initially isolated as a HIFα interacting protein following a yeast two-hybrid screen, is an asparaginyl hydroxylase that negatively regulates transcriptional activation by HIF. This study aimed to define the mechanisms that govern transitions of FIH between the nucleus and cytoplasm. We report that FIH accumulates in the nucleus within a short time window during hypoxia treatment. We provide evidence, based on the application of genetic interventions and small molecule inhibition of the HIF hydroxylases, that the nuclear localization of FIH is governed by two opposing processes: nuclear entry by ‘coupling’ with HIF1α for importin β1-mediated nuclear import and active export via a Leptomycin B-sensitive exportin1-dependent pathway.

This article has an associated First Person interview with the first author of the paper.
Hepatocyte-like cells reveal novel role of SERPINA1 in transthyretin amyloidosis
Authors: Niemietz Christoph , Fleischhauer Lutz , Sandfort Vanessa , Guttmann Sarah , Zibert Andree , Schmidt Hartmut H.-J.
Published: October 2018

Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTR) results from aggregation and extracellular disposition of misfolded TTR mutants. Growing evidence suggests the importance of hepatic chaperones for the modulation of pathogenesis. We took advantage of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from ATTR patients (ATTR-HLCs) to compare chaperone gene expression to that in HLCs from healthy individuals (H-HLCs). From the set of genes analyzed, chaperones that are predominantly located extracellularly were differently expressed. Expression of the chaperones showed a high correlation with TTR in both ATTR-HLCs and H-HLCs. In contrast, after TTR knockdown, the correlation was mainly affected in ATTR-HLCs suggesting that differences in TTR expression triggers aberrant chaperone expression. Serpin family A member 1 (SERPINA1) was the only extracellular chaperone that was markedly upregulated after TTR knockdown in ATTR-HLCs. Co-immunoprecipitation revealed that SERPINA1 physically interacts with TTR. In vitro assays indicated that SERPINA1 can interfere with TTR aggregation. Taken together, our results suggest that extracellular chaperones play a crucial role in ATTR pathogenesis, in particular SERPINA1, which may affect amyloid formation.
Dorsal ruffles enhance activation of Akt by growth factors
Authors: Yoshida Sei , Pacitto Regina , Sesi Catherine , Kotula Leszek , Swanson Joel A.
Published: October 2018

In fibroblasts, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) stimulate the formation of actin-rich, circular dorsal ruffles (CDRs) and phosphatidylinositol 3-kinase (PI3K)-dependent phosphorylation of Akt. To test the hypothesis that CDRs increase synthesis of phosphorylated Akt1 (pAkt), we analyzed the contributions of CDRs to Akt phosphorylation in response to PDGF and EGF. CDRs appeared within several minutes of growth factor addition, coincident with a peak of pAkt. Microtubule depolymerization with nocodazole blocked CDR formation and inhibited phosphorylation of Akt in response to EGF but not PDGF. Quantitative immunofluorescence showed increased concentrations of Akt, pAkt and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the phosphoinositide product of PI3K that activates Akt, concentrated in CDRs and ruffles. EGF stimulated lower maximal levels of pAkt than did PDGF, which suggests that Akt phosphorylation requires amplification in CDRs only when PI3K activities are low. Accordingly, stimulation with low concentrations of PDGF elicited lower levels of Akt phosphorylation, which, like responses to EGF, were inhibited by nocodazole. These results indicate that when receptor signaling generates low levels of PI3K activity, CDRs facilitate local amplification of PI3K and phosphorylation of Akt.

This article has an associated First Person interview with the first author of the paper.
GCN5L1 interacts with αTAT1 and RanBP2 to regulate hepatic α-tubulin acetylation and lysosome trafficking
Authors: Wu Kaiyuan , Wang Lingdi , Chen Yong , Pirooznia Mehdi , Singh Komudi , Wälde Sarah , Kehlenbach Ralph H. , Scott Iain , Gucek Marjan , Sack Michael N.
Published: October 2018

Although GCN5L1 (also known as BLOC1S1) facilitates mitochondrial protein acetylation and controls endosomal-lysosomal trafficking, the mechanisms underpinning these disparate effects are unclear. As microtubule acetylation modulates endosome-lysosome trafficking, we reasoned that exploring the role of GCN5L1 in this biology may enhance our understanding of GCN5L1-mediated protein acetylation. We show that α-tubulin acetylation is reduced in GCN5L1-knockout hepatocytes and restored by GCN5L1 reconstitution. Furthermore, GCN5L1 binds to the α-tubulin acetyltransferase αTAT1, and GCN5L1-mediated α-tubulin acetylation is dependent on αTAT1. Given that cytosolic GCN5L1 has been identified as a component of numerous multiprotein complexes, we explored whether novel interacting partners contribute to this regulation. We identify RanBP2 as a novel interacting partner of GCN5L1 and αTAT1. Genetic silencing of RanBP2 phenocopies GCN5L1 depletion by reducing α-tubulin acetylation, and we find that RanBP2 possesses a tubulin-binding domain, which recruits GCN5L1 to α-tubulin. Finally, we find that genetic depletion of GCN5L1 promotes perinuclear lysosome accumulation and histone deacetylase inhibition partially restores lysosomal positioning. We conclude that the interactions of GCN5L1, RanBP2 and αTAT1 function in concert to control α-tubulin acetylation and may contribute towards the regulation of cellular lysosome positioning.

This article has an associated First Person interview with the first author of the paper.
Constitutive P2Y2 receptor activity regulates basal lipolysis in human adipocytes
Authors: Ali Seema B. , Turner Jeremy J. O. , Fountain Samuel J.
Published: October 2018

White adipocytes are key regulators of metabolic homeostasis, which release stored energy as free fatty acids via lipolysis. Adipocytes possess both basal and stimulated lipolytic capacity, but limited information exists regarding the molecular mechanisms that regulate basal lipolysis. Here, we describe a mechanism whereby autocrine purinergic signalling and constitutive P2Y2 receptor activation suppresses basal lipolysis in primary human in vitro-differentiated adipocytes. We found that human adipocytes possess cytoplasmic Ca2+ tone due to ATP secretion and constitutive P2Y2 receptor activation. Pharmacological antagonism or knockdown of P2Y2 receptors increases intracellular cAMP levels and enhances basal lipolysis. P2Y2 receptor antagonism works synergistically with phosphodiesterase inhibitors in elevating basal lipolysis, but is dependent upon adenylate cyclase activity. Mechanistically, we suggest that the increased Ca2+ tone exerts an anti-lipolytic effect by suppression of Ca2+-sensitive adenylate cyclase isoforms. We also observed that acute enhancement of basal lipolysis following P2Y2 receptor antagonism alters the profile of secreted adipokines leading to longer-term adaptive decreases in basal lipolysis. Our findings demonstrate that basal lipolysis and adipokine secretion are controlled by autocrine purinergic signalling in human adipocytes.
Establishing an international laboratory network for neglected tropical diseases: Understanding existing capacity in five WHO regions
Authors: Dean Laura , Njelesani Janet , Mulamba Charles , Dacombe Russell , Mbabazi Pamela S. , Bates Imelda
Published: October 2018

Background. Limited laboratory capacity is a significant bottleneck in meeting global targets for the control and elimination of neglected tropical diseases (NTD). Laboratories are essential for providing clinical data and monitoring data about the status and changes in NTD prevalence, and for detecting early drug resistance. Currently NTD laboratory networks are informal and specialist laboratory expertise is not well publicised, making it difficult to share global expertise and provide training, supervision, and quality assurance for NTD diagnosis and research. This study aimed to identify laboratories within five World Health Organisation regions (South-East Asia, Eastern Mediterranean, Americas, Western Pacific and Europe) that provide NTD services and could be regarded as national or regional reference laboratories, and to conduct a survey to document their networks and capacity to support NTD programmes.

Methods. Potential NTD reference laboratories were identified through systematic searches, snowball sampling and key informants.

Results. Thirty-two laboratories responded to the survey. The laboratories covered 25 different NTDs and their main regional and national roles were to provide technical support and training, research, test validation and standard setting. Two thirds of the laboratories were based in academic institutions and almost half had less than 11 staff. Although greater than 90 per cent of the laboratories had adequate technical skills to function as an NTD reference laboratory, almost all laboratories lacked systems for external verification that their results met international standards.

Conclusions. This study highlights that although  many laboratories believed they could act as a reference laboratory, only a few had all the characteristics required to fulfil this role as they fell short in the standard and quality assurance of laboratory processes. Networks of high quality laboratories are essential for the control and elimination of disease and this study presents a critical first step in the development of such networks for NTDs.
The epithelialisation phase in wound healing: options to enhance wound closure
Authors: Tomic-Canic Majana , Wong Lulu L. , Smola Hans
Published: October 2018

This review highlights epithelialisation and therapeutic options to optimise and speed the epithelialisation process. To influence this process therapeutically, it is important for clinicians to understand the underlying principles of epithelialisation. The role of growth factors and the hostile local wound environment can explain why epithelial wound closure is so difficult to speed up in some chronic wounds. Clinicians should be aware of the different surgical techniques of skin grafting and more advanced technologies, such as skin substitutes, as options for wounds which fail to respond to standard protocols. Finally, novel dressing-based concepts are discussed, including macromolecular crowding, a concept which aims at boosting growth factor activities produced in the wound space once wound healing is normalised and underway.
An in vitro assessment of bacterial transfer by products used in debridement
Authors: Rippon Mark G. , Rogers Alan A. , Sellars Laura , Purcell Liam E. J. , Westgate Samantha
Published: October 2018

Objective:

The aim of this in vitro study was to investigate the transfer of viable Pseudomonas aeruginosa biofilm microorganisms following treatment with debridement tools.

Method:

The level of viable biofilm microorganisms transferred by debridement tools was compared following treatment that reflected the clinical practice of each product.

Results:

A significant level of microorganism transfer was seen in response to the mechanical debridement tool. Minimal transfer of microorganisms was seen when in vitro-established biofilms were treated with hydroresponsive wound dressing + polyhexamethylene biguanide (HRWD+PHMB, HydroClean plus). Less Pseudomonas aeruginosa was recovered from explants exposed to dressings compared with those exposed to debridement tools suggesting that there was less transfer of bacteria by dressings.

Conclusion:

The reduced transfer of viable microorganisms by HRWD+PHMB may be the result of significant binding and retention of microbes by the superabsorbent polymer within the dressing, together with enhanced sequestered bacterial killing within the dressing by polymer-bound PHMB. The high levels of microbial transfer/transmission seen for debridement tools suggests that, in the clinical setting, a significant level of bacterial spread over the wound surface and/or surrounding skin by these cleansing tools is likely.
Pharmacology and prescribing in hypertension
Authors: Robertson Deborah
Published: October 2018

In this article in the series of ‘bite sized’ pharmacology, we will look at the pharmacological actions of drugs used in the management of hypertension. This article will outline the issues and areas of intervention required in hypertension with reference to current guidelines and formulary. It will illustrate the common therapeutic interventions in patients with stage 1, stage 2 and severe hypertension taking into account a step-wise approach incorporating individual variations affecting drug choice. The article will also examine the main types of drug used and their pharmacodynamic actions. Exercises will be provided to help you apply this knowledge to your prescribing practice
Following own ideas and leading learning
Authors: Barber Jenny
Published: October 2018

It's always worth re-assessing what makes free-flow particularly effective and strong. Here Jenny Barber emphasises the importance of practitioners who are sensitive enablers, embracing free-flow for themselves.
How to use this pull-out section
Authors: White Hilary
Published: October 2018

Tuff Trays are a fantastic resource for giving children hands-on experience of key mathematical concepts such as capacity, weight and measure. Try my ideas for pouring coloured water from one container to another to decide which contains more. You can support children to mix colours and focus on the mathematical process of adding two or more things together to make something different (see page 11).
Tuff problems
Authors: White Hilary
Published: October 2018

Capacity, distance and measure are key mathematical concepts which are accessible to the youngest learners. Hilary White suggests ways to set up Tuff Trays as an ideal resource for hands-on exploration.
Flights of fancy
Authors: Hart Karen
Published: October 2018

Karen Hart suggests ways to turn old carboard boxes, paper and card into simple models and artworks which will encourage children to understand ideas to do with flight and aerodynamics.
Outdoor thrills
Authors: Rawstrone Annette
Published: October 2018

It's important that parents understand the benefits of outdoor play. As well as fuelling physical development, independence and confidence, it also has a positive influence on children's mental health.
Full of beans
Authors: Clarke Jenni
Published: October 2018

Beanbags are easy for young children to hold, catch and throw. Jenni Clarke suggest some new ideas for using this timeless resource to support both physical development, collaborative play and language skills.
Short Communication: Javan Leopard Cat (Prionailurus bengalensis javanensis Desmarest, 1816) in the Cisokan non-conservation forest areas, Cianjur, West Java, Indonesia
Authors: SHANIDA SYA SYA , PARTASASMITA RUHYAT , HUSODO TEGUH , PARIKESIT PARIKESIT , MEGANTARA ERRI NOVIAR
Published: October 2018

Shanidah SS, Partasasmita R, Hudoso T. Parikesit, Meganatara EN. 2018. Short Communication: Javan Leopard Cat (Prionailurus bengalensis javanensis Desmarest, 1816) in the Cisokan non-conservation forest areas, Cianjur, West Java, Indonesia. Biodiversitas 19: 37-41. Javan Leopard Cat (Prionailurus bengalensis javanensis Desmarest, 1816) in the Cisokan non-conservation forest areas, Cianjur, West Java, Indonesia. Biodiversitas 19: xx, xxx.There is no accurate data about the number of leopard individuals in Java Island in both conservation and non-conservation areas. Besides, human continue to deforestation for the necessities of life, such as agriculture, plantation, etc. Therefore, it is important to research about the existence of leopard cat in Cisokan of Cianjur Regency. The aim of this research is to investigate evidence of the leopard cat’s existence, encounter rate of leopard cat and estimation of leopard cat individual in the non-conservation forest areas, Cisokan, Cianjur. Indirect observation sign survey and direct observation with camera trap were carried out to find evidence of the existence of leopard cat (feces and footprint). The results of the study showed that the evidence of leopard cat’s existence are 6 footprints, 27 feces, and 1 individual which was able to observe. The encounter with camera traps was 29.16 independent detections /100 camera days, resulting in 7-12 estimated individuals.
The ethnobotanical study of edible and medicinal plants in the home garden of Batak Karo sub-ethnic in North Sumatra, Indonesia
Authors: SILALAHI MARINA , NISYAWATI NISYAWATI
Published: October 2018

Silalahi M, Nisyawati. 2018. The ethnobotanical study of edible and medicinal plants in the home garden of Batak Karo sub-ethnic in North Sumatra, Indonesia. Biodiversitas 19: 229-238. The cultivation of plants in home gardens for self-sufficiency is a long tradition in Karo District, but the documentation of local knowledge about edible and medicinal plants in home gardens in Karo District is limited. This study aimed to (i) document the uses of the edible and medicinal plants in home gardens; (ii) to analyze the diversity of edible and medicinal plants in home gardens. Data were collected using the ethnobotanical surveys and interviews methods. The Shannon Weiner and Margalef indices were calculated to determine the diversity levels of medicinal and edible species in the home gardens of Karo ethnic. The surveys were conducted in 30 home gardens (7 villages), Karo District, North Sumatra. The 85 recorded species belonged to 43 families, and 73 genera were used as edible and medicinal plants. The plants studied in the home gardens used for human consumption were i.e. fruits, vegetables, spices, tubers and medicinal plants. Among 85 plant species growing in home gardens, 52 species were cultivated, and the rest were semi cultivated. Home gardens had the Shannon Wiener index ranging from 1.164 to 3.123 while Margalef index ranging from 0.929-2.531.
Short Communication: Identification and evaluation of bioactivity in forest plants used for medicinal purposes by the Kutai community of East Kalimantan, Indonesia
Authors: ZARTA ABDUL RASYID , SUWINARTI WIWIN , ARIYANI FARIDA , KUSUMA IRAWAN WIJAYA , ARUNG ENOS TANGKE
Published: October 2018

Zarta AR, Ariyani F, Suwinarti W, Kusuma IW, Arung ET. 2018. Short Communication: Identification and evaluation of bioactivity in forest plants used for medicinal purposes by the Kutai community of East Kalimantan, Indonesia. Biodiversitas 19: 253-259. The Indonesian forest is one of the most species-rich ecosystems in the world. Within such forests are plant species with secondary metabolites that have novel molecular structure and diverse biological activity with excellent potential to be used medicinally in prevention and cure of various diseases afflicting humans. Plant materials often contain various forms of antioxidants. Phenolic compounds found in plants have many biological effects. Flavonoids and other phenolics play a protective role against metabolic damage caused by disease and environmental stressors. The communities of Kutai Kartanegara in East Kalimantan Indonesia are representative of many traditional peoples who have evolved ways of treating human ailment and disease by use of specific plants sourced from their forests. The purpose of the research described in this paper was to identify significant medicinal plant species used by the Kutai ethnic community and to prepare extracts from these plants, mainly from the leaves, and to evaluate the extracts for bioactivity; namely by general identification of secondary metabolites, and by estimation of their antioxidant activity, toxicity, and anti-bacterial activity. Samples of ten plant species, used medicinally by the Kutai community, were extracted using ethanol solvent. Assay of antioxidant activity was carried out by the spectrophotometric method using DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as the control. The degree of toxicity of the extracts was determined by the BSLT (Brine Shrimp Lethality Test) while anti-bacterial activity was evaluated using an in vitro assay of growth inhibition of cultures of the bacterium Escherichia coli. The result showed that nine of the plant species had strong antioxidant activity (IC50); extracts of two of the species were very toxic, while one other was toxic; and at least eight of the species had extracts that exhibited anti-bacterial activity. The phytochemical compounds identified in several of the ten species included flavonoids, tannins, saponins, steroids, triterpenoids, and alkaloids.