bluuebunny/crossref_metadata_2025 huggingface dataset:
SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer
Authors: Monteleone Emanuele , Orecchia Valeria , Corrieri Paola , Schiavone Davide , Avalle Lidia , Moiso Enrico , Savino Aurora , Molineris Ivan , Provero Paolo , Poli Valeria
Published: August 2018

Breast cancer is a complex disease in which heterogeneity makes clinical management very challenging. Although breast cancer subtypes classified according to specific molecular features are associated to better or worse prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical WNT and the STAT3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase RhoU gene transcription. Here we show that RhoU transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of JNK and the recruitment of the SP1 transcription factor to the RhoU promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. RhoU down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors lead to impaired cell migration in basal-like MDA-MB-231 cells, which display constitutive activation of both the non-canonical WNT and STAT3 pathways. These data suggest that STAT3 and SP1 can cooperate to induce high RhoU expression and enhance migration of breast cancer cells.In vivobinding of both factors characterizes a group of SP1/STAT3 responsive genes belonging to the non-canonical WNT and the IL-6/STAT3 pathways. High expression of this signature is significantly correlated with poor prognosis across all profiled patients. Thus, concomitant binding of both STAT3 and SP1 defines a subclass of genes contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators.

Novelty and Impact

The WNT and STAT3 pathways are often activated in breast tumors, but whether they can cooperate towards aggressiveness is not presently known. Here the authors show that WNT ligands can elicit the activation of the transcription factor SP1, which cooperates with STAT3 to induce a subset of non-canonical WNT and IL-6/STAT3 genes. Expression of this gene signature correlates with bad prognosis in breast cancer, suggesting coordinated interference with both TFs as a novel therapeutic option.
Genome-wide chromatin accessibility and transcriptome profiling show minimal epigenome changes and coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice
Authors: Orchard Peter , White James S. , Thomas Peedikayil E. , Mychalowych Anna , Kiseleva Anya , Hensley John , Allen Benjamin , Parker Stephen C. J. , Keegan Catherine E.
Published: August 2018

Danforth’s short tail(Sd)mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10,000 live births.Sdanimals exhibit aberrant axial skeleton, urogenital, and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. Previous studies have shown that theSdmutation results from an endogenous retroviral (ERV) insertion upstream of thePtf1agene resulting in its ectopic expression at E9.5. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue, which revealed minimal changes in chromatin accessibility inSd/Sdmutant embryos. Interestingly, chromatin changes were localized to a small interval adjacent to theSdERV insertion overlapping a knownPtf1aenhancer region, which is conserved in mice and humans. Furthermore, mRNA-seq experiments revealed increased transcription of PTF1A target genes and, importantly, downregulation of hedgehog pathway genes. Reduced sonic hedgehog (SHH) signaling was confirmed by in situ hybridization and immunofluorescence suggesting that theSdphenotype results, in part, from downregulated SHH signaling. Taken together, these data demonstrate substantial transcriptome changes in theSdmouse, and indicate that the effect of the ERV insertion onPtf1aexpression may be mediated by increased chromatin accessibility at a conservedPtf1aenhancer. We propose that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways.
Early and Late Effects of Maternal Experience on Hippocampal Neurogenesis, Microglia, and the Circulating Cytokine Milieu
Authors: Eid Rand S , Chaiton Jessica A , Lieblich Stephanie E , Bodnar Tamara S , Weinberg Joanne , Galea Liisa AM
Published: August 2018

The maternal brain displays considerable plasticity, and motherhood is associated with changes in affective and cognitive function. Motherhood can alter the trajectory of brain ageing, including modifications to neuroplasticity and cognition. Here, we investigated the short- and long-term effects of motherhood on hippocampal neurogenesis, microglial density and morphology, and circulating cytokines, domains known to be altered with age and implicated in cognition and mood. Female rats were bred then euthanized during gestation or at various postpartum timepoints, culminating in middle age, and nulliparous rats served as age-matched controls. Hippocampal neurogenesis was significantly suppressed during gestation and the postpartum period. Interestingly, neurogenesis declined significantly in middle-aged nulliparous rats, but increased in primiparous rats across the same period. Transient postpartum adaptations to the neuroimmune environment of the hippocampus were evidenced, as Iba-1-immunoreactive microglia assumed a de-ramified morphology followed by increased density. Intriguingly, ageing-related changes in circulating cytokines were dependent on parity. These adaptations in neurogenic and immune processes may have ramifications for maternal mood and cognition across the peripartum period and beyond.
Molecular bases for the constitutive photomorphogenic phenotypes in Arabidopsis
Authors: Pham Vinh Ngoc , Xu Xiaosa , Huq Enamul
Published: August 2018

Summary statement

Strikingly similar morphological and gene expression phenotypes among cop1, spaQ and pifQ mutants suggest that the cop phenotype of the cop1 and spaQ mutants might be due in part to a reduced level of PIFs

The transition from skotomorphogenesis to photomorphogenesis is regulated in part by COP1/SPA complex and PIFs in Arabidopsis. The constitutive photomorphogenic (cop) phenotypes of the cop1 and spaQ mutants were shown to be due to a high abundance of the positively acting transcription factors. Here we show that the four major PIF proteins are unstable in cop1 mutant, and an overexpression of P1F1, P1F3, P1F4 and P1F5 suppresses the cop1 phenotypes in the dark. A comparison of the transcriptome data among cop1, spaQ and pifQ reveals remarkably overlapping gene expression profiles with a preferential regulation of the PIF direct target genes. Additionally, HFR1 strongly inhibits the in vivo binding and transcriptional activation activity of PIF1 in the dark. Taken together, these data suggest that the cop phenotypes of the cop1 and spaQ mutants might be due to a combination of the reduced level of PIFs, increased level of the positive factors (e.g., HY5/HFR1 and others), and the HFR1-mediated inhibition of PIF targeted gene expression in the dark.
Cholinergic Midbrain Afferents Modulate Striatal Circuits and Shape Encoding of Action Control
Authors: Dautan Daniel , Huerta-Ocampo Icnelia , Valencia Miguel , Kondabolu Krishnakanth , Gerdjikov Todor V. , Mena-Segovia Juan
Published: August 2018

Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses that, in turn, mediate inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs action shifting and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.
Magnaporthe oryzae SMO1encodes a Ras GTPase-activating protein required for spore morphology, appressorium function and rice blast disease
Authors: Kershaw Michael J. , Basiewicz Magdalena , Soanes Darren M. , Yan Xia , Ryder Lauren S. , Csukai Michael , Valent Barbara , Talbot Nicholas J.
Published: August 2018

The pathogenic life cycle of the rice blast fungusMagnaporthe oryzaeinvolves a series of morphogenetic changes, essential for its ability to cause disease. Thesmomutation was identified more than twenty-five years ago and affects the shape and development of diverse cell types inM. oryzae,including conidia, appressoria and asci. All attempts to clone theSMO1gene by map-based cloning and/or complementation, have failed over many years. Here, we report the identification ofSMO1by a combination of bulk segregant analysis and comparative genome analysis.SMO1encodes a GTPase-activating protein (GAP), which regulates Ras signalling during infection-related development. Targeted deletion ofSMO1results in abnormal, non-adherent conidia, impaired in their production of spore tip mucilage. Smo1 mutants also develop smaller appressoria, with a severely reduced capacity to infect rice plants.SMO1is necessary for organisation of microtubules and for septin-dependent remodelling of the F-actin cytoskeleton at the appressorium pore. Smo1 physically interacts with components of the Ras2 signaling complex, and a range of other signalling and cytoskeletal components, including the four core septins.SMO1is therefore necessary for regulation of RAS activation required for conidial morphogenesis and septin-mediated plant infection.
Interpretable genotype-to-phenotype classifiers with performance guarantees
Authors: Drouin Alexandre , Letarte Gaël , Raymond Frédéric , Marchand Mario , Corbeil Jacques , Laviolette François
Published: August 2018

Understanding the relationship between the genome of a cell and its phenotype is a central problem in precision medicine. Nonetheless, genotype-to-phenotype prediction comes with great challenges for machine learning algorithms that limit their use in this setting. The high dimensionality of the data tends to hinder generalization and challenges the scalability of most learning algorithms. Additionally, most algorithms produce models that are complex and difficult to interpret. We alleviate these limitations by proposing strong performance guarantees, based on sample compression theory, for rule-based learning algorithms that produce highly interpretable models. We show that these guarantees can be leveraged to accelerate learning and improve model interpretability. Our approach is validated through an application to the genomic prediction of antimicrobial resistance, an important public health concern. Highly accurate models were obtained for 12 species and 56 antibiotics, and their interpretation revealed known resistance mechanisms, as well as some potentially new ones. An open-source disk-based implementation that is both memory and computationally efficient is provided with this work. The implementation is turnkey, requires no prior knowledge of machine learning, and is complemented by comprehensive tutorials.
Effects of the anesthetic MS-222 on silver pomfret (Pampus argenteus) juveniles under aquaculture treatment stresses
Authors: Yu Na , Cao Xiaohuan , Wang Yajun , Kuang Siwen , Hu Jiabao , Yang Yang , Xu Shanliang , Zhang Man , Sun Yibo , Gu Weiwei , Yan Xiaojun
Published: August 2018

The silver pomfret (Pampus argenteus) is a major economically important marine fish in China. However, P. argenteus is sensitive to many stress factors and susceptible to injury. This problem could be resolved using anesthesia. We determined the lowest effective dose (LED) of tricaine methanesulfonate (MS-222) and assessed the longest safe deep anesthesia time and effect after aquaculture treatment stresses. P. argenteus juveniles were exposed to six concentrations of MS-222 (10, 25, 50, 75, 100, and 125 mg L-1); LED was established at 75 mg L-1. The juveniles were exposed to different deep anesthesia times (4, 7, 10, 12, and 15 min) at 75 mg L-1; the longest safe deep anesthesia time under LED was 10 min. Finally, the juveniles were randomly divided into four groups: control group (CG), draining group (DG, drain), anesthetic group (AG, drain + MS-222 + aquaculture treatment); and non-anesthetic group (NAG, drain + aquaculture treatment). Plasma cortisol levels in the NAG, AG, DG, and CG groups were 38.739 ± 1.065 (highest), 25.083 ± 0.587, 28.644 ± 0.612, and 22.620 ± 0.836 ng mL-1 (lowest). The AG group showed significant differences in superoxide dismutase, catalase, and malondialdehyde activities, except for glutathione. HSP70, HSP90, GR1, and GR2 mRNA levels in the NAG group increased sharply in response to stressors. GR1 and GR2 mRNA levels in the AG group also increased significantly, whereas HSP70 and HSP90 mRNA levels showed no significant differences. Thus, MS-222 can reduce oxidative damage, stress reaction, and resistance to aquaculture treatment stresses in P. argenteus.
Longitudinal Surveys Show that Urethral Catheters Harbor Recurrent Polymicrobial Biofilms with Cooperative and Competitive Behaviors Among Cohabitating Pathogens
Authors: Yu Yanbao , Singh Harinder , Tsitrin Tamara , Bekele Shiferaw , Moncera Kelvin J. , Sikorski Patricia , Torralba Manolito G. , Morrow Lisa , Wolcott Randall , Nelson Karen E. , Pieper Rembert
Published: August 2018

The analysis of catheter biofilms (CBs) from patients with neurogenic bladder disorders revealed persistent colonization by polymicrobial communities. The recurrence of bacterial species in the CBs of sequentially replaced catheters suggests urothelial reservoirs responsible for recolonization of the catheter surface. Proteomic data for CB samples were indicative of chronic inflammation in the patients’ urinary tracts via neutrophil and eosinophil infiltration and epithelial cell exfoliation. These host defense pathways, effective in killing pathogens during uncomplicated urinary tract infection, failed to eliminate CBs. Intermittent antibiotic drug treatment had different outcomes: either replacement of drug-susceptible by drug-tolerant bacteria or transient microbial biomass reduction followed by resurgence of the previously colonizing bacteria. Proteins that sequester iron and zinc such as lactotransferrin, lipocalin-2 and calprotectin were abundant in the patient’s CBs and urine sediments. Indicative of a host-pathogen battle for bivalent metal ions, acquisition and transport systems for such ions were highly expressed by many organisms residing in CBs. Species part of the Enterococcaceae and Aerococcaceae families, generally not well-characterized in their ability to synthesize siderophores, frequently cohabitated biofilms dominated by siderophore-producingEnterobacteriaceae.In support of metal acquisition cooperativity, we noticed positive abundance correlations for aProteus mirabilisyersiniabactin-type siderophore system and twoEnterococcus faecalisABC transporters. Distinct bacterial strains highly expressed known or putative cytotoxins that appeared to compromise the survival of co-resident bacteria, e.g. aP. mirabilishemolysin andPseudomonas aeruginosatype 6 secretion and pyoverdin biosynthesis systems. In conclusion, there is support for cooperative and competitive behaviors among bacteria cohabitating CBs.
HIV-Attributed Causes of Death in the Medical Ward at the Chris Hani Baragwanath Hospital, South Africa
Authors: Black Andrew , Sitas Freddy , Chibrawara Trust , Gill Zoe , Kubanje Mmamapudi , Williams Brian
Published: August 2018

Background

There are sparse data in Africa on the association between HIV infection and deaths from underlying medical conditions. Using records from the Chris Hani Baragwanath Hospital (CHBH) in Soweto, South Africa, we determined mortality from medical conditions associated with HIV.

Methods

From January 2006 to December 2009 AB collected data on 15,725 deaths including age, sex, day of admittance and death, HIV status, ART initiation and CD4+ cell counts and reviewed the underlying cause of death using medical notes. Conditions known to be associated with HIV were cases; conditions not associated with HIV were controls. We calculate the HIV odds-ratios for cases relative to controls and HIV-attributable deaths as the fraction of those with each condition, the disease-attributable fraction (DA), and as the fraction of all deaths, the population-attributable fraction (PAF).

Interpretation

The high prevalence of HIV among those that died in the medical wards at the CHBH, especially in those below the age of 50 years, demonstrates the impact of the HIV-epidemic on adult mortality and hospital services and the extent to which early antiretroviral treatment would have reduced the burden of both. Of the deaths included in the analysis the prevalence of HIV was 61% and the prevalence of AIDS related conditions was 69%. The HIV-attributable fraction was 36% in the whole sample and 60% in those that were HIV-positive. Cryptococcosis, Kaposi’s sarcoma and Pneumocystis jeroveci are highly predictive of HIV while TB, gastroenteritis and anaemia are very strongly associated with HIV. The greatest number of deaths attributable to HIV was among those dying of TB or of other respiratory conditions.

Funding

No funding was received for this study.
MAP7 family proteins regulate kinesin-1 recruitment and activation
Authors: Hooikaas Peter Jan , Martin Maud , Mühlethaler Tobias , Kuijntjes Gert-Jan , Peeters Cathelijn A.E. , Katrukha Eugene A. , Ferrari Luca , Stucchi Riccardo , Verhagen Daan G.F. , Riel Wilhelmina E. van , Grigoriev Ilya , Altelaar A.F. Maarten , Hoogenraad Casper C. , Rüdiger Stefan G.D. , Steinmetz Michel O. , Kapitein Lukas C. , Akhmanova Anna
Published: August 2018

Kinesin-1 is responsible for microtubule-based transport of numerous cellular cargoes. Here, we explored the regulation of kinesin-1 by MAP7 proteins. We found that all four mammalian MAP7 family members bind to kinesin-1. In HeLa cells, MAP7, MAP7D1 and MAP7D3 act redundantly to enable kinesin-1-dependent transport and microtubule recruitment of the truncated kinesin-1 KIF5B-560, which contains the stalk but not the cargo-binding and autoregulatory regions. In vitro, purified MAP7 and MAP7D3 increase microtubule landing rate and processivity of kinesin-1 through transient association with the motor. MAP7 proteins promote binding of kinesin-1 to microtubules both directly, through the N-terminal microtubule-binding domain and unstructured linker region, and indirectly, through an allosteric effect exerted by the kinesin-binding C-terminal domain. Compared to MAP7, MAP7D3 has a higher affinity for kinesin-1 and a lower affinity for microtubules and, unlike MAP7, can be co-transported with the motor. We propose that MAP7 proteins are microtubule-tethered kinesin-1 activators, with which the motor transiently interacts as it moves along microtubules.

A combination of experiments in cells and in vitro reconstitution assays demonstrated that mammalian MAP7 family proteins act redundantly to activate kinesin-1 and promote its microtubule binding and processivity by transiently associating with the stalk region of the motor.
Stimulus-induced Gamma Power Predicts the Amplitude of the Subsequent Visual Evoked Response
Authors: van Es Mats W.J. , Schoffelen Jan-Mathijs
Published: August 2018

The efficiency of neuronal information transfer in activated brain networks may affect behavioral performance. Gamma-band synchronization has been proposed to be a mechanism that facilitates neuronal processing of behaviorally relevant stimuli. In line with this, it has been shown that strong gamma-band activity in visual cortical areas leads to faster responses to a visual go cue. We investigated whether there are directly observable consequences of trial-by-trial fluctuations in non-invasively observed gamma-band activity on the neuronal response. Specifically, we hypothesizedthat the amplitude of the visual evoked response to a go cue can be predicted by gamma power in the visual system, in the window preceding the evoked response. Thirty-three human subjects (22 female) performed a visual speeded response task while their magnetoencephalogram (MEG) was recorded. The participants had to respond to a pattern reversal of a concentric moving grating. We estimated single trial stimulus-induced visual cortical gamma power, and correlated this with the estimated single trial amplitude of the most prominent event-related field (ERF) peak within the first 100 ms after the pattern reversal. In parieto-occipital cortical areas, the amplitude of the ERF correlated positively with gamma power, and correlated negatively with reaction times. No effects were observed for the alpha and beta frequency bands, despite clear stimulus onset induced modulation at those frequencies. These results support a mechanistic model, in which gamma-band synchronization enhances the neuronal gain to relevant visual input, thus leading to more efficient downstream processing and to faster responses.

Significance statement

Gamma-band activity has been associated with many cognitive functions and improved behavioral performance. For example, high amplitude gamma-band activity in visual cortical areas before a go cue leads to faster reaction times. However, it remains unclear through which neural mechanism(s) gamma-band activity eventually affects behavior. We tested whether the strength of induced gamma-band activity affects evoked activity elicited by a subsequent visual stimulus. We found enhanced amplitudes of early visual evoked activity, and faster responses with higher gamma power. This suggests that gamma-band activity affects the neuronal gain to new sensory input, and thus these results bridge the gap between gamma power and behavior, and support the putative role of gamma-band activity in the efficiency of cortical processing.
Modern botanical analogue of endangered Yak (Bos mutus) dung from India: Plausible linkage with living and extinct megaherbivores
Authors: Basumatary Sadhan K. , Singh Hukam , McDonald H. Gregory , Tripathi Swati , Pokharia Anil K.
Published: August 2018

The study present to document the micro and macrobotanical remain on wild Yak dung to understand the diet, habitat, and ecology in relation to determining possible ecological relationships with extant and extinct megaherbivores. Grasses are the primary diet of the yak as indicated by the abundance of grass pollen and phytoliths, though it is obvious. The other associates non-arboreal and arboreal taxa namely, Cyperacaeae, Rosaceae, Chenopodiaceae,Artemisia, Prunus, andRhododendronare also important dietary plants for their survival. The observation of plant macrobotanical remains especially the vegetative part and seed of the grasses and Cyperaceae also indicates good agreement with the palynodata. The documented micro and macrobotanical data is indicative of both Alpine meadow and steppe vegetation under cold and dry climate which exactly reflected the current vegetation composition and climate in the region. The recovery ofBotryococcus, Arcella, and diatom was marked though in trace values and suggestive of the perennial water system in the region which incorporated through the ingestion of water. Energy dispersive spectroscopy analysis marked that the element contained in dung samples has variation in relation to the summer and winter which might be the availability of the food plants and vegetation. This generated multiproxy data serves as a strong supplementary data for modern pollen and vegetation relationship based on surface soil samples in the region. The recorded multiproxy data could be useful to interpret the coprolites of herbivorous fauna in relation to the palaeodietary and paleoecology in the region and to correlate with other mega herbivores in a global context.
Are these cardiomyocytes? Protocol development reveals impact of sample preparation on the accuracy of identifying cardiomyocytes by flow cytometry
Authors: Waas Matthew , Weerasekera Ranjuna , Kropp Erin M. , Romero-Tejeda Marisol , Poon Ellen , Boheler Kenneth R. , Burridge Paul W. , Gundry Rebekah L.
Published: August 2018

Modern differentiation protocols enable efficient, yet imperfect, differentiation of human pluripotent stem cells into cardiomyocytes (hPSC-CM). As the number of laboratories and studies implementing this technology expands, the accurate assessment of cell identity in differentiation cultures is paramount to well-defined studies that can be replicated among laboratories. While flow cytometry is apt for routine assessment, a standardized protocol for assessing cardiomyocyte identity in hPSC-CM cultures has not yet been established. To address this gap, the current study leveraged targeted mass spectrometry to confirm the presence of troponin proteins in hPSC-CM and systematically evaluated multiple anti-troponin antibodies and sample preparation protocols for their suitability in assessing cardiomyocyte identity. Results demonstrate challenges of interpreting data generated by published methods and informed the development of a robust protocol for routine assessment of hPSC-CM. Overall, the new data, workflow for evaluating fit-for-purpose use of antibodies, and standardized protocol described here should benefit investigators new to this field as well as those with expertise in hPSC-CM differentiation.
ChIP-seq meta-analysis yields high quality training sets for enhancer classification
Authors: Imrichova Hana , Aerts Stein
Published: August 2018

Genome-wide prediction of enhancers depends on high-quality positive and negative training sets. The use of ChIP-seq peaks as positive training data can be problematic due to high degrees of indirectly bound regions, and often poor overlap between experimental conditions.

Here we explore meta-analysis of ChIP-seq data to generate high-quality training data for enhancer modeling. Our method is based on rank aggregation and identifies a core set of directly bound regions per transcription factor, exploiting between five and twenty ChIP-seq data sets per factor. We applied this method to six different transcription factors, namely TP53, REST, SOX2, GRHL2, HIF1A and PPARG. Sequence analysis and modeling of recurrently bound enhancers yielded distinct enhancer features for the different factors, whereby binding sites of REST and TP53 are strongly determined by their motif; binding of GRHL2 and SOX2 is determined by nucleosome positioning; and binding of PPARG and HIF1A depends on other transcription factors. In conclusion, meta-analysis of ChIP-seq peaks, and centering on motifs, allowed discovering new properties of transcription factor binding.
Parallel evolution of frog antimicrobial peptides produces identical conformations but subtly distinct membrane and antibacterial activities
Authors: Manzo Giorgia , Ferguson Philip M. , Hind Charlotte , Clifford Melanie , Gustilo V. Benjamin , Ali Hind , Bansal Sukhvinder S. , Bui Tam T. , Drake Alex F. , Atkinson R. Andrew , Sutton Mark J. , Lorenz Christian D. , Phoenix David A. , Mason A. James
Published: August 2018

Frogs such as Rana temporaria and Litoria aurea secrete numerous closely related antimicrobial peptides (AMPs) as an effective chemical dermal defence. Despite the high similarity in physical properties and preference for adopting secondary amphipathic, α-helix conformations in membrane mimicking milieu, their spectrum of activity and potency often varies considerably. Damage or penetration of the bacterial plasma membrane is considered essential for AMP activity and hence distinguishing apparently similar AMPs according to their behaviour in, and effects on, model membranes will inform understanding of species specific effective antimicrobial mechanisms. Here we use a combination of molecular dynamics simulations, circular dichroism and patch-clamp to investigate the basis for differing anti-bacterial activities in representative AMPs from each species; temporin L and aurein 2.5. Despite adopting near identical, α-helix conformations in the steady-state in a variety of membrane models, these two AMPs can be distinguished both in vitro and in silico based on their dynamic interactions with model membranes; the greater conformational flexibility and the higher amplitude channel conductance induced offers a rationale for the greater potency and broader spectrum of activity of temporin L over aurein 2.5. Specific contributions from individual residues are identified that define the mechanisms of action of each AMP. Our findings suggest AMPs in frogs are examples of parallel evolution whose utility is based on apparently similar but subtly distinct mechanisms of action.
UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates
Authors: Lu Gang , Weng Stephanie , Matyskiela Mary , Zheng Xinde , Fang Wei , Wood Scott , Surka Christine , Mizukoshi Reina , Lu Chin-Chun , Mendy Derek , Jang In Sock , Wang Kai , Marella Mathieu , Couto Suzana , Cathers Brian , Carmichael James , Chamberlain Philip , Rolfe Mark
Published: August 2018

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.
Hidden variation in polyploid wheat drives local adaptation
Authors: Gardiner Laura-Jayne , Joynson Ryan , Omony Jimmy , Rusholme-Pilcher Rachel , Olohan Lisa , Lang Daniel , Bai Caihong , Hawkesford Malcolm , Salt David , Spannagl Manuel , Mayer Klaus F.X. , Kenny John , Bevan Michael , Hall Neil , Hall Anthony
Published: August 2018

Wheat has been domesticated into a large number of agricultural environments and has the ability to adapt to diverse environments. To understand this process, we survey genotype, repeat content, and DNA methylation across a bread wheat landrace collection representing global genetic diversity. We identify independent variation in methylation, genotype, and transposon copy number. We show that these, so far unexploited, sources of variation have had a significant impact on the wheat genome and that ancestral methylation states become preferentially “hard coded” as single nucleotide polymorphisms (SNPs) via 5-methylcytosine deamination. These mechanisms also drive local adaption, impacting important traits such as heading date and salt tolerance. Methylation and transposon diversity could therefore be used alongside SNP-based markers for breeding.
Serial electron crystallography for structure determination and phase analysis of nanocrystalline materials
Authors: Smeets Stef , Zou Xiaodong , Wan Wei
Published: August 2018

Serial electron crystallography has been developed as a fully automated method to collect diffraction data on polycrystalline materials using a transmission electron microscope. This enables useful data to be collected on materials that are sensitive to the electron beam and thus difficult to measure using the conventional methods that require long exposure of the same crystal. The data collection strategy combines goniometer translation with electron beam shift, which allows the entire sample stage to be probed. At each position of the goniometer, the locations of the crystals are identified using image recognition techniques. Diffraction data are then collected on each crystal using a quasi-parallel focused beam with a predefined size (usually 300–500 nm). It is shown that with a fast and sensitive Timepix hybrid pixel area detector it is possible to collect diffraction data of up to 3500 crystals per hour. These data can be indexed using a brute-force forward-projection algorithm. Results from several test samples show that 100–200 frames are enough for structure determination using direct methods or dual-space methods. The large number of crystals examined enables quantitative phase analysis and automatic screening of materials for known and unknown phases.
PDFgetN3: atomic pair distribution functions from neutron powder diffraction data using ad hoc corrections
Authors: Juhás Pavol , Louwen Jaap N. , van Eijck Lambert , Vogt Eelco T. C. , Billinge Simon J. L.
Published: August 2018

PDFgetN3, a new software tool for the extraction of pair distribution functions (PDFs) from neutron powder diffraction intensity data, is described. Its use is demonstrated with constant-wavelength neutron data measured at the new powder diffractometer PEARL at the Delft University of Technology. PDFgetN3 uses an ad hoc data collection protocol similar to PDFgetX3. The quality of the resulting PDFs is assessed by structure refinement and by comparison with established results from synchrotron X-ray scattering.
PETRA IV: the ultralow-emittance source project at DESY
Authors: Schroer Christian G. , Agapov Ilya , Brefeld Werner , Brinkmann Reinhard , Chae Yong-Chul , Chao Hung-Chun , Eriksson Mikael , Keil Joachim , Nuel Gavaldà Xavier , Röhlsberger Ralf , Seeck Oliver H. , Sprung Michael , Tischer Markus , Wanzenberg Rainer , Weckert Edgar
Published: August 2018

The PETRA IV project aims at upgrading the present synchrotron radiation source PETRA III at DESY into an ultralow-emittance source. Being diffraction limited up to X-rays of about 10 keV, PETRA IV will be ideal for three-dimensional X-ray microscopy of biological, chemical and physical processes under realistic conditions at length scales from atomic dimensions to millimetres and time scales down to the sub-nanosecond regime. In this way, it will enable groundbreaking studies in many fields of science and industry, such as health, energy, earth and environment, mobility and information technology. The science case is reviewed and the current state of the conceptual design is summarized, discussing a reference lattice, a hybrid multi-bend achromat with an interleaved sextupole configuration based on the ESRF-EBS design, in more detail as well as alternative lattice concepts.
An iterative image reconstruction algorithm combined with forward and backward diffusion filtering for in-line X-ray phase-contrast computed tomography
Authors: Zhao Yuqing , Sun Mengyu , Ji Dongjiang , Cong Changhong , Lv Wenjuan , Zhao Qi , Qin Lili , Jian Jianbo , Chen Xiaodong , Hu Chunhong
Published: August 2018

In-line X-ray phase-contrast computed tomography (IL-PCCT) can reveal fine inner structures for low-Z materials (e.g. biological soft tissues), and shows high potential to become clinically applicable. Typically, IL-PCCT utilizes filtered back-projection (FBP) as the standard reconstruction algorithm. However, the FBP algorithm requires a large amount of projection data, and subsequently a large radiation dose is needed to reconstruct a high-quality image, which hampers its clinical application in IL-PCCT. In this study, an iterative reconstruction algorithm for IL-PCCT was proposed by combining the simultaneous algebraic reconstruction technique (SART) with eight-neighbour forward and backward (FAB8) diffusion filtering, and the reconstruction was performed using the Shepp–Logan phantom simulation and a real synchrotron IL-PCCT experiment. The results showed that the proposed algorithm was able to produce high-quality computed tomography images from few-view projections while improving the convergence rate of the computed tomography reconstruction, indicating that the proposed algorithm is an effective method of dose reduction for IL-PCCT.
Brazilian infant dairy foods: mineral content and daily intake contribution
Authors: Pimentel Luana S. , Moraes Jeremias , Luna Aderval S. , Barros Diego B. , Pimentel Tatiana C. , Guimarães Jonas T. , Silva Hugo L.A. , Balthazar Celso F. , Esmerino Erick A. , Freitas Mônica Q. , Ranadheera C.S. , Silva Marcia C. , Quitério Simone L. , Raices Renata S.L. , Cruz Adriano G.
Published: August 2018

Purpose

The purpose of this paper is to investigate the mineral content of seven Brazilian infant dairy product categories (petit Suisse cheeses, fermented milks, yogurts, fermented dairy beverage, dairy dessert, Requeijão cremoso spreadable cheese and UHT dairy beverages) and estimate their contribution to daily intake.

Design/methodology/approach

The composition of major (Ca, K, Mg, and Na) and trace (Pb, Cd, Cu and Mn) minerals was determined using Inductively Coupled Plasma Optical Emission Spectrometry. Furthermore, a comparative analysis of the mineral levels with the Reference Daily Intake (RDI) at different child development stages was carried out.

Findings

High Ca levels were observed in petit Suisse (3.44±1.66 mg g−1), dairy dessert (3.88±0.02 mg g−1) and Requeijão cremoso (4.14±0.07 mg g−1). Dairy dessert presented the highest K level (2.57±0.07 mg g−1), while the Requeijão cremoso presented the highest Na content (4.78±0.10 mg g−1), and both products had the highest Mg contents (238.55±16.27 and 197.39±5.18 µg g−1, respectively). Trace elements (Cd, Cu, Mn and Pb) were below the limit of detection for all commercial dairy foods. Among food products analyzed, petit Suisse cheese and dairy dessert can be considered good sources of calcium, while Requeijão cremoso is high in both calcium and sodium.

Originality/value

This study is the first to analyze the mineral levels of several Brazilian infant dairy foods and the daily intake contribution during important child development stages. These findings provide valuable guidance for researchers and practitioners trying to develop healthy and nutritious dairy products for infants and children.
Attributes determining consumer preference for organic rice in Bangkok, Thailand
Authors: Sakolwitayanon Hatairat , Soni Peeyush , Damien Jourdain
Published: August 2018

Purpose

The purpose of this paper is to explore key attributes of organic rice that consumers use in the process of choosing organic rice, and to segment organic rice market in Bangkok. Moreover, the study tends to identify the best clustering techniques, between latent class cluster analysis (LCCA) and traditional cluster analysis (CA), for precise segmentation.

Design/methodology/approach

Best–worst scaling (BWS) method was applied to measure the level of relative importance of organic rice attributes. Then, LCCA and CA techniques were applied to recognize market segmentation. Finally, homogeneity and heterogeneity of the resulting clusters were determined to compare performance of the two clustering techniques.

Findings

The LCCA technique was identified better than the CA in classification of consumers. According to LCCA solution, the organic rice market in Bangkok (Thailand) consisted of six distinct clusters, which can be grouped into three categories based on consumers’ profile. Organic rice consumer categories were identified as “Art of eating” and “Superior quality seeker” clusters focusing on special features and quality of the organic rice; consumer category “Basic concern” cluster heavily relied on organic certification logo and manufacturing information; and other consumer categories were “Price driven,” “Eyes on price” and “Thorough explorer” clusters.

Originality/value

This study first applies BWS score to examine consumers’ preference for organic rice attributes and segments market, providing results for practical use for retailers, producers and marketers.
Knowledge transfer in a start-up craft brewery
Authors: Cardoni Andrea , Dumay John , Palmaccio Matteo , Celenza Domenico
Published: August 2018

Purpose

The purpose of this paper is to explore the role of the entrepreneur in the knowledge transfer (KT) process of a start-up enterprise and the ways that role should change during the development phase to ensure mid-term business survival and growth.

Design/methodology/approach

An in-depth, qualitative case study of Birra Flea, an Italian Craft Brewery, is presented and analysed using Liyanageet al.’s (2009) framework to identify the key components of the KT process, including relevant knowledge, key actors, transfer steps and the criteria for assessing its effectiveness and success.

Findings

The entrepreneur played a fundamental and crucial role in the start-up process, acting as a selective and passionate broker for the KT process. As Birra Flea matures and moves into the development phase, the role of the entrepreneur as KT’s champion needs to be integrated and distributed throughout the organisation, with the entrepreneur serving as a performance controller.

Research limitations/implications

This study enriches the knowledge management literature by applying a framework designed to provide a general description of KT, with some modifications, to a single case study to demonstrate its effectiveness in differentiating types of knowledge and outlining how KT can be configured to support essential business functions in an SME.

Practical implications

The analysis systematises the KT mechanisms that govern the start-up phase of an award-winning SME, with suggestions for how to manage KT during the development phase. Seldom are practitioners given insight into the mechanics of a successful SME start-up; this analysis serves as a practical guide for those wishing to implement effective KT strategies to emulate Birra Flea’s success.

Originality/value

The world’s economy thrives on SMEs, yet many fail as start-ups before they even have a chance to reach the development phase, presenting a motivation to study the early stages of SMEs. This study addresses that gap with an in-depth theoretical analysis of successful, effective KT processes in an SME, along with practical implications to enhance the knowledge, experience and skills of the actors that sustain these vital economic enterprises.
When hierarchy becomes collaborative
Authors: Rice Rebecca M.
Published: August 2018

Purpose

The purpose of this paper is to expand understandings of interorganizational collaboration among high reliability organizations (HROs). It proposes that HROs face unique needs for relationship building, pre-planning, and retrospective sensemaking that do not fit within prior models of collaboration. For HROs, definitions of collaboration vary contextually based on needs that arise during emergency situations. HROs have a need for both hierarchical structure and collaborative processes and use collaboration as a sensemaking frame that allows practitioners to attend to both needs.

Design/methodology/approach

The paper uses a case study from an ongoing ethnographic study of an emergency response collaboration. The paper uses open-ended interviews about collaboration with all key members of the incident response hierarchy, and participant observation of collaboration before, during and after a key emergency incident.

Findings

The paper proposes a new framework for HRO collaboration: that collaboration is a sensemaking frame for HROs used to make sense of individual actions, that HRO collaboration is more complex during pre-planning and focused on individual decision making during incidents, and that members can communicatively make sense of the need for hierarchy and collaborative action by defining these needs contextually.

Research limitations/implications

The paper uses an in-depth case study of an incident to explore this collaborative framework; therefore, researchers are encouraged to test this framework in additional high reliability collaborative contexts.

Practical implications

The paper includes implications for best communicative practices to recognize the need to be both hierarchical and flexible in high reliability organizing.

Originality/value

This paper fulfills a need to expand collaboration literature beyond idealized and egalitarian definitions, in order to understand how practitioners use communication to understand their actions as collaborative, especially in organizations that also require hierarchy and individual actions. This case study suggests that collaboration as a sensemaking frame creates collaborative advantages for HROs, but can also limit sensemaking about incident management.
Cannabis use as harm reduction in the Eastern Caribbean
Authors: Day Marcus
Published: August 2018

Purpose

The purpose of this paper is to present evidence of the therapeutic value of cannabis as a harm reduction intervention with people who smoke crack cocaine.

Design/methodology/approach

A desk study of published peer-reviewed material supporting the use of cannabis as therapeutic in mitigating some of the harms associated with crack cocaine smoking.

Findings

The use of cannabis as a harm reduction strategy for crack cocaine use has been commented on in the scientific literature since the 1980s. The officially scheduling of cannabis as having no medicinal value hampered further study despite the reporting of positive findings and numerous calls for more research.

Practical implications

There are currently no approved pharmaceutical substitutions for crack cocaine. Cannabis has shown itself effective in mitigating harms for 30–40 per cent of people. Cannabis is inexpensive and readily available and should be allowed for those people who want to use it.

Originality/value

Poly drug use is often framed in a negative context. In this paper, the author shows that with cannabis and crack, the poly drug use is actually a valid harm reduction strategy.