bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement from ixekizumab treatment in patients with psoriatic arthritis who have had an inadequate response to one or two TNF inhibitors
Authors: Kirkham Bruce , Sesin Carlos , Gellett Amanda M. , Sprabery Aubrey T. , Lin Chen-Yen , Turkiewicz Anthony
Published: November 2020

Objective

To evaluate the efficacy of ixekizumab (IXE), a monoclonal antibody selectively targeting interleukin-17A, in patients with inadequate response to one or two TNF inhibitors (TNFi).

Methods

A phase 3 study (SPIRIT-P2; NCT02349295) randomized patients with PsA with inadequate response or intolerance to one or two TNFi to receive 80-mg IXE every 2 weeks (n = 123) or every 4 weeks (n = 122) after a 160-mg starting dose or placebo (PBO; n = 118) through week 24. This post hoc analysis used data from inadequate responders to one or two TNFi, measuring the percentage achieving: ≥50% improvement in ACR response criteria (ACR50) and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100), ACR50, improvement in HAQ-Disability Index (HAQ-DI) ≥0.35, minimal disease activity (MDA), European League Against Rheumatism (EULAR) Good Response Criteria [improvement in Disease Activity Score 28 CRP (DAS28-CRP) >1.2], and Disease Activity in PsA (DAPSA) ≤14.

Results

There were no significant differences in baseline characteristics between inadequate responders to one and two TNFi. At week 24, significantly more patients irrespective of previous TNFi experience receiving IXE than PBO achieved ACR50, HAQ-DI ≥0.35 improvement, MDA, EULAR good response, and DAPSA ≤14, and significantly more patients with inadequate response to one TNFi receiving IXE than PBO achieved ACR50 and PASI 100. Improvement persisted in all measures through week 52.

Conclusion

IXE improved the signs and symptoms of PsA in a population of difficult-to-treat patients with inadequate response to one or two TNFi.
Time-Varying Crash Risk Embedded in Index Options: The Role of Stock Market Liquidity
Authors: Christoffersen Peter , Feunou Bruno , Jeon Yoontae , Ornthanalai Chayawat
Published: November 2020

We estimate a continuous-time model for the stock market index where the stochastic volatility and crash probability depend on the realized spot variance and the stock market illiquidity. We find that market illiquidity is a useful economic covariate in the modeling of time-varying stock market crash risk embedded in index options. The relative contribution of spot variance in the time-varying crash risk is weakened once the market illiquidity variable is added to the model, and out-of-sample option pricing error also improves. Examining the relationship between market illiquidity and option-implied crash risk, we find that the availability of arbitrage capital and adverse selection facing liquidity providers are potential economic links. Our study highlights the benefits of adding a market illiquidity measure to index return models with time-varying crash risk.
The Balanced State of Application-oriented Public Research and Technology Organisations
Authors: Borsi Balázs
Published: November 2020

Analytical tools that systematically take into account the contexts and complexities of innovations can provide valuable insights. Public research and technology organizations (PROs) are at the intersection of contextual complexities involving business, government, and academia. Hence, studying and strategically managing them call for specific methods. In the article, the Triple Helix (TH) viewpoints of business, government, and academia are used to study activities and processes of PROs. Building on theories of academic capitalism, resource dependency, and related strategic management research, a TH-specific analytical framework is proposed to assist in establishing a common language and structural construct for PRO strategic management. Using the framework, a secondary analysis of nineteen case studies from eleven European countries and Japan points to the main elements of the balanced TH regime PROs. In the case of these specific, historically embedded organizations and during their ‘endless transition’, attention is called to the strategic need for fit between the external environments and internal capabilities and the TH-related factors facilitating strategic congruence.
Reconceptualizing Vulnerability and Safeguarding in the Humanitarian and Development Sector
Authors: Daoust Gabrielle , Dyvik Synne L
Published: November 2020

Since 2018, “safeguarding” has been hailed as the answer to abuse, exploitation, and harassment in the humanitarian and development sector. However, safeguarding as a concept relies on conceptions of vulnerability, which are rarely critically interrogated. Bringing feminist, postcolonial, and critical disability studies to bear on what is conventionally viewed as an apolitical policy response, we argue that the need for safeguarding should be located within wider racialized, gendered, ableist, and geographic structures of power within which the sector is embedded. We conclude with theoretical reflections and directions for change centering intersectional and repoliticized conceptualizations of vulnerability and thus safeguarding.
Myelination of Callosal Axons Is Hampered by Early and Late Forelimb Amputation in Rats
Authors: Vianna-Barbosa Rodrigo , Bahia Carlomagno P , Sanabio Alexandre , de Freitas Gabriella P A , Madeiro da Costa Rodrigo F , Garcez Patricia P , Miranda Kildare , Lent Roberto , Tovar-Moll Fernanda
Published: November 2020

Deafferentation is an important determinant of plastic changes in the CNS, which consists of a loss of inputs from the body periphery or from the CNS itself. Although cortical reorganization has been well documented, white matter plasticity was less explored. Our goal was to investigate microstructural interhemispheric connectivity changes in early and late amputated rats. For that purpose, we employed diffusion-weighted magnetic resonance imaging, as well as Western blotting, immunohistochemistry, and electron microscopy of sections of the white matter tracts to analyze the microstructural changes in the corticospinal tract and in the corpus callosum (CC) sector that contains somatosensory fibers integrating cortical areas representing the forelimbs and compare differences in rats undergoing forelimb amputation as neonates, with those amputated as adults. Results showed that early amputation induced decreased fractional anisotropy values and reduction of total myelin amount in the cerebral peduncle contralateral to the amputation. Both early and late forelimb amputations induced decreased myelination of callosal fibers. While early amputation affected myelination of thinner axons, late amputation disrupted axons of all calibers. Since the CC provides a modulation of inhibition and excitation between the hemispheres, we suggest that the demyelination observed among callosal fibers may misbalance this modulation.
Timing of Surgical Intervention for Dysphagia in Patients With Diffuse Idiopathic Skeletal Hyperostosis
Authors: Gendreau Julian L. , Sheaffer Kristin , Bennett Josiah , Abraham Mickey , Patel Nitesh V. , Herschman Yehuda , Ruh Nikki , Lindley James G.
Published: November 2020

Study Design:

This was a systematic review and meta-analysis.

Objective:

The objective was (1) to measure rates of successful resolution of dysphagia in patients after undergoing surgical intervention for diffuse idiopathic skeletal hyperostosis (DISH); and (2) to determine if older age, longer duration of preoperative symptoms, or increased severity of disease was correlated with unsuccessful surgical intervention.

Summary of Background Data:

DISH, also known as Forestier disease, is an enthesopathy affecting up to 35% of the elderly population. Many patients develop osteophytes of the anterior cervical spine, which contribute to chronic symptoms of dysphagia causing debilitating weight loss and possibly resulting in the placement of a permanent gastrostomy feeding tube. For patients that fail conservative medical management, an increase in surgical interventions have been reported in the literature in the last 2 decades.

Materials and Methods:

A systematic search was performed on PubMed, Medline, Cochrane Library, and Embase. Studies measuring outcomes after surgical intervention for patients with dysphagia from DISH were selected for inclusion. Two independent reviewers screened and assessed all literature in accordance with Cochrane systematic reviewing standards.

Results:

In total, 22 studies reporting 119 patients were selected for inclusion. Successful relief of dysphagia was obtained in 89% of patients after surgical intervention. Failure to relieve dysphagia was associated with increased length of symptoms preoperatively (P<0.01) using logistic regression. Patients with more severe preoperative symptoms also seem to have an increased risk for treatment failure (risk ratio, 2.86; 95% confidence interval, 1.19–6.85; P=0.02). Treatment failure was not associated with patient age, use of intraoperative tracheostomy, implementation of additional fusion procedures, level of involved segments, or number of involved segments.

Conclusions:

Patients undergoing surgical intervention have a higher likelihood of failing surgery with increasing preoperative symptom length and increased preoperative symptom severity.

Level of Evidence:

Level III.
Hypertension management in frail older adults: a gap in evidence
Authors: Rivasi Giulia , Tortù Virginia , D’Andria Maria F. , Turrin Giada , Ceolin Ludovica , Rafanelli Martina , Mossello Enrico , Ungar Andrea
Published: November 2020

Hypertension management is challenging in frail older adults. The balance between treatment risks and benefits may be difficult to achieve due to an increased vulnerability to treatment-related adverse events, and limited evidence is available to support clinical decisions. The effects of frailty on blood pressure are unclear, as well as its impact on antihypertensive treatment benefits. Appropriate blood pressure targets in frail patients are debated and the frailty measure which best inform clinical decisions in hypertensive patients has yet to be identified. Therefore, hypertension management in frail older adults still represents a ‘gap in evidence’. Knowledge of currently available literature is a fundamental prerequisite to develop future research and may help to implement frailty assessment and improve hypertension management in this vulnerable population. Given these premises, we present a narrative review illustrating the most relevant issues that are a matter of debate and that should be addressed in future studies.
The association between indices of blood pressure waveforms (PTC1 and PTC2) and incident heart failure
Authors: Brumback Lyndia C. , Andrews Leah I.B. , Jacobs David R. , Duprez Daniel A. , Shah Sanjiv J. , Dougherty Cynthia M. , Denenberg Julie O. , Allison Matthew A.
Published: November 2020

Objectives:

The radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle, and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown.

Methods:

Among 6229 adults (mean age 62 years) from four race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000–2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure.

Results:

Mean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 ms, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63--0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56--0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure.

Conclusion:

The PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction.
Upper Lumbar Bone Stress Injuries in Elite Cricketers
Authors: Saw Richard , Saw Anna , Kountouris Alex , Orchard John
Published: November 2020

Objective:

Describe the proportion of upper lumbar bone stress injuries (LBSI; T12-L3) relative to all LBSI, and the clinical presentation and diagnosis of upper LBSI in elite cricketers.

Design:

Case series.

Setting:

Professional domestic and international cricket teams over a 9-year period.

Participants:

Elite Australian cricketers.

Independent Variables:

Symptomatic upper LBSI diagnosed based on clinical findings and medical imaging.

Main Outcome Measures:

Prevalence, injury history, and clinical management.

Results:

Twenty-four pace bowlers (22 male and 2 female) sustained 39 cases of upper LBSI (T12:2, L1:3, L2:20, L3:14). Upper lumbar vertebrae were involved in 41% (95% CI 31-51) of all LBSI in this cohort. Twenty-seven (69%, 54-81) cases had an injury that occurred only on the side contralateral to the bowling arm. Ipsilateral injuries tended to occur secondary to a contralateral nonunited defect. In all 7 cases with known radiology follow-up that had a contralateral then ipsilateral LBSI, the contralateral injury did not achieve bony union before the onset of the ipsilateral LBSI. For stress fractures with imaging follow-up, those who achieved bony union took longer to return to bowling training [median 152 days (IQR 117-188)], compared to those who achieved partial or no union [median 68 days (IQR 46-115)].

Conclusions:

Upper LBSI in elite cricketers occurs in approximately 2 out of 5 cases of LBSI. Clinicians should allow sufficient time for upper LBSI to resolve and unite (if a fracture) because cases that returned to bowling training earlier were less likely to achieve bony union, and those that failed to unite commonly went on to have a recurrent LBSI.

Level of Evidence:

Therapy/prognosis/diagnosis level 2b.
Automatic reconstruction of metabolic pathways from identified biosynthetic gene clusters
Authors: Sulheim Snorre , Fossheim Fredrik A. , Wentzel Alexander , Almaas Eivind
Published: November 2020

Background

A wide range of bioactive compounds are produced by enzymes and enzymatic complexes encoded in biosynthetic gene clusters (BGCs). These BGCs can be identified and functionally annotated based on their DNA sequence. Candidates for further research and development may be prioritized based on properties such as their functional annotation, (dis)similarity to known BGCs, and bioactivity assays. Production of the target compound in the native strain is often not achievable, rendering heterologous expression in an optimized host strain as a promising alternative. Genome-scale metabolic models are frequently used to guide strain development, but large-scale incorporation and testing of heterologous production of complex natural products in this framework is hampered by the amount of manual work required to translate annotated BGCs to metabolic pathways. To this end, we have developed a pipeline for an automated reconstruction of BGC associated metabolic pathways responsible for the synthesis of non-ribosomal peptides and polyketides, two of the dominant classes of bioactive compounds.

Results

The developed pipeline correctly predicts 72.8% of the metabolic reactions in a detailed evaluation of 8 different BGCs comprising 228 functional domains. By introducing the reconstructed pathways into a genome-scale metabolic model we demonstrate that this level of accuracy is sufficient to make reliablein silicopredictions with respect to production rate and gene knockout targets. Furthermore, we apply the pipeline to a large BGC database and reconstruct 943 metabolic pathways. We identify 17 enzymatic reactions using high-throughput assessment of potential knockout targets for increasing the production of any of the associated compounds. However, the targets only provide a relative increase of up to 6% compared to wild-type production rates.

Conclusions

With this pipeline we pave the way for an extended use of genome-scale metabolic models in strain design of heterologous expression hosts. In this context, we identified generic knockout targets for the increased production of heterologous compounds. However, as the predicted increase is minor for any of the single-reaction knockout targets, these results indicate that more sophisticated strain-engineering strategies are necessary for the development of efficient BGC expression hosts.
Specific norovirus interaction with Lewis x and Lewis a on human intestinal inflammatory mucosa during refractory inflammatory bowel disease
Authors: Tarris Georges , de Rougemont Alexis , Estienney Marie , Charkaoui Maeva , Mouillot Thomas , Bonnotte Bernard , Michiels Christophe , Martin Laurent , Belliot Gael
Published: November 2020

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is related to immunological and microbial factors with the possible implication of enteric viruses. We characterize the interaction between human noroviruses (HuNoVs) and blood group antigens in refractory CD and UC using HuNoV Virus Like Particles (VLPs) and histological tissues. Immunohistochemistry was conducted on inflammatory tissue samples from the small intestine, colon and rectum in 15 CD and 9 UC patients. Analysis of the regenerative mucosa of the colon and rectum revealed strong expression of sialylated Lewis a (sLea) and Lewis x (sLex) antigens, and HuNoV VLP binding in the absence of ABO antigen expression in both UC and CD. Competition experiments using sialidase, lectins and monoclonal antibodies demonstrated that HuNoV attachment mostly involved Leaand to a lesser extent, Lexmoieties on regenerative mucosa in both UC and CD. Further studies will be required to understand the implications of specific HuNoV binding to regenerative mucosa in refractory IBD.

IMPORTANCE

Inflammatory Bowel Disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are progressive diseases affecting millions of people each year. Flare-ups during IBD result in severe mucosal alterations of the small intestine (CD), colon and rectum (CD and UC). Immunohistochemical analysis of CD and UC samples showed strong expression of known tumoral markers, Sialyl-Lewis a (CA19.9) and Sialyl-Lewis x (CD15s) antigens on colonic and rectal regenerative mucosa, concurrent with strong human norovirus (HuNov) VLP GII.4 affinity. Sialidase treatment and competition experiments using HBGA-specific monoclonal antibodies and lectins clearly demonstrated the implication of the Lewis a moiety, and to a lesser extent Lewis x, in HuNov recognition in regenerative mucosa of CD and UC tissues. Further studies are required to explore the possible implications of enteric viruses in the impairment of epithelial repair and dysregulation of inflammatory pathways during severe IBD.
Explainable Machine Learning models for Rapid Risk Stratification in the Emergency Department: A multi-center study
Authors: van Doorn William P.T.M. , Helmich Floris , van Dam Paul M.E.L. , Jacobs Leo H.J. , Stassen Patricia M. , Bekers Otto , Meex Steven J.R.
Published: November 2020

Background

Risk stratification of patients presenting to the emergency department (ED) is important for appropriate triage. Diagnostic laboratory tests are an essential part of the work-up and risk stratification of these patients. Using machine learning, the prognostic power and clinical value of these tests can be amplified greatly. In this study, we applied machine learning to develop an accurate and explainable clinical decision support tool model that predicts the likelihood of 31-day mortality in ED patients (the RISKINDEX). This tool was developed and evaluated in four Dutch hospitals.

Methods

Machine learning models included patient characteristics and available laboratory data collected within the first two hours after ED presentation, and were trained using five years of data from consecutive ED patients from the Maastricht University Medical Centre+ (Maastricht), Meander Medical Center (Amersfoort), and Zuyderland (Sittard and Heerlen). A sixth year of data was used to evaluate the models using area-under-the-receiver-operating-characteristic curve (AUROC) and calibration curves. The SHapley Additive exPlanations (SHAP) algorithm was used to obtain explainable machine learning models.

Results

The present study included 266,327 patients with 7.1 million laboratory results available. Models show high diagnostic performance with AUROCs of 0.94,0.98,0.88, and 0.90 for Maastricht, Amersfoort, Sittard and Heerlen, respectively. The SHAP algorithm was utilized to visualize patient characteristics and laboratory data patterns that underlie individual RISKINDEX predictions.

Conclusions

Our clinical decision support tool has excellent diagnostic performance in predicting 31-day mortality in ED patients. Follow-up studies will assess whether implementation of these algorithm can improve clinically relevant endpoints.
Pupal cannibalism by worker honey bees contributes to the spread of Deformed wing virus
Authors: Posada-Florez Francisco , Lamas Zachary S. , Hawthorne David J. , Chen Yanping , Evans Jay D. , Ryabov Eugene V.
Published: November 2020

Transmission routes impact pathogen virulence and genetics, therefore comprehensive knowledge of these routes and their contribution to pathogen circulation is essential for understanding host-pathogen interactions and designing control strategies. Deformed wing virus (DWV), a principal viral pathogen of honey bees associated with increased honey bee mortality and colony losses, became highly virulent with the spread of its vector, the ectoparasitic miteVarroa destructor. Reproduction ofVarroamites occurs in capped brood cells and mite-infested pupae from these cells usually have high levels of DWV. The removal of mite-infested pupae by worker bees,VarroaSensitive Hygiene (VSH), leads to cannibalization of pupae with high DWV loads, thereby offering an alternative route for virus transmission. We used genetically tagged DWV to investigate virus transmission to and between worker bees following pupal cannibalisation under experimental conditions. We demonstrated that cannibalization of DWV-infected pupae resulted in high levels of this virus in worker bees and that the acquired virus was then transmitted between bees via trophallaxis, allowing circulation ofVarroa-vectored DWV variants without the mites. Despite the known benefits of hygienic behaviour, it is possible that higher levels of VSH activity may result in increased transmission of DWV via cannibalism and trophallaxis.
Infertility and fecundity loss ofWolbachia-infectedAedes aegyptihatched from quiescent eggs is expected to alter invasion dynamics
Authors: Lau Meng-Jia , Ross Perran A. , Hoffmann Ary A.
Published: November 2020

The endosymbiotic bacteriumWolbachiashows viral blockage in its mosquito host, leading to its use in arboviral disease control. Releases withWolbachiastrainswMel andwAlbB infectingAedes aegyptihave taken place in several countries. Mosquito egg survival is a key factor influencing population persistence and this trait is also important when eggs are stored prior to releases. We therefore tested the viability of mosquitoes derived fromWolbachia wMel andwAlbB-infected as well as uninfected eggs after long-term storage under diurnal temperature cycles of 11-19°C and 22-30°C. Eggs stored at 11-19°C had higher hatch proportions than those stored at 22-30°C. AdultWolbachiadensity declined when they emerged from eggs stored for longer, which was associated with incomplete cytoplasmic incompatibility (CI) whenwMel-infected males were crossed with uninfected females.wAlbB-infected males continued to show complete CI. Females from stored eggs at both temperatures continued to show perfect maternal transmission ofWolbachia, but storage reduced the fecundity of bothwMel andwAlbB-infected females relative to uninfected mosquitoes. Furthermore, we found a very strong negative impact of thewAlbB infection on the fertility of females stored at 22-30°C, with almost 80% of females hatching after 11 weeks of storage being infertile. Our findings provide guidance for storingWolbachia-infectedAe. aegyptieggs to ensure high fitness adult mosquitoes for release. Importantly, they also highlight the likely impact of egg quiescence on the population dynamics ofWolbachia-infected populations in the field, and the potential forWolbachiato suppress mosquito populations through cumulative fitness costs across warm and dry periods, with expected effects on dengue transmission.
Extreme value theory as a general framework for understanding mutation frequency distribution in cancer genomes
Authors: Tokutomi Natsuki , Nakai Kenta , Sugano Sumio
Published: November 2020

Currently, there is no recognized population genetics framework describing the population dynamics of cancer cells that is applicable to real cancer genome data. By focusing on cancer as a Darwinian evolutionary system, we formulated and analyzed the observed mutation frequency among tumors (MFaT) as a proxy for the hypothesized sequence read frequency and beneficial fitness effect of a cancer driver mutation. Analogous to intestinal crypts, we assumed that sample donor patients are separate culture tanks where proliferating cells follow certain population dynamics described by extreme value theory (EVT). To validate this, we analyzed three large-scale cancer genome datasets, each harboring > 10 000 tumor samples and in total involving > 177 898 observed mutation sites. We clarified the necessary premises for the application of EVT in the strong selection and weak mutation (SSWM) regime in relation to cancer genome sequences at scale. We also confirmed that the stochastic distribution of MFaT is likely of the Fréchet type, which challenges the well-known Gumbel hypothesis of beneficial fitness effects. Based on statistical data analysis, we demonstrated the potential of EVT as a population genetics framework to understand and explain the stochastic behavior of driver-mutation frequency in cancer genomes as well as its applicability in real cancer genome sequence data.
How human intervention and climate change shaped the fate of the Northern Bald Ibis from ancient Egypt to the presence: an interdisciplinary approach to extinction and recovery of an iconic bird species
Authors: Fritz Johannes , Janák Jiří
Published: November 2020

Once widespread around the Mediterranean, the Northern Bald Ibis (Geronticus eremita) became one of the rarest birds in the world. We trace the history of this species through different epochs to the present. A particular focus is on its life and disappearance in ancient Egypt, where it attained the greatest mythological significance as a hieroglyphic sign for ‘blessed ancestor spirits’, and on modern endeavours to rewild and restore the species. The close association of the Northern Bald Ibis with human culture in ancient Egypt, as in other regions, is caused by primarily two reasons, the characteristic appearance and behaviour, as well as the need for open foraging areas. In consequence, a mutualistic relationship between humans and birds was formed in some cultures. The benefit for the Northern Bald Ibis was mainly the availability of feeding habitats, which were cleared by humans for farming or grazing and might have contributed to the spread of the species. The benefit to people was primarily cultural and mythological, whereby the bird was worshiped in ancient Egypt and in Muslim cultures, while Christian cultures in Europe rather regarded it as bad omen or nuisance, like any black bird species. Another benefit was profane in nature, the species was also hunted for food, mainly in Europe. But alike many other species, proximity to humans also carried a high risk for the Northern Bald Ibis. We discuss various kinds of human impacts that were driving causes for the extinction of the species in almost all regions. However, the historical disappearance of populations also correlates markedly with changes in climate, especially in ancient Egypt and the Middle Ages. This fact has important implications for current conservation efforts, especially since international action plans for the Northern Bald Ibis have taken little account of climate change effects so far. The Northern Bald Ibis is an outstanding example of how an interdisciplinary cultural-historical and natural-scientific approach significantly promotes the interpretation of historical evidence as well as the implementation of current rewilding and restoration efforts.
PLD2-phosphatidic acid recruit ESCRT-I to late endosomes for exosome biogenesis
Authors: Egea-Jimenez Antonio Luis , Audebert Stéphane , Castro-Cruz Monica , Borg Jean-Paul , David Guido , Camoin Luc , Zimmermann Pascale
Published: November 2020

It is important to understand the biogenesis of exosomes, extracellular vesicles of endosomal origin controlling cell-to-cell communication. We previously reported that Phospholipase D2 (PLD2) supports late endosome (LE) budding and the biogenesis of syntenin-dependent exosomes. Here, we reveal that PLD2 has a broader generic effect on exosome production. Combining gain- and loss-of-function experiments, proteomics, microscopy and lipid-binding studies with reconstituted liposomes mimicking LE, we show that: (i) PLD2 activity controls the recruitment of MVB12B to LE and the exosomal secretion of ESCRT-I; (ii) loss-of-MVB12B phenocopies loss-of-PLD2, similarly affecting LE budding, the number of exosomes released and exosome loading with cargo; (iii) MVB12B MABP domain directly interacts with phosphatidic acid, the product of PLD2. We therefore propose that PLD2 and phosphatidic acid support ESCRT-I recruitment to LE for the formation of exosomes. This work highlights a major unsuspected piece of the molecular framework supporting LE and exosome biogenesis.
Selective transport of fluorescent proteins into the phage nucleus
Authors: Nguyen Katrina T. , Sugie Joseph , Khanna Kanika , Egan MacKennon E. , Birkholz Erica A. , Lee Jina , Beierschmitt Christopher , Villa Elizabeth , Pogliano Joe
Published: November 2020

Upon infection ofPseudomonascells, jumbo phages 201Φ2-1, ΦPA3, and ΦKZ assemble a phage nucleus. Viral DNA is enclosed within the phage-encoded proteinaceous shell along with proteins associated with DNA replication, recombination and transcription. Ribosomes and proteins involved in metabolic processes are excluded from the nucleus. RNA synthesis occurs inside the phage nucleus and messenger RNA is presumably transported into the cytoplasm to be translated. Newly synthesized proteins either remain in the cytoplasm or specifically translocate into the nucleus. The molecular mechanisms governing selective protein sorting and nuclear import in these phage infection systems are currently unclear. To gain insight into this process, we studied the localization of five reporter fluorescent proteins (GFP+, sfGFP, GFPmut1, mCherry, CFP). During infection with ΦPA3 or 201Φ2-1, all five fluorescent proteins were excluded from the nucleus as expected; however, we have discovered an anomaly with the ΦKZ nuclear transport system. The fluorescent protein GFPmut1, expressed by itself, was transported into the ΦKZ phage nucleus. We identified the amino acid residues on the surface of GFPmut1 required for nuclear targeting. Fusing GFPmut1 to any protein, including proteins that normally reside in the cytoplasm, resulted in transport of the fusion into the nucleus. Although the mechanism of transport is still unknown, we demonstrate that GFPmut1 is a useful tool that can be used for fluorescent labelling and targeting of proteins into the ΦKZ phage nucleus.
Direct information estimation from cryo-EM Movies with CARYON
Authors: Ramlaul Kailash , Burt Alister , de Martín Garrido Natàlia , MacDonald James T. , Palmer Colin M. , Jakobi Arjen , Aylett Christopher H. S.
Published: November 2020

While cryo-EM with modern direct electron detectors has proven incredibly powerful, becoming a dominant technique in structural biology, the analysis of cryo-EM images is significantly complicated by their exceptionally low signal-to-noise ratio, limiting the accuracy of the parameterisation of the physical models required for successful classification and reconstruction.

Micrographs from modern direct electron detectors are typically collected as dose-fractionated multi-frame movies to allow the recording of separated individual electron impacts. These detectors improve electron detection and allow for both inter-frame motion correction, and dose-dependent image filtering, lessening the overall impact of effects deleterious to the recovery of high-resolution information.

In this study we measured the information content at each spatial frequency in cryo-EM movies as it accrues during the course of an exposure. We show that, as well as correction for motion and radiation damage, the use of the information within movies allows substantially improved direct estimation of the remaining key image parameters required for accurate 3D reconstruction: the image CTF and spectral SNR.

We are developing “CARYON” {insert contrived acronym here}, as a LAFTER-family filter for cryo-EM movies based upon such measurements. CARYON is intended to provide the best parameter estimation and filtration possible for a single complete, or large sub-section from a, movie micrograph without the use of a previously refined density. We demonstrate its utility in both single-particle and tomographic cryo-EM data processing.
Broad-spectrum antiviral activity of 3D8, a nucleic acid-hydrolyzing single chain variable fragment (scFv), targeting SARS-CoV-2 and multiple coronavirusesin vitro
Authors: Lee Gunsup , Budhathoki Shailesh , Lee Geum-Young , Oh Kwang-ji , Ham Yeon Kyoung , Kim Young Jun , Lim Ye Rin , Hoang Phuong Thi , Lee Yongjun , Lim Seok-Won , Kim Jun-Mo , Cho Seungchan , Kim Tai-Hyun , Song Jin-Won , Lee Sukchan , Kim Won-Keun
Published: November 2020

Background

The current pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the etiology of Coronavirus-induced disease 19 (COVID-19) and poses a critical public health threat worldwide. Effective therapeutics and vaccines against multiple coronaviruses remain unavailable. Single chain variable fragment (scFv), a recombinant antibody exhibits broad-spectrum antiviral activity against DNA and RNA viruses owing to its nucleic acid-hydrolyzing property.

Objective

This study is aimed to investigate an antiviral activity of 3D8 scFv against SARS-CoV-2 and other coronaviruses.

Methods

3D8, a recombinant scFv antibody was evaluated for antiviral activity against SARS-CoV-2, HCoV-OC43 and PEDV in Vero E6 cell cultures. Viral growth was quantified with quantitative RT-qPCR and plaque assay. Nucleic acid hydrolyzing activity of 3D8 was assessed through abzyme assays ofin vitroviral transcripts and cell viability was determined by MTT assay.

Results

3D8 inhibited the replication of SARS-CoV-2, human coronavirus OC43 (HCoV-OC43), and porcine epidemic diarrhea virus (PEDV). Our results revealed the prophylactic and therapeutic effects of 3D8 scFv against SARS-CoV-2 in Vero E6 cells. Immunoblot and plaque assays showed the reduction of coronavirus nucleoproteins and infectious particles respectively in 3D8 scFv-treated cells.

Conclusions

This data demonstrates the broad-spectrum antiviral activity of 3D8 against SARS-CoV-2 and other coronaviruses. Thus, it could be considered a potential antiviral countermeasure against SARS-CoV-2 and zoonotic coronaviruses.
Electron momentum density of hexagonal Zn studied by high-resolution Compton scattering
Authors: Brancewicz Marek , Andrejczuk Andrzej , Żukowski Eugeniusz , Dobrzyński Ludwik , Sakurai Yoshiharu , Itou Masayoshi , Pylak Maciej
Published: November 2020

High-resolution (0.12 a.u.) electron momentum density projections (Compton profiles) of a hexagonal Zn single crystal have been measured along five high-symmetry directions in reciprocal space. The experiment was performed with the use of 115.6 keV synchrotron radiation on the BL08W station at SPring-8. The quality of the measured Compton profiles is significantly better than that of previous medium- and high-resolution data. The experimental data were compared with the corresponding theoretical Korringa–Kohn–Rostoker (KKR) and density functional theory (DFT) calculations. Some minor and major differences between the two theoretical band-structure calculations have been observed. However, the good quality experimental results indicate their better agreement with DFT.
Benefits and challenges of developing an eco-social orientation: implications for marketing practice
Authors: Gabler Colin Bauer , Landers V. Myles , Richey R. Glenn
Published: November 2020

Purpose

Social and environmental actors have been added to the stakeholder balancing act required of organizations in today’s competitive marketplace. To address this, the firms may create orientations to convey their strategic priorities. The purpose of this paper is to explore how different levels of environmental orientation (EO) and social orientation (SO) influence firm outcomes. This paper leverages logic from the too-much-of-a-good-thing effect to predict that firms must strategically align their resources with performance goals to optimize these resources.

Design/methodology/approach

The paper outlines a step-by-step guide that combines latent moderated structural equation modeling with response surface analysis to estimate curvilinear relationships. The approach leverages the benefits of both techniques to produce precise results and more nuanced – and meaningful – implications.

Findings

The procedure is effective in uncovering a curvilinear relationship between the indicator variables. Specifically, firms optimize environmental performance when EO is higher than SO. The opposite is the case for the outcome of social value and manager trust. Economic performance is highest when both indicators are simultaneously high.

Research limitations/implications

This study tests the relationships between social and EOs and performance. As such, the exploratory data in this study are US-centric and self-assessment in design. These limitations open the door to confirmatory studies using objective outcome data and cross-cultural comparisons. Such studies should embrace more variables and examine potential moderating influences. Most importantly, future research should work to expand and verify the development of the eco-SO construct presented here, as the dynamics of these relationships have been overlooked in most social responsibility and sustainability research. Future studies should adopt this construct into extant models and also consider the dynamics and inter-organizational fit for partner firms with competing orientations.

Practical implications

For managers, the results show that conveying an environmental or social outcome has unique benefits to the firm. Further, there is an incentive to try and do both simultaneously. However, there is a critical point where the effects taper off, which can guide managers as they implement social and/or environmental strategies.

Social implications

The research questions ask if a company can simultaneously deliver: economic value to shareholders, environmental value to the planet and social value to consumers while maintaining the trust of its managers. The results generally support that to fully serve one group, a firm must underserve another.

Originality/value

The study introduces SO as a valid construct to mirror EO and then models their interaction in three-dimensional space to present an optimal firm strategy.
“Us” to co-create value and hate “them”: examining the interplay of consumer-brand identification, peer identification, value co-creation among consumers, competitor brand hate and individualism
Authors: Itani Omar S.
Published: November 2020

Purpose

The purpose of this paper is to understand the role of identity-based relationships, customer brand identification and peer identification, in driving customer outcomes including customer experiential hedonic value, social influence and repurchase intentions through the effects on value co-creation among customers and competitor brand hate, while taking into consideration the moderating impact of individualism.

Design/methodology/approach

The study integrates social identity theory, identity-based marketing perspective and self-construal theory to develop relationships. The data comprises a web-based survey of customers in the USA and was analyzed using structural equation modeling.

Findings

Customer brand identification and peer identification are drivers of value co-creation among customers, which leads to favorable outcomes at the customer and brand levels. Customer brand identification drives customers to hate competing brands, which, in turn, motivates customers to exert social influence in favor of their brand and to hold additional repurchase intentions. Customer brand identification and peer identification play different roles in motivating customers to co-create value with their fellows and drive customers to feel hatred toward competing brands contingent on customer individualism.

Research limitations/implications

Customer brand identification and peer identification play different roles in engaging customers in value co-creation with their peers and competing brands have with their rivals. Individualism self-construal holds a dual role when interacting with customer identification. The study fills multiple gaps in the literature by examining additional effects of customer brand identification and peer identification and exploring a relatively new dimension of the value co-creation process, as well as the role of customers in the competition between brands.

Practical implications

Brands need to view customers who identify with them as socially active customers capable of participating in value co-creation with other customers and engaging in the rivalry faced by the brands. Moreover, brands are required to build and nurture relationships that are based on social identification to encourage customer brand identification and peer identification which results in favorable customer and business outcomes.

Originality/value

This study examines the effects of two forms of customer identification on value co-creation between customers and competitor brand hate. In addition, it identifies the dual moderating role of customer individualism on the effects of both social identification forms. The study fills multiple gaps in the literature by understanding new aspects of customer identification, value co-creation and brand hate.
Demonstrating the motivational scale for commitments toward teachers’ turnover intentions using self-determination theory: a case of higher education institutions in Pakistan
Authors: Maryam Sayeda Zeenat , Ali Fouzia , Rizvi Mehvish , Farooq Sadia
Published: November 2020

Purpose

This paper aims to demonstrate the turnover intentions (TIs) among the academic faculty of higher education institutions (HEIs) in Pakistan through their motivation and commitment toward the concerned institution. It inspects the relationship of dimensions of motivation including an absence of motivation (AM), extrinsic motivation (ExM) and intrinsic motivation (InM) with the dimensions of commitment including affective commitment (AC), continuous commitment (CC) and normative commitment (NC) and finally the academic's TIs.

Design/methodology/approach

The paper used the self-determination theory (SDT), the theory of organizational commitment (OC) and the theory of planned behavior (TPB) for its proposed model. A sample of 500 academics, working under higher education commission recognized public and private universities in Punjab Pakistan. A structural equation modeling (SEM) conducted for analysis using an algorithm, bootstrapping and blindfolding techniques.

Findings

The outcomes of the research are attention-grabbing, as no direct relationship has been observed between the dimensions of motivation and TIs except InM. The dimensions of commitments are mediating the relationship between motivation and TIs with high significance value. The results reveal a significant adverse effect on TIs through two dimensions of commitment.

Research limitations/implications

As it is the case of a developing country like Pakistan therefore the finding cannot generalize to developed countries.

Practical implications

The findings of this research may lead the policymakers and practitioners of HEIs and controlling body to retain their competent teachers.

Social implications

This research can help the private sector to develop strategies about the retention of their competent teachers within the institutions that not just value the institution but also will be much beneficial for the students and society.

Originality/value

This paper is identifying how motivation is related to TIs and the role of commitment in it at HEIs. Still, no research has been conducted considering this avenue of SDT, OC and TPB
Micro, small and medium enterprises’ competitiveness and micro-takāfuladoption
Authors: Md Husin Maizaitulaidawati , Haron Razali
Published: November 2020

Purpose

This paper aims to attempt to first examine the competitiveness of micro, small and medium-sized enterprises (MSMEs) in the logistics industry; second, to identify the MSMEs’ perception towardstakāful(Islamic insurance); third, to recognise the challenges in the adoption oftakāful; and fourth, to suggest strategies to enhance the micro-takāfulpenetration rate.

Design/methodology/approach

The SWOT (strengths, weaknesses, opportunities and threats) analysis was used to measure the MSMEs’ competitiveness. Interview sessions were conducted with 13 owners of MSMEs in the logistics industry from the period November 2018 until January 2019 in Selangor, Malaysia.

Findings

The SWOT analysis identified several strengths (e.g. advanced infrastructure, rising number of new entrants and contribution to the local economy), weaknesses (e.g. lack of digital culture and training and a dearth of expertise), opportunities (e.g. supportive government initiatives and evolution of the mobile internet) and threats (e.g. changing customer expectations and limited financing facilities). The MSMEs’ perception towards micro-takāfuland challenges in the adoption oftakāfulwere also identified.

Research limitations/implications

This paper provides an understanding of the MSMEs’ perception towards micro-takāfulproducts, sheds light on the challenges faced by MSME owners in protecting their businesses from risk exposures and offers strategies to enhance the micro-takāfulpenetration rate. This study, however, is limited to Malaysia’s experience.

Practical implications

The identification of MSMEs’ SWOT will be useful for these businesses as it provides solid information that can be used to improve business performance while also seekingtakāfulprotection. This paper, other than serving as a guideline for stakeholders in the logistics industry to have a better understanding of their business environment, may also provide useful insights to practitioners and policymakers.

Originality/value

This paper integrates the SWOT analysis into a study on business risk exposure andtakāfulprotection from the MSMEs’ perspective. Hence, the findings could broaden available knowledge on MSMEs, especially for businesses in the logistics industry. The knowledge may also facilitate matters fortakāfuloperators interested in tapping into the market.