bluuebunny/crossref_metadata_2025 huggingface dataset:
A fifteen‐year review of skin allergy testing in Irish patients with symptomatic rhinitis
Authors: Nae Andreea , Hinchion K. , Keogh I.J.
Published: October 2020

Objective

Our objective was to review skin prick allergy testing (SPAT) results in patients with symptomatic rhinitis in an Irish population.

Methods

A fifteen‐year retrospective review of our database of symptomatic patients with rhinitis was performed. All patients who had SPAT performed during this interval were included. Data was analysed in terms of demographics and dominant allergens.

Results

1158 patients were included. 617 Females vs 541 Males. Age range five to eighty‐five years old. Mean age thirty‐four years. 49% of our patients tested positive to at least one aeroallergen. The most common allergens were dust mites (23%) and timothy grass (22%). Patients born during the Irish pollen season (April–July) were between 5 and 7 times more likely to be sensitive to timothy and ryegrass pollens compared to others tested. 241 patients had both SPAT and serum allergen specific IgE testing (SASIgET) performed; positive results were consistent between both groups.

Conclusion

Results demonstrated that half of our patients with symptomatic rhinitis had allergen sensitisation. Dust mites and grass were the main allergens in our area. Our nurse led clinic has allowed efficient patient education and the development of a unique Irish SPAT database. Retesting a patient with a known allergy test result it is not indicated.
Exploitable hosts used in cloud native cyber attacks
Authors: Morag Assaf
Published: October 2020

Can an in-depth analysis of elements from cyber attack campaigns teach us something new? The answer is yes. As we've seen all too often, crypto-mining campaigns often initiate a vicious circle that starts by infecting and exploiting the host to seek new targets and infect new victims with the same malware.

Can an in-depth analysis of elements from cyber attack campaigns teach us something new? The answer is yes.

Based on data from a honeypot, Assaf Morag of Aqua Security examines the mechanisms used to automatically infect a host with crypto-miners and then seek out new vulnerable hosts and infect them as well. He also analyses the IPs of the victims. The conclusions reveal an increasing number of vulnerable IPs and ever-greater sophistication by attackers.
How organisations can ethically negotiate ransomware payments
Authors: Hofmann Tom
Published: October 2020

By 2021, a new organisation will be falling victim to ransomware every 11 seconds. 1 However, ransomware figures have been skyrocketing since 2017 when the globe was hit by WannaCry and NotPetya. At that time, the term ‘ransomware’ entered common parlance and 54% of businesses were hit by these attacks.

Ransomware figures have been skyrocketing since 2017 when the globe was hit by WannaCry and NotPetya.

The onus lies on business leaders to make the ultimate decision – to pay or not to pay. Many leaders will take the high ground because they don't want to be seen negotiating with criminals. Yet other organisations have no option but to pay if they are to survive. Tom Hofmann of Flashpoint negotiates a way through this ethical minefield.
Data highway and the digital transformation: arguments for secure, centralised log management
Authors: Meyers Robert
Published: October 2020

Digital transformation happened all of a sudden, not with a gradual shift towards more sophisticated tools, but with a televised announcement from prime ministers and presidents across the globe asking organisations to do their part in containing the coronavirus outbreak. Almost overnight, companies found themselves having to adapt to a completely new mode of working. Some saw their remote workforce increasing exponentially, others had to swiftly make arrangements as they had previously always worked on-premise.
Moving from blocker to enabler: cloud security and the modern CISO
Authors: Subramanian Olivier
Published: October 2020

The role of the chief information security officer (CISO) is changing. It's an exciting time for many working in information security as the new world of public cloud comes to fruition and is driving an evolution. Yet this pace of change for some can feel unsettling, so it is not uncommon for CISOs and security teams to want to revert to older models and this has become more prevalent with the increasing shift to public cloud.

The role of the chief information security officer (CISO) is changing. It's an exciting time for many as the new world of public cloud comes to fruition.

But change often brings fear and anxiety, and it's not unusual for the IT security function to act as ‘blockers’. Yet with the right changes, modern CISOs can act as a springboard to demonstrate relevance and the importance of their role while shaping a more secure IT landscape, says Olivier Subramanian of Contino.
How to leverage data security in a post-Covid world
Authors: Babbs Andrea
Published: October 2020

Cyber security is often pushed down the list of priorities, and this was abundantly clear as businesses had to rush to get employees up and running for business continuity in recent months. Many already had some level of protection in place, but with a lasting switch to remote working and changing work habits and practices, there must be a refreshed emphasis on data security to protect employees, customers and businesses.

Cyber security is often pushed down the list of priorities and this became abundantly clear as businesses had to rush to get employees up and running when working from home in recent months.

With a lasting switch to remote working and changing work habits and practices, there must be a refreshed emphasis on data security. The new normal of hybrid workforces must have the correct layers of security that protect all types of employees. It's about increasing awareness and improving email culture, argues Andrea Babbs of Vipre Security.
Security controls in infrastructure as code
Authors: Almuairfi Sadiq , Alenezi Mamdouh
Published: October 2020

The development, deployment and management of software applications have shifted dramatically in the past 10 years. This fundamental shift is what we now know as development operations (DevOps). Infrastructure as Code (IaC) is one of the main tenets of DevOps. Previously, manual configuration via cloud providers’ UI consoles and physical hardware used to take place. But now, with the concept of IaC, the IT infrastructure can be automated by using blueprints that are easily readable by machines.
The Oscillatory Nature of Language
Authors: Murphy Elliot
Published: October 2020

Drawing on cutting-edge ideas from the biological and cognitive sciences, this book presents both an innovative neuro-computational model of language comprehension and a state-of-the-art review of current topics in neurolinguistics. It explores a range of newly-emerging topics in the biological study of language, building them into a framework which views language as grounded in endogenous neural oscillatory behaviour. This allows the author to formulate a number of hypotheses concerning the relationship between neurobiology and linguistic computation. Murphy also provides an extensive overview of recent theoretical and experimental work on the neurobiological basis of language, from which the reader will emerge up-to-date on major themes and debates. This lively overview of contemporary issues in theoretical linguistics, combined with a clear theory of how language is processed, is essential reading for scholars and students across a range of disciplines.
Trade Law and Supply Chain Regulation in a Post-COVID-19 World
Authors: Meyer Timothy
Published: October 2020

This Essay argues that trade agreements may overly constrain the ability of states to regulate supply chains for critical products such as medical supplies. Free trade agreements (FTAs) may exacerbate supply chain concentration, especially through loose rules of origin. And WTO rules constrain preventative regulation of supply chain risks designed to prevent a crisis, while providing exceptions for aggressive action only in the face of a crisis. Thus, WTO members risk flouting WTO rules if they do not limit aggressive, preventative supply chain regulation.
Factors associated with non-optimal resource utilization of air ambulance for interfacility transfer of injured patients
Authors: Quirion Andrew , Ahghari Mahvareh , Nolan Brodie
Published: October 2020

Objective

Timely access to definitive care is associated with improved outcomes in trauma patients. The goal of this study is to identify patient, institutional and paramedic risk factors for non-optimal resource utilization for interfacility transfers of injured adult patients transported by air ambulance to a LTC.

Methods

This is a retrospective cohort study of adult emergent interfacility transports via Ornge with data collected on patient demographics, clinical status, sending facilities, transport details and paramedic qualifications. A logistic regression model was used to analyze data.

Results

1777 injured patients undergoing transport with Ornge were analyzed with 805 of these undergoing non-optimal transport. Patients who had an optimal resource use were found to be older and mechanically ventilated. Risk factors increasing odds of non-optimal transport included patients transported from a nursing station (OR 1.94), transport with primary or advanced care paramedics (OR 6.57 and 1.44, respectively) and transport between both 0800-1700 and 1700-0000 (OR 1.40 and 1.54, respectively). The median delay to arrival to receiving facility if a patient had a non-optimal resource use was 40 minutes.

Conclusions

Three main risk factors were identified in this study. We believe that nursing stations as a sending facility and type of paramedics crew transporting patients resulted in non-optimal resource utilization primarily due to triage of lower acuity patients. However the timing of day is more likely to be a resource availability issue and something that can be further studied and potentially improved moving forward.
Automation risk and support for welfare policies: how does the threat of unemployment affect demanding active labour market policy support?
Authors: Im Zhen Jie
Published: October 2020

How does unemployment risk affect workers’ support for demanding active labour market policies (ALMPs)? There may be a substantial number of workers who experience unemployment risk from labour market disruptions. Yet, we know less about its impact on demanding ALMP support than the impact of unemployment status. Here, I explore the impact of unemployment risk through automation. Automation-threatened workers’ support for demanding ALMPs may be influenced by two opposing considerations that are linked to their potential reliance on welfare. First, they may worry about barriers to welfare access. Second, they may worry about welfare competition, especially under austerity. Their support for demanding ALMPs would hence depend on which consideration they find to be most salient. Based on the European Social Survey (2016) data on West European countries, I find that automation-threatened workers significantly support such policies. This may indicate that they find welfare competition concerns more salient than welfare access ones.
Computational Identification of Repeat-Containing Proteins and Systems
Authors: Altae-Tran Han , Gao Linyi , Strecker Jonathan , Macrae Rhiannon K. , Zhang Feng
Published: October 2020

Repetitive sequence elements in proteins and nucleic acids are often signatures of adaptive or reprogrammable systems in nature. Known examples of these systems, such as transcriptional activator-like effectors (TALE) and CRISPR, have been harnessed as powerful molecular tools with a wide range of applications including genome editing. The continued expansion of genomic sequence databases raises the possibility of prospectively identifying new such systems by computational mining. By leveraging sequence repeats as an organizing principle, here we develop a systematic genome mining approach to explore new types of naturally adaptive systems, five of which are discussed in greater detail. These results highlight the existence of a diverse range of intriguing systems in nature that remain to be explored and also provide a framework for future discovery efforts.
Translation, Print Media, and Image in Arab Modern Art
Authors: Gencer Yasemin
Published: October 2020

The anthology of primary sources presented in Modern Art in the Arab World reveals a wealth of ideas, attitudes, hopes, fears, and concerns surrounding the many facets of modernism and art. The essays therein provide first-hand accounts of developing art scenes from across the Arab world and their relationships to their audiences on local, national, transnational, and global scales. These documents, many of which have been translated from Arabic or French into English for the first time, offer individual, in situ insights into a broad range of issues pertaining to art in the twentieth century while furnishing readers with numerous threads that connect these geographies with changes through time. Four matters in particular – the centrality of translation, print media, art, and image management to modernization – permeate this anthology's content and will be explored further in the following essay.
THE SOCIAL NETWORKS OF INVESTMENT IN EARLY MODERN ENGLAND
Authors: SMITH EDMOND
Published: October 2020

The launch of the East India Company in 1599 relied on the engagement of an investing public. Despite this, little is known about how and why ordinary individual investors chose to invest in the corporation or what institutional frameworks supported them. While the later ‘financial revolution’ would radically alter the relationship between the state, investors, and financial organizations, this process does not adequately explain the earlier development of an investing public. Using a newly developed dataset of members’ familial, neighbourhood, civic, and business connections, this article reconstructs the social networks of East India Company investors in 1599. This analysis reveals that the company was formulated within an intensely interconnected investment environment – linkages that were used to distribute information and provide access to seemingly illiquid markets. Social networks played a key role in how people decided about where, when, with whom, and how much to invest during the expansion of investment opportunities in early modern England.
Finnish word order: Does comprehension matter?
Authors: Brattico Pauli
Published: October 2020

Finnish word order is relatively free, making room for all mathematically possible word orders in many constructions. Because there is no evidence in this language for radical nonconfigurationality, explanations must be sought from syntax. It is argued in this article that morphosyntax and word order represent syntactic structure at the PF-interface. Rich morphosyntax frees word order, poor morphosyntax freezes it. The hypothesis is formalized within the context of a parsing-oriented theory of the human language faculty (UG) combining left-to-right minimalism with the dynamic syntax approach. The analysis was implemented as an algorithm and successfully tested with a corpus of 119,800 unique Finnish word orders.
Embryo co-culture with bovine amniotic membrane stem cells can enhance the cryo-survival of IVF-derived bovine blastocysts comparable with co-culture with bovine oviduct epithelial cells
Authors: Nejat-Dehkordi Shayan , Ahmadi Ebrahim , Shirazi Abolfazl , Nazari Hassan , Shams-Esfandabadi Naser
Published: October 2020

Culture conditions have a profound effect on the quality of in vitro-produced embryos. Co-culturing embryos with somatic cells has some beneficial effects on embryonic development. Considering the ability of stem cells to secrete a broad range of growth factors with different biological activities, we hypothesized that bovine amniotic membrane stem cells (bAMSCs) might be superior to bovine oviduct epithelial cells (BOECs) in supporting embryonic development and enhancing their cryo-survival. Bovine abattoir-derived oocytes were matured and fertilized in vitro. The resultant presumptive zygotes were then cultured up to the blastocyst stage in the following groups: (i) co-culture with bAMSCs, (ii) co-culture with BOECs, and (iii) cell-free culture (Con). Embryos that reached the blastocyst stage were vitrified and warmed, and their post-warming re-expansion, survival and hatching rates were evaluated after 72 h culture. Results showed that the cleavage, blastocyst, and 2 h post-warming re-expansion rates of embryos did not differ between groups. However, their survival rates in BOEC and bAMSC groups were significantly higher compared with the control (72.7, 75.6 and 37.5%, respectively, P < 0.05). In conclusion, our results showed that the cryo-survivability of IVF-derived bovine embryos could be improved through co-culturing with bAMSCs. Moreover, considering the possibility to provide multiple passages from bAMSCs compared with BOECs, due to their stemness properties and their ability to produce growth factors, the use of bAMSCs is a good alternative to BOECs in embryo co-culture systems.
Governance in a Digital Age and Wuhan’s Fight against the Coronavirus
Authors: He Weihua
Published: October 2020

Shortly after hosting the Seventh CISM Military World Games, the city of Wuhan was hit by Covid-19, and thus became a centre of global attention. To protect the life and health of the people in Wuhan, China declared an all-out war to contain the virus. Using drastic measures that exacted high socio-economic costs, Wuhan was gradually restored to peace, vitality, and prosperity. In a city under lockdown, coordination, management, and governance at different levels were facilitated by information and communication technologies. This article examines the enhanced capabilities of individuals and institutions in a digital age to respond to crises, and the debates and ideological entanglements relating to the virus. It concludes with an anticipation of the ‘New Normal’ after the pandemic by responding to Giorgio Agamben’s views on the ‘state of exception’.
Biopolitical Practices in Beijing
Authors: Li Ming
Published: October 2020

The Covid-19 pandemic reminds people of the 1918 influenza pandemic which lasted for two years and which is estimated to have taken between 17 million to 50 million lives. The current Covid-19 pandemic, a force majeure, causing tension between states and the distancing of people physically, is steering the world into an unknown future. This article attempts to delineate the biopolitical practices in Beijing, from spring to summer, in the dimensions of the disciplinary supervision of government work, the allocation of medical resources, and the implementation of social control. Therein lies the mingling of sovereign power and biopower, conceptualized as a mutated pattern of ‘governmentality’. The public obedience to strict social control, an expression of the ‘general will’, originates from the conception of nationalism, underpinning the official narrative of ‘China’s experience’. Finally, a new pattern to handle the second outbreak, which started at Xinfadi market, has shed a new light on the thinking about ‘China’s path’.
Neurological manifestations in coronavirus disease 2019 (COVID-19) patients: a systematic review of literature
Authors: Ibrahim Wael
Published: October 2020

Background

The exact incidence of neurological complications from coronavirus disease 2019 (COVID-19) infection remains unknown. Neurological symptoms are more common with severe form of the disease. Through neuro-invasion, the virus can affect both neurons and glial cells and induce wide range of neurological pathologies.

Objectives

To systematically assess the neurological manifestations in patients diagnosed with COVID-19.

Methods

A systematic literature search of the PubMed, Scopus, and Cochrane databases was performed. Randomized controlled trials, nonrandomized controlled trials, observational studies of neurological manifestations in patients diagnosed with COVID-19.

Results

All three-database search identified 89 publications. A total of 22 full-text articles assessed for eligibility with 12 articles excluded. Altogether, the included studies reported 290 patients with neurological manifestations. Neurological manifestations were subdivided into central causes (CNS) and peripheral causes (PNS). CNS symptoms is commoner representing 91% of all neurological patients with 9% only with PNS. Headache represented the commonest neurological symptoms in regard to number of patients, meanwhile dizziness has the highest incidence with 11.9%. Neurological manifestations were divided according to COVID-19 severity into: (1) nonsevere and (2) severe; with all CNS manifestations were more in severe patients except headache were more in nonsevere patients. All included studies were on adult patients except one study in pediatric patients with limited number of participants.

Conclusions

From the descriptive analyses and available data of relatively small sample-sized studies, it can be concluded that in spite of the aforementioned limitations, that a wide spectrum of neurological manifestations including CNS and PNS can occur in COVID-19 patients.
Natural Law and the Chair of Ethics in the University of Naples, 1703–1769
Authors: Waldmann Felix
Published: October 2020

This articles focuses on a significant change to the curriculum in “ethics” (moral philosophy) in the University of Naples, superintended by Celestino Galiani, the rector of the university (1732–53), and Antonio Genovesi, Galiani's protégé and the university's professor of ethics (1746–54). The article contends that Galiani's and Genovesi's sympathies lay with the form of “modern natural law” pioneered by Hugo Grotius and his followers in Northern Europe. The transformation of curricular ethics in Protestant contexts had stemmed from an anxiety about its relevance in the face of moral skepticism. The article shows how this anxiety affected a Catholic context, and it responds to John Robertson's contention that Giambattista Vico's use of “sacred history” in hisScienza nuova(1725, revised 1730, 1744) typified a search among Catholics for an alternative to “scholastic natural law,” when the latter was found insufficiently to explain the sources of human sociability.
EXPLORING THE LANDSCAPE OF RELATIONAL SYLLOGISTIC LOGICS
Authors: KRUCKMAN ALEX , MOSS LAWRENCE S.
Published: October 2020

This paper explores relational syllogistic logics, a family of logical systems related to reasoning about relations in extensions of the classical syllogistic. These are all decidable logical systems. We prove completeness theorems and complexity results for a natural subfamily of relational syllogistic logics, parametrized by constructors for terms and for sentences.
How are Social Ties Protective?
Authors: Taylor Shelley E.
Published: October 2020

Social ties are the most important resource human beings have. Although other people can be difficult and challenging, they can also provide protection, solace, and social support, among other benefits. However, some relationships can be toxic and because these adverse conditions can be physiologically taxing, they can negatively affect both mental and physical health. Changes such as these can operate in large part through alterations in the sympathetic nervous system, the hypothalamic-pituitary-adrenal system, and the immune system. Much of the benefit of social support is perceptual and stems from the comfort of believing that supportive others can or will be there when times are stressful. The abilities to gain and perceive social support begin early in life and are heavily influenced by the climate of the family. Social support depends, in part, on reciprocity, yet many challenges to receiving support exist. Giving support to others has its own psychological and physiological benefits, although at intense levels, such as demanding caregiving responsibilities, these benefits dwindle. Moreover, social support needs change over time with changing circumstances. Public policy efforts to help people build and capitalize on their potential support networks is essential to maximize the impact of social ties on mental and physical health.
Injection‐Induced Earthquakes Near Milan, Kansas, Controlled by Karstic Networks
Authors: Joubert Charlène , Sohrabi Reza , Rubinstein Justin L. , Jansen Gunnar , Miller Stephen A.
Published: October 2020

Induced earthquakes from waste disposal operations in otherwise tectonically stable regions significantly increases seismic hazard. It remains unclear why injections induce large earthquakes on non‐optimally oriented faults kilometers below the injection horizon, particularly since fluids are not injected under pressure, but rather poured, into the well as observed in the Milan, Kansas area. Here we propose a mechanism for induced earthquakes whereby the karstic lower Arbuckle provides the short‐circuit that establishes a tens of MPa stepwise fluid pressure increase within the basement upon arrival of the hydraulic connection to the free surface and ultimately induce slip on the deeper fault. We investigate this scenario through modeling and mechanical analysis and show that earthquakes near Milan are likely induced by large (and sudden) fluid pressure changes when the karst network links two previously isolated hydrological systems.
Poleward Shift of Atmospheric Rivers in the Southern Hemisphere in Recent Decades
Authors: Ma Weiming , Chen Gang , Guan Bin
Published: October 2020

The atmospheric river (AR) frequency trends over the Southern Hemisphere are investigated using three reanalyses and two Community Earth System Model (CESM) ensembles. The results show that AR frequency has been increasing over the Southern Ocean and decreasing over lower latitudes in the past four decades and that ARs have been shifting poleward. While the observed trends are mostly driven by the poleward shift of the westerly jet, fully coupled CESM experiments indicate anthropogenic forcing would result in positive AR frequency trends over the Southern Ocean due mostly to moisture changes. The difference between the observed trends and anthropogenically driven trends can be largely reconciled by the atmosphere‐only CESM simulations forced by observed sea surface temperatures: Sea surface temperature variability characteristic of the negative phase of the Interdecadal Pacific Oscillation strongly suppresses the moisture‐driven trends while enhances the circulation‐induced trends over the Southern Ocean, thus bringing the simulated trends into closer agreement with the observed trends.
Stable Isotope Composition of Cyclone Mekunu Rainfall, Southern Oman
Authors: Müller Thomas , Friesen Jan , Weise Stephan M. , Al Abri Omar , Bait Said Ali Bakhit Ali , Michelsen Nils
Published: October 2020

Cyclone Mekunu hit the southern Arabian Peninsula in late May 2018 and brought rainfall amounts that accounted for up to 6 times the mean annual precipitation. Coming from the Arabian Sea, a quite underdocumented region with regard to cyclones, the storm eye crossed the Omani coast approximately 80 km east of the border to Yemen. Using automatic samplers, rainfall samples were collected during the event at three locations along a transect almost parallel to the storm track. The stable isotope analyses show a wide range of δ values, with minimum and maximum values of −17.01‰ δ18O and −1.77‰ δ18O and −122.2‰ δ2H and −1.6‰ δ2H. On average, rainfall becomes isotopically lighter with elevation, but rather irregularly. In view of high wind speeds probably precluding a gradual rainout of ascending air masses, a “pseudo elevation effect” seems likely. Our measurements expand the known δ value range of local cyclones by about 6‰ for δ18O and by nearly 50‰ for δ2H. The isotopic composition of the annual Indian Summer Monsoon shows values of −0.93‰ δ18O to 2.21‰ δ18O and −2.1‰ δ2H to 23.7‰ δ2H. Thus, there is a clear difference in the dual isotope signatures of the two precipitation systems in the area. Our findings enable an assessment of the impact of cyclones on the hydro(geo)logical system. For the arid Najd area, we demonstrate that the isotopic signatures of groundwater samples fall between those of cyclone and (paleo)monsoon precipitation, suggesting that several rainfall types may have contributed to replenishment.
CHIP-mediated CIB1 ubiquitination regulated epithelial–mesenchymal transition and tumor metastasis in lung adenocarcinoma
Authors: Liu Yuanqi , Zhou Yanwu , Zhang Pengfei , Li Xizhe , Duan Chaojun , Zhang Chunfang
Published: October 2020

CIB1 is a homolog of calmodulin that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in many tumor cells; however, its role in lung adenocarcinoma (LAC) has not been studied. In this study, the expression levels of CIB1 in LAC tissues and adjacent normal tissues were examined by immunohistochemistry, and the relationship between CIB1 expression and patient clinicopathological characteristics was analyzed. The effects of CIB1 on epithelial–mesenchymal transition (EMT), migration, and metastasis of LAC cells were determined in vitro and vivo. Proteins interacting with CIB1 were identified using electrospray mass spectrometry (LS-MS), and CHIP was selected in the following assays. Carboxyl-terminus of Hsp70-interacting protein (CHIP) is a ubiquitin E3 ligase. We show that CHIP can degrade CIB1 via promoting polyubiquitination of CIB1 and its subsequent proteasomal degradation. Besides, lysine residue 10 and 65 of CIB1 is the ubiquitinated site of CIB1. Furthermore, CHIP-mediated CIB1 downregulation is critical for the suppression of metastasis and migration of LAC. These results indicated that CHIP-mediated CIB1 ubiquitination could regulate epithelial–mesenchymal and tumor metastasis in LAC.
Consequences of Zmat3 loss in c-MYC- and mutant KRAS-driven tumorigenesis
Authors: Best Sarah A. , Vandenberg Cassandra J. , Abad Etna , Whitehead Lachlan , Guiu Laia , Ding Sheryl , Brennan Margs S. , Strasser Andreas , Herold Marco J. , Sutherland Kate D. , Janic Ana
Published: October 2020

TP53 is a critical tumor suppressor that is mutated in approximately 50% of human cancers. Unveiling the downstream target genes of TP53 that fulfill its tumor suppressor function is an area of intense investigation. Zmat3 (also known as Wig-1 or PAG608) is one such downstream target of p53, whose loss in hemopoietic stem cells lacking the apoptosis and cell cycle regulators, Puma and p21, respectively, promotes the development of leukemia. The function of Zmat3 in tumorigenesis however remains unclear. Here, to investigate which oncogenic drivers co-operate with Zmat3 loss to promote neoplastic transformation, we utilized Zmat3 knockout mice in models of c-MYC-driven lymphomagenesis and KrasG12D-driven lung adenocarcinoma development. Interestingly, unlike loss of p53, Zmat3 germline loss had little impact on the rate of tumor development or severity of malignant disease upon either the c-MYC or KrasG12D oncogenic activation. Furthermore, loss of Zmat3 failed to rescue KrasG12D primary lung tumor cells from oncogene-induced senescence. Taken together, we conclude that in the context of c-MYC-driven lymphomagenesis or mutant KrasG12D-driven lung adenocarcinoma development, additional co-occurring mutations are required to resolve Zmat3 tumor suppressive activity.
EVI1 phosphorylation at S436 regulates interactions with CtBP1 and DNMT3A and promotes self-renewal
Authors: Paredes Roberto , Kelly James R. , Geary Bethany , Almarzouq Batool , Schneider Marion , Pearson Stella , Narayanan Prakrithi , Williamson Andrew , Lovell Simon C. , Wiseman Daniel H. , Chadwick John A. , Jones Nigel J. , Kustikova Olga , Schambach Axel , Garner Terence , Amaral Fabio M. R. , Pierce Andrew , Stevens Adam , Somervaille Tim C. P. , Whetton Anthony D. , Meyer Stefan
Published: October 2020

The transcriptional regulator EVI1 has an essential role in early development and haematopoiesis. However, acute myeloid leukaemia (AML) driven by aberrantly high EVI1 expression has very poor prognosis. To investigate the effects of post-translational modifications on EVI1 function, we carried out a mass spectrometry (MS) analysis of EVI1 in AML and detected dynamic phosphorylation at serine 436 (S436). Wild-type EVI1 (EVI1-WT) with S436 available for phosphorylation, but not non-phosphorylatable EVI1-S436A, conferred haematopoietic progenitor cell self-renewal and was associated with significantly higher organised transcriptional patterns. In silico modelling of EVI1-S436 phosphorylation showed reduced affinity to CtBP1, and CtBP1 showed reduced interaction with EVI1-WT compared with EVI1-S436A. The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. These data point to EVI1-S436 phosphorylation directing functional protein interactions for haematopoietic self-renewal. Targeting EVI1-S436 phosphorylation may be of therapeutic benefit when treating EVI1-driven leukaemia.
Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode
Authors: Yan Wei , Cheng Lin , Wang Wei , Wu Chao , Yang Xin , Du Xiaozhe , Ma Liang , Qi Shiqian , Wei Yuquan , Lu Zhiliang , Yang Shengyong , Shao Zhenhua
Published: October 2020

Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.
Molecular motor-functionalized porphyrin macrocycles
Authors: Gilissen Pieter J. , White Paul B. , Berrocal José Augusto , Vanthuyne Nicolas , Rutjes Floris P. J. T. , Feringa Ben L. , Elemans Johannes A. A. W. , Nolte Roeland J. M.
Published: October 2020

Molecular motors and switches change conformation under the influence of an external stimulus, e.g. light. They can be incorporated into functional systems, allowing the construction of adaptive materials and switchable catalysts. Here, we present two molecular motor-functionalized porphyrin macrocycles for future photo-switchable catalysis. They display helical, planar and point chirality, and are diastereomers, which differ in the relative orientation of the motor and macrocyclic components. Fluorescence, UV-vis, and 1H NMR experiments reveal that the motor-functionalized macrocycles can bind and thread different variants of viologen guests, including a one-side blocked polymeric one of 30 repeat units. The latter feature indicates that the motor systems can find the open end of a polymer chain, thread on it, and move along the chain to eventually bind at the viologen trap, opening possibilities for catalytic writing on single polymer chains via chemical routes.
Exploring the synthetic biology potential of bacteriophages for engineering non-model bacteria
Authors: Lammens Eveline-Marie , Nikel Pablo Ivan , Lavigne Rob
Published: October 2020

Non-model bacteria like Pseudomonas putida, Lactococcus lactis and other species have unique and versatile metabolisms, offering unique opportunities for Synthetic Biology (SynBio). However, key genome editing and recombineering tools require optimization and large-scale multiplexing to unlock the full SynBio potential of these bacteria. In addition, the limited availability of a set of characterized, species-specific biological parts hampers the construction of reliable genetic circuitry. Mining of currently available, diverse bacteriophages could complete the SynBio toolbox, as they constitute an unexplored treasure trove for fully adapted metabolic modulators and orthogonally-functioning parts, driven by the longstanding co-evolution between phage and host.
The tomato receptor CuRe1 senses a cell wall protein to identify Cuscuta as a pathogen
Authors: Hegenauer Volker , Slaby Peter , Körner Max , Bruckmüller Julien-Alexander , Burggraf Ronja , Albert Isabell , Kaiser Bettina , Löffelhardt Birgit , Droste-Borel Irina , Sklenar Jan , Menke Frank L. H. , Maček Boris , Ranjan Aashish , Sinha Neelima , Nürnberger Thorsten , Felix Georg , Krause Kirsten , Stahl Mark , Albert Markus
Published: October 2020

Parasitic plants of the genus Cuscuta penetrate shoots of host plants with haustoria and build a connection to the host vasculature to exhaust water, solutes and carbohydrates. Such infections usually stay unrecognized by the host and lead to harmful host plant damage. Here, we show a molecular mechanism of how plants can sense parasitic Cuscuta. We isolated an 11 kDa protein of the parasite cell wall and identified it as a glycine-rich protein (GRP). This GRP, as well as its minimal peptide epitope Crip21, serve as a pathogen-associated molecular pattern and specifically bind and activate a membrane-bound immune receptor of tomato, the Cuscuta Receptor 1 (CuRe1), leading to defense responses in resistant hosts. These findings provide the initial steps to understand the resistance mechanisms against parasitic plants and further offer great potential for protecting crops by engineering resistance against parasitic plants.
Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
Authors: Choquet Caroline , Kelly Robert G. , Miquerol Lucile
Published: October 2020

The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.
Author Correction: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Authors: Vuong Wayne , Khan Muhammad Bashir , Fischer Conrad , Arutyunova Elena , Lamer Tess , Shields Justin , Saffran Holly A. , McKay Ryan T. , van Belkum Marco J. , Joyce Michael A. , Young Howard S. , Tyrrell D. Lorne , Vederas John C. , Lemieux M. Joanne
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
The essential inner membrane protein YejM is a metalloenzyme
Authors: Gabale Uma , Peña Palomino Perla Arianna , Kim HyunAh , Chen Wenya , Ressl Susanne
Published: October 2020

Recent recurrent outbreaks of Gram-negative bacteria show the critical need to target essential bacterial mechanisms to fight the increase of antibiotic resistance. Pathogenic Gram-negative bacteria have developed several strategies to protect themselves against the host immune response and antibiotics. One such strategy is to remodel the outer membrane where several genes are involved.yejMwas discovered as an essential gene inE. coliandS. typhimuriumthat plays a critical role in their virulence by changing the outer membrane permeability. How the inner membrane protein YejM with its periplasmic domain changes membrane properties remains unknown. Despite overwhelming structural similarity between the periplasmic domains of two YejM homologues with hydrolases like arylsulfatases, no enzymatic activity has been previously reported for YejM. Our studies reveal an intact active site with bound metal ions in the structure of YejM periplasmic domain. Furthermore, we show that YejM has a phosphatase activity that is dependent on the presence of magnesium ions and is linked to its function of regulating outer membrane properties. Understanding the molecular mechanism by which YejM is involved in outer membrane remodeling will help to identify a new drug target in the fight against the increased antibiotic resistance.
Accurate population estimation of Caprinae using camera traps and distance sampling
Authors: Harris Grant M. , Butler Matthew J. , Stewart David R. , Rominger Eric M. , Ruhl Caitlin Q.
Published: October 2020

With most of the world’sCaprinaetaxa threatened with extinction, the IUCN appeals to the development of simple and affordable sampling methods that will produce credible abundance and distribution data for helping conserve these species inhabiting remote areas. Traditional sampling approaches, like aerial sampling or mark-capture-recapture, can generate bias by failing to meet sampling assumptions, or by incurring too much cost and logistical burden for most projects to address them. Therefore, we met the IUCN’s challenge by testing a sampling technique that leverages imagery from camera traps with conventional distance sampling, validating its operability in mountainous topography by comparing results to known abundances. Our project occurred within a captive facility housing a wild population of desert bighorn sheep (Ovis canadensis) in the Chihuahuan desert of New Mexico, which is censused yearly. True abundance was always within our 90% confidence bounds, and the mean abundance estimates were within 4.9 individuals (average) of the census values. By demonstrating the veracity of this straightforward and inexpensive sampling method, we provide confidence in its operability, urging its use to fill conservation voids forCaprinaeand other data-deficient species inhabiting rugged or heavily vegetated terrain.
Author Correction: Helicobacter pylori eradication affects platelet count recovery in immune thrombocytopenia
Authors: Lee Ayoung , Hong Junshik , Chung Hyunsoo , Koh Youngil , Cho Soo-Jeong , Byun Ja Min , Kim Sang Gyun , Kim Inho
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Impact of low lethal concentrations of buprofezin on biological traits and expression profile of chitin synthase 1 gene (CHS1) in melon aphid, Aphis gossypii
Authors: Ullah Farman , Gul Hina , Yousaf Hafiz Kamran , Xiu Wang , Qian Ding , Gao Xiwu , Tariq Kaleem , Han Peng , Desneux Nicolas , Song Dunlun
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
LC–MS/MS and GC–MS profiling as well as the antimicrobial effect of leaves of selected Yucca species introduced to Egypt
Authors: El Sayed Abeer M. , Basam Samar M. , El-Naggar El-Moataz bellah A. , Marzouk Hanan S. , El-Hawary Seham
Published: October 2020

Few studies thoroughly investigated different Yucca species introduced to Egypt. As a part of our ongoing investigation of the Yucca species; Yucca aloifolia and its variety Yucca aloifolia variegata, Yucca filamentosa, and Yucca elephantipes (Asparagaceae) were extensively subjected to phytochemical and antimicrobial investigation. Yucca species cultivated in Egypt showed no antimicrobial effect. GC/MS of the lipoid contents of Y. aloifolia variegata was carried out. Twenty-six fatty acids were identified. Saturated fatty acids established almost twice the unsaturated ones and constituted 64.64% of which palmitic acid and palmitoleic acid signifying 58.28% and 30.98%, respectively. Hydrocarbons were 21 constituting 39.64% of the unsaponifiable fraction. Only three sterols 42.36% were detected, major was γ-sitosterol. LC–MS/MS comparison of the 4 plant extracts imply that Y.aloifolia variegata L extract was the richest, which was apparent through its superior biological activity. LC–MS/MS analysis of the total alcoholic extract (Alc) of the leaves of Y.aloifolia variegata L. was performed using MS-techniques at different voltages; equal to 35 and 135 eV. Negative and positive-ion modes analyses at low fragmentation energy allowed the tentative identification of 41 and 34 compounds, respectively. The LC–ESI–MS/MS analysis in the positive mode proved to be better in the identification of saponins.
CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats
Authors: Unoki Motoko , Sharif Jafar , Saito Yuichiro , Velasco Guillaume , Francastel Claire , Koseki Haruhiko , Sasaki Hiroyuki
Published: October 2020

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that is caused by mutations in either DNMT3B, ZBTB24, CDCA7, HELLS, or yet unidentified gene(s). Previously, we reported that the CDCA7/HELLS chromatin remodeling complex facilitates non-homologous end-joining. Here, we show that the same complex is required for the accumulation of proteins on nascent DNA, including the DNMT1/UHRF1 maintenance DNA methylation complex as well as proteins involved in the resolution or prevention of R-loops composed of DNA:RNA hybrids and ssDNA. Consistent with the hypomethylation state of pericentromeric repeats, the transcription and formation of aberrant DNA:RNA hybrids at the repeats were increased in ICF mutant cells. Furthermore, the ectopic expression of RNASEH1 reduced the accumulation of DNA damage at a broad range of genomic regions including pericentromeric repeats in these cells. Hence, we propose that hypomethylation due to inefficient DNMT1/UHRF1 recruitment at pericentromeric repeats by defects in the CDCA7/HELLS complex could induce pericentromeric instability, which may explain a part of the molecular pathogenesis of ICF syndrome.