bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission, tropism and biological impacts of torixRickettsiain the common bed bugCimex lectularius(Hemiptera: Cimicidae)
Authors: Thongprem Panupong , Evison Sophie EF , Hurst Gregory DD , Otti Oliver
Published: September 2020

The torix group ofRickettsiahave been recorded from a wide assemblage of invertebrates, but details of transmission and biological impacts on the host have rarely been established. The common bed bug(Cimex lectularius)is a hemipteran insect which lives as an obligatory hematophagous pest of humans and is host to a primaryWolbachiasymbiont and two facultative symbionts, a BEV-like symbiont, and a torix groupRickettsia. In this study, we first note the presence of a singleRickettsiastrain in multiple laboratory bed bug isolates derived from Europe and Africa. Importantly, we discovered that theRickettsiahas segregated in two laboratory strains, providing infected and uninfected isogenic lines for this study. Crosses with these lines established transmission was purely maternal, in contrast to previous studies of torix infections in planthoppers where paternal infection status was also important. Fluorescencein-situhybridization analysis indicatesRickettsiainfected in oocytes and bacteriomes, and other somatic tissues. There was no evidence thatRickettsiainfection was associated with sex ratio distortion activity, butRickettsiainfected individuals developed from first instar to adult more slowly. The impact ofRickettsiaon fecundity and fertility were investigated.Rickettsiainfected females produced fewer fertile eggs, but there was no evidence for cytoplasmic incompatibility. These data imply the existence of an unknown benefit toC. lectulariuscarryingRickettsiathat awaits further research.
Ligand Modulation of the Conformational Dynamics of the A2AAdenosine Receptor Revealed by Single-Molecule Fluorescence
Authors: Fernandes Dennis D. , Neale Chris , Gomes Gregory-Neal W. , Li Yuchong , Malik Aimen , Pandey Aditya , Orazietti Alexander , Wang Xudong , Ye Libin , Prosser R. Scott , Gradinaru Claudiu C.
Published: September 2020

G protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an important target for therapeutics. Activation of these receptors is modulated by orthosteric ligands, which stabilize one or several states within a complex conformational ensemble. The intra-and inter-state dynamics, however, is not well documented. Here, we used single-molecule fluorescence to measure ligand-modulated conformational dynamics of the adenosine A2AReceptor (A2AR) on nanosecond to millisecond timescales. Experiments were performed on detergent-purified A2R in either the ligand-free (apo) state, or when bound to an inverse, partial or full agonist ligand. Single-molecule Förster resonance energy transfer (smFRET) was performed on detergent-solubilized A2AR to resolve active and inactive states via the separation between transmembrane (TM) helices 4 and 6. The ligand-dependent changes of the smFRET distributions are consistent with conformational selection and with inter-state exchange lifetimes ≥ 3 ms. Local conformational dynamics around residue 229 on TM6 was measured using Fluorescence Correlation Spectroscopy (FCS), which captures dynamic quenching due to photoinduced electron transfer (PET) between a covalently-attached dye and proximal aromatic residues. Global analysis of PET-FCS data revealedfast(150-350 ns),intermediate(50-60 μs) andslow(200-300 μs) conformational dynamics in A2AR, with lifetimes and amplitudes modulated by ligands and a G-protein mimetic (mini-Gs). Most notably, the agonist binding and the coupling to mini-Gsaccelerates and increases the relative contribution of the sub-microsecond phase. Molecular dynamics simulations identified three tyrosine residues (Y112, Y288, and Y290) as being responsible for the dynamic quenching observed by PET-FCS and revealed associated helical motions around residue 229 on TM6. This study provides a quantitative description of conformational dynamics in A2AR and supports the idea that ligands bias not only GPCR conformations but also the dynamics within and between distinct conformational states of the receptor.
Inhibitory synaptic vesicles have unique dynamics and exocytosis properties
Authors: Park Chungwon , Chen Xingxiang , Tian Chong-Li , Park Gyu Nam , Chenouard Nicolas , Lee Hunki , Yeo Xin Yi , Jung Sangyong , Bi Guoqiang , Tsien Richard W. , Park Hyokeun
Published: September 2020

Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system, with inhibitory synaptic transmission playing an important role. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and exocytosis of single inhibitory vesicles have not been investigated, due largely to both technical and practical limitations. Using a combination of quantum dots (QDs) conjugated to antibodies against the luminal domain of the vesicular GABA transporter (VGAT) to selectively label GABAergic (i.e., inhibitory) vesicles together with dual-focus imaging optics, we tracked the real-time three-dimensional position of single inhibitory vesicles up to the moment of exocytosis (i.e., fusion). Using three-dimensional trajectories, we found that inhibitory synaptic vesicles traveled a short distance prior to fusion and had a shorter time to fusion compared to synaptotagmin-1 (Syt1)-labeled vesicles, which were mostly from excitatory neurons. Moreover, our analysis revealed a close correlation between the release probability of inhibitory vesicles and both the proximity to their fusion site and the total travel length. Finally, we found that inhibitory vesicles have a higher prevalence of kiss-and-run fusion compared than Syt1-labeled vesicles. These results indicate that inhibitory synaptic vesicles have a unique set of dynamics and fusion properties to support rapid synaptic inhibition, thereby maintaining a tightly regulated balance between excitation and inhibition in the central nervous system.

Significance

Despite playing an important role in maintaining brain function, the dynamics of inhibitory synaptic vesicles are poorly understood. Here, we tracked the three-dimensional position of single inhibitory vesicles up to the moment of exocytosis in real time by loading single inhibitory vesicle with QDs-conjugated to antibodies against the luminal domain of the vesicular GABA transporter (VGAT). We found that inhibitory synaptic vesicles have a smaller total travel length before fusion, a shorter fusion time, and a higher prevalence of kiss-and-run than synaptotagmin-1-lableled vesicles. Our findings provide the first evidence that inhibitory vesicles have a unique set of dynamics and exocytosis properties to support rapid inhibitory synaptic transmission.
Interaction of replication factor Sld3 and histone acetyl transferase Esa1 alleviates gene silencing and promotes the activation of late and dormant replication origins
Authors: Tanaka Seiji
Published: September 2020

DNA replication in eukaryotes is a multi-step process that consists of three main reactions: helicase loading (licensing), helicase activation (firing), and nascent DNA synthesis (elongation). Although the contributions of some chromatin regulatory factors in the licensing and elongation reaction have been determined, their functions in the firing reaction remain elusive. In the budding yeastSaccharomyces cerevisiae, Sld3, Sld7, and Cdc45 (3-7-45) are rate-limiting in the firing reaction and simultaneous overexpression of 3-7-45 causes untimely activation of late and dormant replication origins. Here we found that 3-7-45 overexpression not only activated dormant origins in the silenced locus,HMLα, but also exerted an anti-silencing effect at this locus. For these, interaction between Sld3 and Esa1, a conserved histone acetyltransferase, was responsible. Moreover, the Sld3–Esa1 interaction was required for untimely activation of late origins. These results reveal the Sld3–Esa1 interaction as a novel level of regulation in the firing reaction.
Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism
Authors: Bertoni Alessandra , Schaller Fabienne , Tyzio Roman , Gaillard Stephane , Santini Francesca , Xolin Marion , Diabira Diabé , Vaidyanathan Radhika , Matarazzo Valery , Medina Igor , Hammock Elizabeth , Zhang Jinwei , Chini Bice , Gaiarsa Jean-Luc , Muscatelli Françoise
Published: September 2020

Oxytocin is a master regulator of the social brain. In some animal models of autism, notably inMagel2tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms focusing on social memory performance.

We showed thatMagel2tm1.1Mus-deficient mice present a deficit in social memory and studied the hippocampal circuits underlying this memory. We showed a co-expression ofMagel2andoxytocin-receptorin the dentate gyrus and CA2/CA3 hippocampal regions. Then, we demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin-receptors and of somatostatin interneurons. We also revealed a delay in the GABAergic development sequence inMagel2tm1.1Mus-deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring neuronal alterations and social memory.

Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin-administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.
HRM as a catalyst for innovation in start‐ups
Authors: Jebali Dorra , Meschitti Viviana
Published: September 2020

Purpose

The study seeks to reduce the blurriness remaining around the value that HRM can bring to innovation in the specific context of start‐ups, it advocates that the early adoption of appropriate HRM practices, can act as a catalyst for innovation because they constitute a powerful means to systematically promote and facilitate employees' innovative behaviours.

Design/methodology/approach

In the aim of complementing the existing quantitative work, this paper employs a multiple case study approach to explore the role of HRM in fostering employees' innovative work behaviour in four Tunisian tech companies.

Findings

The study found substantial support for the importance of establishing a work environment for learning where employees can build their innovative capacities by upgrading their knowledge and skills through both formal and informal methods. Work autonomy and freedom are found to be essential parts of this environment. Workspace design that takes into account employees' comfort and the collaborative nature of their work, also stands out as a major contributor to innovative work behaviour.

Originality/value

The adopted qualitative approach enabled a grasp of the less apparent aspects underpinning the HRM and innovation relationship in start‐ups. “Ownership of space” is revealed as a key element of the innovation-supportive work environment. By having a feeling of control on the workspace, employees can develop a sense of ownership towards the organisation which enhances their eagerness to exert innovation efforts. It also demonstrated that developing an overly creative workforce can turn into a source of stagnation which can be mitigated by cultivating “an environment for idea ownership”.
Prevalence and association of discrimination and bullying and the impact on mental health in an occupational setting
Authors: Stratton Elizabeth , Player Michael J. , Dahlheimer Ariane , Choi Isabella , Glozier Nicholas
Published: September 2020

Purpose

Discrimination and bullying contribute to mental ill-health in the workplace. At face value, they would seem linked but are often dealt with by different legislations. Workplace studies generally focus on bullying and population studies on discrimination. The authors aimed to evaluate the prevalence and relationship of discrimination and bullying in a male-dominated workforce, associated factors and relative impact on mental ill-health.

Design/methodology/approach

An online cohort survey was conducted amongst employees of an Australian mining company, measuring discrimination, bullying, demographics and workplace and health factors over two months. Cross-sectional and prospective analyses assessed the prevalence of each, their association and their effects on depression and anxiety.

Findings

A total of 580 employees (82% male) participated. There was no association between workplace bullying (n = 56, 9.7%) and discrimination (n = 160, 27.6%). Discrimination, but not bullying, was associated with higher depression, anxiety and suicidal ideation and lower well-being and resilience. After controlling for demographic, workplace and health and well-being factors, depression had the main effect on discrimination ß = 0.39, p = 0.003. Discrimination predicted an increase in depression scores at follow-up F (1, 129) = 4.88, p = 0.029.

Originality/value

In this male-dominated industry, discrimination was more prevalent than bullying. Discrimination, but not bullying, was associated with poorer mental health both cross sectionally and prospectively. Supporting the need to assess and manage discrimination and bullying in the workplace independently and the need for interventions to reduce a broader range of adverse interpersonal behaviours.
Event study methodology in business research: a bibliometric analysis
Authors: Wang Qian , Ngai Eric W.T.
Published: September 2020

Purpose

This study aims to provide an objective analysis of the state-of-the-art and intellectual development of publications related to event study methodology in business research.

Design/methodology/approach

The sample includes 1,219 papers related to event study methodology, covering all business disciplines and spanning 34 years from 1983 to 2016.

Findings

Through three stages of primary analysis, namely, initial sample, citation and co-citation analyses, the authors identified the publication trends, supplementary techniques, influential publications and intellectual clusters in the area of event study methodology in business.

Research limitations/implications

The findings serve as a benchmark for the extensive literature related to event study methodology in business and may facilitate the transference of the amassed useful techniques among disciplines and the identification of future research directions.

Originality/value

The current study represents as a pioneering effort to review event study-related publications using bibliometric analysis.
Does a salary premium exist for offensive output in Major League Baseball?
Authors: Ehrlich Justin , Perline Justin , Potter Joel , Sanders Shane
Published: September 2020

Purpose

In baseball, a run scored on offense carries the same on-field (win) value as does a run prevented on defense. Both outcomes bear the same score margin implication. This presumption of unit equality is implicit in the Wins Above Replacement (WAR) measure, which treats units of offensive WAR (oWAR) and units of defensive WAR (dWAR) as perfectly substitutable toward win production. The purpose of this paper is to ask whether the salaries of Major League Baseball (MLB) players reveal such an equal valuation among MLB teams.

Design/methodology/approach

The authors examine the relationship between offensive output, defensive output and subsequent salary from free agency in MLB using a set of log-linear OLS, fixed effects regression specifications.

Findings

In general, estimated annual salary from free agency increases significantly and substantially with unit increases in a player's (prior season) wins above replacement WAR. Across specifications, the authors estimate a 42.5–43.4% increase in salary for year t for each additional unit of WAR in yeart−1. The authors disaggregate WAR into offensive and defensive components (oWAR and dWAR) and estimate a 52.4–53.3 (4.8–7.2)% increase in salary for each additional unit of oWAR (dWAR).

Originality/value

The efficiency of the baseball labor market has been studied previously with mixed results. The novelty of the present study is its treatment of inputs not as positions or individual players but as the underlying offensive and defensive win production of players. The authors estimate free agency salary returns to (contract season) oWAR and dWAR in MLB to establish whether (to what extent) a salary premium for offensive output exists within MLB.
Are Patagonia grasslands being overgrazed? A response to Marino et al. (2020)
Authors: Oliva Gabriel , Paredes Paula , Ferrante Daniela , Cepeda Carla , Rabinovich Jorge
Published: September 2020

Based upon primary productivity estimates, Oliva et al. (2019) concluded that, at the end of last century and after long periods of overgrazing, Patagonia's domestic stocks adjusted to regional‐scale herbivore carrying capacity. Populations of guanaco, a native camelid, increased thereafter, driving combined grazing pressures once again over carrying capacity in some areas.

Marino et al. (2020) argued that grazing is not really at equilibrium because domestic stocks are concentrated in areas that remain overgrazed. They support the ideas that guanaco density is auto‐regulated by resource‐defence territoriality, and that guanacos are weak competitors with domestic stock, occupying only marginal areas. In their view, Oliva et al. (2019) put guanacos in the role of scapegoats, leaving domestic stocks unchecked.

Equilibrium at regional scale does not preclude overgrazing and under‐grazing at local scales. By separating areas with and without domestic stocks, Marino et al. (2020) estimated overgrazing at 28% in Chubut Province and 73% in Santa Cruz Province. Our recalculations show 28% and 47% domestic overgrazing, respectively. However, when combined with guanaco densities, these increase to 48% for Chubut and 108% for Santa Cruz.

We question the hypothesised lack of competitive value and efficient self‐regulating mechanisms that would prevent guanaco populations from overshooting carrying capacity. A dataset of 13 sheep farms showed mean density of 26 ± 3.8 guanacos/km2 and high combined grazing pressures. This was also observed in a protected area of Chubut that reached 42 guanacos/km2 and crashed during drought, with 60% mortality. Thereafter, guanacos increased to 70 guanacos/km2, with recruitment rates that showed a complex response of density dependence but remained relatively elevated at densities above the estimated carrying capacity.

Synthesis and applications. Marino et al. (2020) are right to question the apparent equilibrium of domestic stocks that are concentrated in areas that may be still overgrazed. But ground data show that guanaco populations have inefficient density population regulation and can reach densities well over carrying capacity, even in the presence of sheep. This does not mean that the main control should be on growing guanaco populations but it stresses our conclusion that joint management of the native‐domestic herbivore system is urgently needed. Joint management can be effected through local plans, as current guanaco management permits can only be issued in areas that are not overgrazed by sheep. Farm management plans may in this way transform an apparent competitor into a valuable resource, complementary to sheep raising.
Jung and the spirit: a review of Jung’s discussions of the phenomenon of spirit
Authors: Gitz‐Johansen Thomas
Published: September 2020

The phenomenon of spirit is a topic discussed frequently by Jung throughout his writings although spirit is not always considered to be central to the practice of analytical psychology. This article points to the importance of spirit in analytical psychology by presenting a survey of Jung’s discussions of spirit. In Jung’s discussions, spirit is not treated as an abstract concept but as an empirical phenomenon: to Jung, spirit is a psychological reality that can be described and whose effects can be experienced. Spirit is both described as an archetype and as a component of all archetypes. Spirit is related to the principle of life itself and is a prerequisite of both personal and cultural development and transformation. The article documents how Jung’s understanding of spirit developed over time and in relation to different topics: Freud’s psychoanalysis, the Red Book, fairy‐tales, Christianity, Nietzsche’s book on Zarathustra, Germany in the 1930’s, alchemy, and creative work. The paper concludes with a discussion of the relevance of spirit to clinical practice.
Photographic comparison of surface topography as a viable solution when physical match is challenging
Authors: Finkelstein Nir S. , Levy Ophir , Levi Aviad
Published: September 2020

Physical matching methods are a family of well‐known methods that are utilized in order to determine whether two pieces of a tearable/breakable material used to be one object. When performing physical match of polymers, it is sometimes difficult to reach an unambiguous conclusion. This is due to various reasons. One is when the tear/fracture resides in an inaccessible or hidden‐from‐view region of the piece. Another is when the shape of the tear/fracture at the object's tear/fracture line is insufficient for deducing a complete match. Third is deficiency of material along this line. These are examples of processes where the line is affected so drastically, so that a match renders impossible. Specifically, when addressing elastic materials, the tear/fracture line may even be squashed. This may also be a reason for difficulty in performing a physical match. In this paper, a method is proposed where a match is alternatively achieved by means of photographic comparison of marks on the surface topography of the pieces‐in‐question. Comparisons of pairs of torn pieces of silicon rubber were made. The procedure involved photography of the surface topography the pieces. Then, the photographs were horizontally mirror‐flipped. Lastly, a comparison was made between two photographs: a photograph of one piece and a mirror‐flipped photograph of the opposite piece. The results show that after comparing the pieces to one another, only one unique pair turned out to be positively matched. Using the proposed method, not only the comparison is done by a more informative method (comparing to physical match), it is also more convenient, faster, less expensive, and technically simpler.
Smoke and Mirrors? Disclosures in the Marijuana Industry in Canada
Authors: Mangen Claudine , Paduano Alexia , Paduano Bianca , Hadzurik Jessica , Leggio Juliano , Russo Kayla
Published: September 2020

Licensed producers (LPs) of marijuana in Canada are embedded in a highly competitive industry where they raise funds from investors to finance their growth. They face substantial risks from the uncertain legal status of marijuana and from its unsettled health and safety consequences. We argue that this context stands to have implications for the disclosures of firms in the marijuana industry. We rely on a multicase study of three large Canadian LPs to explore their mandatory and voluntary disclosures during the third quarter of 2018. We find that their mandatory interim disclosures are largely consistent with disclosure rules that target marijuana operations. We also find that they make voluntary disclosures relevant for their context (e.g., about risks from legal, health, and safety consequences), and that there is variation in these disclosures. We use our findings as a springboard for discussing the antecedents of mandatory and voluntary disclosures in the marijuana industry (i.e., proprietary costs, investor interest, detection costs of selective disclosures), and their consequence (i.e., lack of comparability). We offer suggestions for future research.
Advancing Sustainability Reporting in Canada: 2019 Report on Progress
Authors: Cho Charles H. , Bohr Kathrin , Choi Tony Jaehyun , Partridge Katharine , Shah Jhankrut Mukesh , Swierszcz Ada
Published: September 2020

This study examines the progress Canada's largest companies are making in their environmental, social, and governance (ESG) disclosures. Given the introduction of the Global Reporting Initiative (GRI) Standards and the United Nations Sustainable Development Goals (UN SDGs) as well as the issuance of the Task Force on Climate‐Related Financial Disclosures (TCFD) recommendations, our research reflects the uptake of these guidance documents by both mature and new reporters. Our analysis suggests that challenges persist—processes and progress often fail to reach investors as they are “lost in translation” when issued through third‐party ESG information providers, and reporters are also pressured to respond to a myriad of requests for information from rating and reporting agencies. Nevertheless, we note that Canada has new reporting sectors that must mature to survive the scrutiny of the markets and also hope that stock markets will respond to the recent announcement by the 181 CEOs of the U.S. Business Roundtable, who committed to lead their companies for the benefit of all stakeholders—customers, employees, suppliers, communities, and shareholders. Overall, we believe that our research will provide food for thought for companies interested in continuous improvement.
Cellular senescence as a potential mediator of COVID‐19 severity in the elderly
Authors: Nehme Jamil , Borghesan Michela , Mackedenski Sebastian , Bird Thomas G. , Demaria Marco
Published: September 2020

SARS‐CoV‐2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID‐19), a complex respiratory distress syndrome. Epidemiological data show that COVID‐19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS‐CoV‐2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long‐term disease. Here, we discuss how cellular senescence—a state of stable growth arrest characterized by pro‐inflammatory and pro‐disease functions—can hypothetically be a contributor to COVID‐19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID‐19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS‐CoV‐2‐mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi‐tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy. Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID‐19 severity, and targeting senescence‐associated mechanisms prior and after SARS‐CoV‐2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.
Perceived Control Buffers the Effects of the COVID‐19 Pandemic on General Health and Life Satisfaction: The Mediating Role of Psychological Distance
Authors: Zheng Lei , Miao Miao , Gan Yiqun
Published: September 2020

Background

Ways to maintain good health during a pandemic are very important for the general population; however, little is known about the impact of the coronavirus disease 2019 (COVID‐19) on individuals’ life satisfaction and perceived general health. This study aimed to examine the effects of COVID‐19 on life satisfaction and perceived general health and reveal the buffering effect of perceived control on coping with COVID‐19.

Methods

We collected 1,847 participants’ data from 31 pandemic‐affected provinces in China and obtained regional epidemic data of the same provinces. We employed a moderated mediation model with both individuals’ self‐report data and regional epidemic data to verify the hypotheses.

Results

Psychological distance mediated the relationships of regional pandemic severity with perceived general health and life satisfaction. Perceived control moderated the detrimental effects of regional pandemic severity through the moderating effects of regional pandemic severity on psychological distance, as well as the moderating effects of psychological distance on life satisfaction.

Conclusions

Our findings indicate that perceived control may act as a protective factor buffering the psychological impact of the pandemic on general health and life satisfaction. Psychological distance can serve as a mediator that explains how the COVID‐19 pandemic impacts perceived general health and life satisfaction.
Systematic review with meta‐analysis: abnormalities in the international normalised ratio do not correlate with periprocedural bleeding events among patients with cirrhosis
Authors: Kovalic Alexander J. , Majeed Chaudry Nasir , Samji Naga Swetha , Thuluvath Paul J. , Satapathy Sanjaya K.
Published: September 2020

Background

Cirrhotic coagulopathy is a delicate interplay comprising deficiencies of both procoagulant and anticoagulant factors.

Aim

To identify the relationship between international normalised ratio [INR] with periprocedural bleeding risk among patients with cirrhosis.

Methods

Following a thorough database search of the primary literature, 29 studies were targeted for analysis, including 13 276 patients with cirrhosis undergoing indicated procedures.

Results

There was no significant association between periprocedural bleeding events and pre‐procedural INR [pooled odds ratio 1.52; 95% CI 0.99, 2.33; P = 0.06]. Furthermore, there was no significant difference in mean INR [pooled mean difference 0.05; 95% CI −0.03, 0.13; P = 0.23] upon comparison of patients who either did or did not experience a periprocedural bleeding event. Significant heterogeneity among some studies was primarily fuelled by significant subgroup effects of both specific procedure types performed. Additionally, there were markedly inconsistent transfusion practices across studies.

Conclusions

INR fails to serve as a significant correlate for periprocedural bleeding events among patients with cirrhosis. Ideally, these new findings will help serve as a springboard for future studies, as well as to minimize transfusion of blood products, which command a myriad of adverse effects among patients with cirrhosis.
European research networks to facilitate drug research in children
Authors: Turner Mark A. , Cheng Katharine , de Wildt Saskia , Hildebrand Heidrun , Attar Sabah , Rossi Paolo , Bonifazi Donato , Ceci Adriana , Claverol Joana , Nafria Begonya , Giaquinto Carlo
Published: September 2020

Paediatric drug development faces several barriers. These include fragmentation of stakeholders and inconsistent processes during the conduct of research. This review summarises recent efforts to overcome these barriers in Europe. Two exemplar initiatives are described. The European Paediatric Translational Research Infrastructure facilitates preclinical research and other work that underpins clinical trials. conect4children facilitates the design and implementation of clinical trials. Both these initiatives listen to the voices of children and their advocates. Coordination of research needs specific effort that supplements work on science, resources and the policy context.
The roles of carbonic anhydrases IX and XII in cancer cell adhesion, migration, invasion and metastasis
Authors: Daunys Simonas , Petrikaitė Vilma
Published: September 2020

The main function of carbonic anhydrases (CAs) in cancer cells is the pH regulation through a conversion of H2O and CO2 to H+ and HCO3−. However, the data of in vitro and in vivo studies have demonstrated that transmembrane isoforms of CA IX and CA XII are involved in various steps of cancer cell migration, invasion and metastasis. According to literature, inhibition of these CAs can affect the expression of multiple proteins. Some scientific groups have reported the possible interactions between CA IX and E‐cadherin–catenin system, CA IX and integrins, CA IX, CA XII and ion transporters, which all are highly involved in cell‐to‐cell adhesion, the formation of membrane protrusions and focal adhesions. Nevertheless, CA IX and CA XII have a high impact on tumour growth and metastases formation. The data discussed in this review are quite recent. It highly support the role of CA IX and CA XII in various cancer metastasis processes through their interactions to other invasion proteins. Nevertheless, all findings show the great potential of these CAs in the context of research and application in clinical use.
Formyl peptide receptor type 2 agonists to kick‐start resolution pharmacology
Authors: Perretti Mauro , Godson Catherine
Published: September 2020

One way to develop innovative approaches for the treatment of chronic diseases is to exploit the biology of the resolution of inflammation. With this terminology, we identify the integrated and complex network of mediators and pathways that ensure a timely and spatially regulated inflammatory response. Pro‐resolving mediators act on specific receptors. This provides an opportunity for developing a new arm of pharmacology we have termed “resolution pharmacology.” Here we present the reasoning behind the need to develop new medicines based on resolution and use a prototype GPCR as an example. Understanding how the formyl peptide receptor type 2 (FPR2) operates in a cell‐specific manner can guide the development of agonists as new therapeutics that could be of benefit as a therapy or co‐therapy for several diseases that affect our society. FPR2 agonists would be among the first drugs to establish “resolution pharmacology” as the pharmacological approach for the third decade of the millennium.
A 6 Ma record of palaeodenudation in the central Himalayas from in situ cosmogenic 10Be in the Surai section
Authors: Charreau Julien , Lavé Jérôme , France‐Lanord Christian , Puchol Nicolas , Blard Pierre‐Henri , Pik Raphaël , Gajurel Ananta Prasad ,   ASTER Team
Published: September 2020

To better constrain late Neogene denudation of the Himalayas, we analysed in situ 10Be concentrations in 17 Neogene sediment samples of the Surai section (central Nepal) and two modern sediment samples of the Rapti River. We first refined the depositional ages of the Surai section from 36 new paleomagnetic analyses, five 26Al/10Be burial ages, and, based on the Dynamic Time Warping algorithm, 104 automatically calculated likely magnetostratigraphic correlations. We also traced changing sediment sources using major element and Sr‐Nd isotopic data, finding at 4–3 Ma a switch from a large, trans‐Himalayan river to a river draining only the Lesser Himalaya and Siwalik piedmont, increasing the contribution of recycled sediments at that time. 10Be concentrations in Neogene sediments range from (1.00 ± 0.36) to (5.22 ± 0.98) × 103 at g–1 and decrease with stratigraphic age. Based on a flood plain transport model, our refined age model, and assuming a drainage change at 4–3 Ma, we reconstructed 10Be concentrations at the time of deposition. Assuming cosmogenic production rates similar to those of the modern basins, we calculated palaeodenudation rates of 0.9 ± 0.5 to 3.9 ± 2.7 mm a–1 from ca. 6 to 3 Ma in the palaeo‐Karnali basin and 0.6 ± 0.2 to 1.6 ± 0.8 mm a–1 since ca. 3 Ma in the palaeo‐Rapti basin. Given the uncertainties and similar modern values of ~2 mm a–1, the palaeo‐Karnali denudation rates may have been steady at ~1.7 ± 0.3 mm a–1 for the last ca. 6 Ma. A transient acceleration of the denudation in the palaeo‐Rapti basin of ~1.5 mm a–1 since ca. 1.5 Ma was likely due to the reworking of older, 10Be‐depleted Siwalik sediments in the foreland. If true, this steadiness of the denudation rates may suggest that Quaternary glaciations did not largely affect Himalayan denudation.
Reconstructing the level of the central Red Sea evaporites at the end of the Miocene
Authors: Mitchell Neil C. , Shi Wen , Izzeldin A.Y. , Stewart Ian C. F.
Published: September 2020

Reconstructing the original depositional level of the Mesozoic and older c‘salt giants’ can reveal if their basins became filled to global sea level, but is complicated by dissolution, diapirism and because the time elapsed is so great. This is less of a problem in the Red Sea, a young rift basin that is transitioning to an ocean basin and where the evaporites away from coastal fringes are less affected by diapirism. In this study, we explore vertical movements of the evaporite surface of the central Red Sea imaged with deep seismic profiling, for the period of time after most evaporite deposition ended at 5.3 Ma (the Miocene‐Pliocene boundary). This boundary is readily mapped across the basin as a prominent reflection in seismic data correlated with stratigraphy at three DSDP sites. We quantify changes in the average elevation of the evaporite surface due to (a) thermal lithospheric subsidence, (b) isostatic loading by Plio‐Pleistocene sediments and water, (c) deflation needed to balance the volume of evaporites overflowing oceanic crust of 5.3 Ma age, (d) loss of halite by dissolution and (e) dynamic topography. Our best estimate of the evaporite level (−132 m air‐loaded or −192 m water‐loaded) lies below the range of estimated global sea level towards the end of the Miocene, suggesting that the basin remained under‐filled. If geological interpretations of shallow water conditions existing at the end of the Miocene (Zeit Formation) are correct, this implies that the water level of the Red Sea declined and was unstable. These calculations illustrate how spreading of evaporites can enhance thermal subsidence to cause rapid development of accommodation space above major evaporite bodies, which in the Red Sea case has remained largely unfilled.
Fine‐scale habitat heterogeneity influences browsing damage by elephant and giraffe
Authors: Kimuyu Duncan M. , Kenfack David , Musili Paul M. , Ang’ila Robert O.
Published: September 2020

Effects of large mammalian herbivores on woody vegetation tend to be heterogeneous in space and time, but the factors that drive such heterogeneity are poorly understood. We examined the influence of fine‐scale habitat heterogeneity on the distribution and browsing effects of two of the largest African terrestrial mammals, the elephant and giraffe. We conducted this study within a 120‐ha (500 x 2,400 m) ForestGEO long‐term vegetation monitoring plot located at Mpala Research Center, Kenya. The plot traverses three distinct topographic habitats (“plateau,” “steep slopes,” and “valley”) with contrasting elevation, slope, soil properties, and vegetation composition. To quantify browsing damage, we focused on Acacia mellifera, a palatable tree species that occurs across the three habitat categories. Overall tree density, species richness, and diversity were highest on the steep slopes and lowest on the plateau. Acacia mellifera trees were tallest and had the lowest number of stems per tree on the steep slopes. Both elephant and giraffe avoided the steep slopes, and their activity was higher during the wet season than during the dry season. Browsing damage on Acacia mellifera was lowest on the steep slopes. Elephant browsing damage was highest in the valley, whereas giraffe browsing damage was highest on the plateau. Our findings suggest that fine‐scale habitat heterogeneity is an important factor in predicting the distribution of large herbivores and their effects on vegetation and may interact with other drivers such as edaphic variations to influence local variation in vegetation structure and composition.
Hepatoprotective activity assessment of amino acids derivatives of picroside I and II
Authors: Dong PeiLiang , Gao ZhenLei , Yin Xin , Li ZhengQing , Han Hua
Published: September 2020

Picrorhiza kurroa has a long medicinal history as a traditional medicinal plant in China and India that is widely used in clinical treatments. It is a common treatment for liver diseases, fever, diarrhoea, indigestion, and some other diseases. Modern pharmacological studies proved that P. kurroa rhizomes have high levels of picroside I and II, which were identified as main constituents with anti‐inflammatory and hepatoprotective activities. In our study, we used picroside I and II as the lead compounds to generate derivatives by reactions with Boc‐valine or Boc‐proline, which underwent dehydration and condensation with the hydroxyl groups in the lead compounds in the presence of coupling reagent N,N′‐dicyclohexylcarbodiimide. We synthesized 11 derivatives and examined their hepatoprotective effects in vitro by assessing the proliferation rates of H2O2‐exposed HepG2 cells using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. We found that some derivatives promoted higher proliferation rates in HepG2 cells than the natural compounds before derivatization, suggesting that those derivatives possessed an improved hepatoprotective capacity. The novel derivatization strategy for picrosides had the additional benefit that the esterification of their hydroxyl groups created derivatives not only with increased stability but also with improved pharmacokinetic properties and potentially prolonged half‐life.
Community‐based conservation strategies to end open access: The case of Fish Refuges in Mexico
Authors: Quintana Anastasia C.E. , Basurto Xavier
Published: September 2020

Secure property rights are often seen as a precondition of incentives for long‐term sustainable use by communities dependent on natural resources. Securing formal property rights can be challenging in coastal small‐scale fisheries, which often operate under open access conditions. We argue that insecure, informal rights can offer one pathway for property‐rights regime change, and may also provide greater flexibility for developing sustainable fishing practices compatible with climate change adaptation, among other policy‐relevant outcomes. The process of establishing short‐term but renewable area‐based conservation tools, such as the Fish Refuges of Baja California Sur, Mexico, offers the opportunity to examine how community‐based strategies can generate incentives for conservation despite the lack of secure property rights. Using in‐depth qualitative methods, socioeconomic surveys, and ecological data from 2009 to 2019, we studied the process of engagement among fishers, civil society, and government. We focused on understanding the emerging transition from a scenario of open access and limited withdrawal property rights, toward locals' attaining of insecure defacto management and exclusion property rights and longer‐term visions of resource use and conservation. Altogether, this case illustrates the potential and limitations of Fish Refuges as an area‐based fisheries and conservation tool.
Risk of Metformin in Patients With Type 2 Diabetes With COVID‐19: A Preliminary Retrospective Report
Authors: Gao Yongchao , Liu Tao , Zhong Weijun , Liu Rong , Zhou Honghao , Huang Weihua , Zhang Wei
Published: September 2020

The current outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has spread across the world. No specific antiviral agents have been adequately evidenced for the treatment of coronavirus disease 2019 (COVID‐19). Although metformin has been recommended as a host‐directed therapy for COVID‐19, there are some opposite views. The effects of metformin on the disease severity of patients with COVID‐19 with diabetes during hospitalization remains unclear. This study aimed to determine the effect of metformin on disease severity. We enrolled 110 hospitalized patients with COVID‐19 with diabetes prescribed either metformin or non‐metformin hypoglycemic treatment for a case‐control study. The primary outcome was the occurrence of life‐threatening complications. There were no differences between the two groups in age, sex, comorbidities, and clinical severity at admission. Blood glucose and lactate dehydrogenase levels of the metformin group were higher than those of the non‐metformin group at admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. Strikingly, the percentage of patients who experienced life‐threatening complications was significantly higher in the metformin group (28.6% (16/56) vs. 7.4% (4/54), P = 0.004). Antidiabetic therapy with metformin was associated with a higher risk of disease progression in patients with COVID‐19 with diabetes during hospitalization (adjusted odds ratio = 3.964, 95% confidence interval 1.034–15.194, P = 0.045). This retrospective analysis suggested a potential safety signal for metformin, the use of which was associated with a higher risk of severe COVID‐19. We propose that metformin withdrawal in patients with COVID‐19 be considered to prevent disease progression.
Discordant anti‐SARS‐CoV‐2 spike protein and RNA staining in cutaneous perniotic lesions suggests endothelial deposition of cleaved spike protein
Authors: Ko Christine J. , Harigopal Malini , Gehlhausen Jeff R. , Bosenberg Marcus , McNiff Jennifer M. , Damsky William
Published: September 2020

Background

Prior studies have shown the presence of immunohistochemical staining for the SARS‐CoV‐2 spike protein (SP) in endothelial cells and eccrine epithelium of acral perniosis classified as “COVID toes.” Yet, other studies have been unable to detect SARS‐CoV‐2 RNA in skin biopsies of “COVID toes” by reverse‐transcriptase polymerase chain reaction testing.

Objective

In order to address these apparently conflicting findings, we compared detection of SARS‐CoV‐2 SP, through RNA in situ hybridization (ISH) vs immunohistochemistry (IHC), in skin biopsies of acral perniotic lesions presenting during the COVID‐19 pandemic.

Results

Three of six cases showed positive immunohistochemical labeling of endothelial cells, with one of three cases with sufficient depth also having labeling of eccrine glands, using an anti‐SP SARS‐CoV‐2 antibody. These three cases positive with IHC were negative for SP by RNA ISH.

Conclusion

While the gold standard for detection of SARS‐CoV‐2 in tissue sections has yet to be determined, the detection of SARS‐CoV‐2 SP alone without spike RNA suggests that cleaved SP may be present in cutaneous endothelial cells and eccrine epithelium, providing a potential pathogenetic mechanism of COVID‐19 endotheliitis.
Research in practice: Therapeutic targeting of oncogenic GNAQ mutations in uveal melanoma
Authors: Gaffal Evelyn
Published: September 2020

Uveal melanoma is the most common form of eye cancer and has a poor prognosis. Although the primary tumor in most cases is treated effectively by local surgery or radiotherapy, over 50 % of patients develop systemic metastasis, especially in the liver. In contrast to cutaneous melanoma, there is no standard‐of‐care treatment for metastasized uveal melanoma. Recently, oncogenic driver mutations in GNAQ or GNA11 were identified in about 85 % of uveal melanomas, which lead to constitutively active signaling in the Gαq/11 pathway and its downstream effectors. Direct targeting of deregulated Gαq/11 signaling might therefore be a therapeutic option for patients with uveal melanoma. In our study we identified the cyclic depsipeptide FR‐900359, which is isolated from the evergreen plant Ardisia crenata as an effective inhibitor of constitutively active Gαq/11 proteins and their downstream targets. Although our data are preliminary, they might contribute to a future treatment option for patients with metastasized uveal melanoma.