bluuebunny/crossref_metadata_2025 huggingface dataset:
Susan Moller Okin,Justice, Gender, and the Family
Authors: Ferguson Michaele
Published: March 2019

Susan Okin’s radical thesis in Justice, Gender, and the Family is that the ideal of the gender-structured family is source of persistent gender inequality in politics, the workplace, and actual families. However, the book has widely been taken to be making a much narrower claim: that theorists of justice should extend their analysis to the family, ensuring that the division of labor in the family is just. As a result of this misreading, feminist theorists dismissed the book as conventional when it was published, whereas political theorists largely viewed it as innovative. This chapter recenters the radical thesis of the book, shows how Okin’s most important critics have misunderstood it, and discusses why now perhaps more than even in 1989, we should revisit this book.
Relaxation and Meditation
Authors: Nathoo Ayesha
Published: March 2019

This chapter elucidates the shared socio-cultural history of modern, therapeutic relaxation and meditation strategies. It demonstrates how the promulgation of relaxation therapies from the early twentieth century strongly influenced the later advancement of secularized, therapeutic meditation practices. It traces the development of scientifically grounded neuromuscular relaxation techniques, visualization methods and Autogenic Training in the first half of the twentieth century, through to the proliferation of modern yoga and Transcendental Meditation practices from the 1960s and mindfulness-based approaches from the late twentieth century. It shows how and why relaxation and meditation have been variously demarcated and amalgamated, in their common outreach to health-seeking Western populations. The chapter contributes a new historical vantage point for better understanding both the appeal and limitations of adapting and appropriating meditative techniques for therapeutic ends.
Disparities Between US Opioid Overdose Deaths and Treatment Capacity: A Geospatial and Descriptive Analysis
Authors: Langabeer James R. , Gourishankar Anand , Chambers Kimberly A. , Giri Sharmila , Madu Renita , Champagne-Langabeer Tiffany
Published: March 2019

Introduction:

With opioid-related deaths reaching epidemic levels, gaining a better understanding of access to treatment for opioid use disorder (OUD) is critical. Most studies have focused on 1 side of the equation—either provider capacity or patients’ need for care, as measured by overdose deaths. This study examines the overlay between treatment program availability and opioid mortality, comparing accessibility by region.

Methods:

Geospatial and statistical analyses were used to model OUD treatment programs relative to population density and opioid overdose death incidence at the state and county level. We computed a ratio between program capacity and mortality called the programs-per-death (PPD) ratio.

Results:

There were 40 274 opioid deaths in 2016 and 12 572 treatment programs across the contiguous 48 states, yielding a ratio of 1 program for every 3.2 deaths. Texas had the lowest number of treatment programs per 100 000 persons (1.4) and Maine the highest (13.2). West Virginia ranked highest in opioid deaths (39.09 per 100 000). Ohio, the District of Columbia, and West Virginia had the greatest mismatch between providers and deaths, with an average of 1 program for every 8.5 deaths. Over 32% of US counties had no treatment programs and among those with >10 deaths, nearly 2.5% had no programs. Over 19% of all counties had a ratio ≤1 provider facility per 10 deaths.

Conclusion:

Assessing the overlay between treatment capacity and need demonstrated that regional imbalances exist. These data can aid in strategic planning to correct the mismatch and potentially reduce mortality in the most challenged geographic regions.
Measuring Mental Stress During Otologic Surgery Using Heart Rate Variability Analysis
Authors: Dedmon Matthew Morris , O’Connell Brendan Powers , Yawn Robert James , Kipper-Smith Adriana , Bennett Marc Logan , Haynes David Scott , Rivas Alejandro
Published: March 2019

Objectives:

Healthy individuals have significant beat-to-beat variability in heart rate, and this variability decreases with mental stress. We aim to use heart rate variability (HRV) to objectively compare mental stress levels in otologic surgeons at rest and during key portions of procedures.

Design:

Pilot study.

Setting:

Operating room and laboratory.

Participants:

Two neurotology fellows performed six mastoidectomy and facial nerve (FN) dissections in the operating room and six in a cadaver lab while continuous electrocardiograms were measured wirelessly. Five-minute samples were recorded during resting, preoperative, mastoidectomy, and FN dissection. Beat-to-beat time intervals were analyzed in time and frequency domains. The standard deviation of normal beat-to-beat intervals (SDNN) and the ratio of low frequency to high frequency power (LF/HF, measure of sympathetic tone) were calculated. Decreases in SDNN and increases in LF/HF indicate elevated mental stress.

Results:

Mean resting SDNN was 43.9 ± 9.2 ms, not statistically different from preoperative SDNN (34.1 ± 8.2 ms, p = 0.13). SDNN decreased during mastoidectomy (29.4 ± 11.7 ms) and FN dissection (22.8 ± 3.1 ms), which was significant compared to preoperative values (p = 0.03). Intraoperative LF/HF increased for FN dissection (6.8 ± 2.6) compared to resting (2.2 ± 0.7, p = 0.004), indicating increased sympathetic tone. Mastoid and FN cadaveric procedures resulted in SDNN of 33.6 ± 3.8 and 32.9 ± 4.7 ms, respectively, not statistically different from preoperative values (p = 0.82 and p = 0.94, respectively). Cadaveric FN dissection did not result in increased LF/HF (2.4 ± 0.9) compared to resting (p = 0.94).

Conclusions:

Decreased HRV and increased sympathetic tone were observed intraoperatively, indicating high levels of mental stress, particularly with FN dissection. Similar changes were not found during cadaveric dissections.
Sudden Sensorineural Hearing Loss in Children: Clinical Characteristics, Etiology, Treatment Outcomes, and Prognostic Factors
Authors: Lu Yuqing , Zhou Liangqiang , Imrit Tejvansh Shenoy , Liu Aiguo
Published: March 2019

Objective:

To investigate the clinical characteristics, etiology, treatment outcomes, and prognostic factors of sudden sensorineural hearing loss (SSNHL) in children to guide the clinical diagnosis and treatment of SSNHL in the pediatric population.

Study Design:

Retrospective case review.

Setting:

Tertiary referral center.

Patients:

Patients diagnosed with SSNHL from November 2011 to December 2017 with relatively complete clinical data.

Intervention:

Diagnosis and systemic treatment of SSNHL.

Main Outcome Measures:

Patients’ clinical characteristics, etiology, laboratory tests, imaging, pure-tone audiometry at admission, and discharge were analyzed.

Results:

A total of 25 children and 149 adults with SSNHL were included. Recent or previous viral infection rates (81.8%) and fasting blood glucose level (5.23 + 1.47 mmol/L) in children with SSNHL were lower than those in adult SSNHL patients (p = 0.033, p = 0.033). Autoimmune abnormalities (90.0%) and plasma fibrinogen abnormalities (27.3%) were higher in children with SSNHL than those in adult SSNHL patients (40.0%, 8.8%, respectively, p < 0.05). The recovery rate in children (38.4%) with SSNHL is comparable to that in adults (22.6%), but children have a higher complete rate compared to adults (26.9%, 11.3%, respectively, p < 0.05). Children with a profound audiometric curve had a worse prognosis in comparison to other types of audiometric curves (p = 0.041).

Conclusions:

Children with SSNHL have a lower rate of viral infection in comparison to adults with SSNHL. Fasting blood glucose levels, complement C3, C4, and fibrinogen may be closely related to childhood SSNHL. The recovery rate in children with SSNHL is comparable to that in adults, but children have a higher complete rate compared to adults. A profound hearing curve is an unfavorable prognostic factor in both children and adults with SSNHL.
Outcomes From Brain Death Donors With Previous Cardiac Arrest Accepted for Pancreas Transplantation
Authors: Ventura-Aguiar Pedro , Ferrer Joana , Paredes David , Rodriguez-Villar Camino , Ruiz Angel , Fuster Josep , Fondevila Constantino , Garcia-Valdecasas Juan Carlos , Esmatjes Enric , Adália Ramon , Oppenheimer Federico , Campistol Josep M. , Diekmann Fritz , Ricart Maria J.
Published: March 2019

Objective:

The aim of the study was to evaluate the effect of cardiac arrest time (CAT) in donors after brain death (DBD) donors on pancreas transplant outcome.

Summary of Background Data:

Results from donors after circulatory death report good outcomes despite warm ischemia times up to 57 minutes. Previous cardiac arrest in DBD has been addressed as a potential risk factor, but duration of the CAT has never been evaluated.

Methods:

We conducted a retrospective analysis including 342 pancreas transplants performed at our center from 2000 to 2016, and evaluated the effect of previous cardiac arrest in DBD (caDBD) on pancreas transplant outcomes.

Results:

A total of 49 (14.3%) caDBD were accepted for transplantation [median CAT of 5.0 min (IQR 2.5–15.0)]. Anoxic encephalopathy was most frequent and P-PASS higher (16.9 vs 15.6) in caDBD group when compared with other DBD. No differences were found in all other characteristics evaluated.

Graft survival was similar between both groups, as was the incidence of early graft failure (EGF). CAT increased the risk for EGF [OR 1.09 (95% CI, 1.01–1.17)], and the duration of CPR discriminated for EGF [AUC of 0.86 (95% CI, 0.74–0.98)], with a sensitivity and specificity of 100% and 75% at a cutoff of 15 minutes. When evaluated separately, caDBD >15 min increased over 5 times the risk for EGF [HR 5.80 (95% CI, 1.82–18.56); P = 0.003], and these presented fewer days on the ICU (1.0 vs 3.0 d).

Conclusion:

CaDBD donors are suitable for routine pancreas transplantation without increasing EGF risk, and in those with longer CAT it may be prudent to postpone donation a few days to allow a thorough evaluation of organ damage following cardiac arrest.
Wounds Inhibit Tumor Growth In Vivo
Authors: Hu Michael S. , Maan Zeshaan N. , Leavitt Tripp , Hong Wan Xing , Rennert Robert C. , Marshall Clement D. , Borrelli Mimi R. , Zhu Ted N. , Esquivel Mikaela , Zimmermann Andrew , McArdle Adrian , Chung Michael T. , Foster Deshka S. , Jones Ruth Ellen , Gurtner Geoffrey C. , Giaccia Amato J. , Lorenz H. Peter , Weissman Irving L. , Longaker Michael T.
Published: March 2019

Objective:

The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.

Summary of Background Data:

Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.

Methods:

To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.

Results:

Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.

Conclusion:

Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.
Species specificity and intraspecific variation in the chemical profiles ofHeliconiusbutterflies across a large geographic range
Authors: Darragh Kathy , Montejo-Kovacevich Gabriela , Kozak Krzysztof M. , Morrison Colin R. , Figueiredo Clarisse M. E. , Ready Jonathan S. , Salazar Camilo , Linares Mauricio , Byers Kelsey J. R. P. , Merrill Richard M. , McMillan W. Owen , Schulz Stefan , Jiggins Chris D.
Published: March 2019

In many animals, mate choice is important for the maintenance of reproductive isolation between species. Traits important for mate choice and behavioural isolation are predicted to be under strong stabilising selection within species, however such traits can also exhibit variation at the population level driven by neutral and adaptive evolutionary processes. Here, we describe patterns of divergence among androconial and genital chemical profiles at inter- and intra-specific levels in mimeticHeliconiusbutterflies. Most variation in chemical bouquets was found between species, but there were also quantitative differences at the population level. We found a strong correlation between interspecific chemical and genetic divergence, however, this correlation varied in intraspecific comparisons. We identified ‘indicator’ compounds characteristic of particular species that included known biologically active compounds, suggesting an approach for identification of candidate compounds for future behavioural studies in novel systems. Overall, the strong signal of species identity suggests a role for these compounds in species recognition, but with additional potentially neutral variation at the population level.
Disruption of the kringle 1 domain of prothrombin leads to late onset mortality in zebrafish
Authors: Grzegorski Steven J. , Hu Zhilian , Liu Yang , Yu Xinge , Ferguson Allison C. , Madarati Hasam , Friedmann Alexander P. , Reyon Deepak , Kim Paul Y. , Kretz Colin A. , Joung J. Keith , Shavit Jordan A.
Published: March 2019

The ability to prevent blood loss in response to injury is a critical, evolutionarily conserved function of all vertebrates. Prothrombin (F2) contributes to both primary and secondary hemostasis through the activation of platelets and the conversion of soluble fibrinogen to insoluble fibrin, respectively. Complete prothrombin deficiency has never been observed in humans and is incompatible with life in mice, limiting the ability to understand the entirety of prothrombin’sin vivofunctions. We have previously demonstrated the ability of zebrafish to tolerate loss of both pro- and anticoagulant factors that are embryonic lethal in mammals, making them an ideal model for the study of prothrombin deficiency. Using genome editing with TALENs, we have generated a null allele in zebrafishf2. Homozygous mutant embryos develop normally into early adulthood, but demonstrate eventual complete mortality with the majority of fish succumbing to internal hemorrhage by 2 months of age. We show that despite the extended survival, the mutants are unable to form occlusive thrombi in both the venous and arterial systems as early as 3-5 days of life, and we were able to phenocopy this early hemostatic defect using direct oral anticoagulants. When the equivalent mutation was engineered into the homologous residues of human prothrombin, there were severe reductions in secretion and activation, suggesting a possible role for kringle 1 in thrombin maturation, and the possibility that the F1.2 fragment has a functional role in exerting the procoagulant effects of thrombin. Together, our data demonstrate the conserved function of thrombin in zebrafish, as well as the requirement for kringle 1 for biosynthesis and activation by prothrombinase. Understanding how zebrafish are able to develop normally and survive into early adulthood without prothrombin will provide important insight into its pleiotropic functions as well as the management of patients with bleeding disorders.

Key Points

Disruption of the kringle 1 domain of prothrombin leads to severe impairment of biosynthesis, activation, and activity

Prothrombin deficiency is compatible with normal development in zebrafish but leads to inability to form clots followed by early mortality
Facilitation and inhibition of firing activity and N-methyl-D-aspartate-evoked responses of CA1 hippocampal pyramidal cells by alpha7 nicotinic acetylcholine receptor selective compounds in vivo
Authors: Bali Zsolt Kristóf , Nagy Lili Veronika , Budai Dénes , Hernádi István
Published: March 2019

Alpha7 nicotinic acetylcholine receptors (nAChRs) are promising novel targets for the treatment of neurocognitive disorders. Although the cognitive enhancer potential of alpha7 nAChR agonists and positive allosteric modulators (PAMs) has been confirmed in several preclinical animal models, there are only sparse in vivo electrophysiological data on their effects on the firing activity and excitability of neurons. The present study investigated and compared local effects of alpha7 nAChR agonist PHA-543613 and PAMs PNU-120596 and NS-1738 on the spontaneous and N-methyl-D-aspartate-evoked (NMDA-evoked) firing rate of rat CA1 hippocampal pyramidal cells, in vivo. Furthermore, effects of alpha7 nAChR antagonist methyllycaconitine (MLA) and GABA were also tested. Results showed substantially different effects of the alpha7 nAChR agonist and PAMs. While PNU-120596 and NS-1738 predominantly and significantly increased both spontaneous and NMDA-evoked firing rate of the neurons, application of PHA-543613 resulted in almost equal distribution of facilitatory and inhibitory effects. The increase of the NMDA-evoked firing rate exerted by NS-1738 was superadditive over the sum of the single effects of NMDA and NS-1738. The simultaneous application of alpha7 nAChR agonist PHA-543613 and PAM NS-1738 resulted in additive increase of both spontaneous and NMDA-evoked firing rate. However, NS-1738 counteracted inhibitory effects of PHA-543613 in 5 out of 6 neurons, resulting in a synergistic potentiation of their firing responses to NMDA. Our results suggest that alpha7 nAChR PAMs increase neuronal excitability more potently than agonists, while the remarkable occurrence of inhibitory effects of PHA-543613 (possibly originating from receptor desensitization) implies that agonists may exert neuroprotective effects.
How pirate phage interferes with helper phage: Comparison of the two distinct strategies
Authors: Mitarai Namiko
Published: March 2019

Pirate phages use the structural proteins encoded by unrelated helper phages to propagate. The best-studied example is the pirate P4 and helper P2 of coliphages, and it has been known that theStaphylococcus aureuspathogenicity islands (SaPIs) that can encode virulence factors act as pirate phages, too. When alone in the host, the pirate phages act as a prophage, but when the helper phage gene is also in the same host cell, the pirate phage has ability to exploit the helper phages structural proteins to produce pirate phage particles and spread, interfering with the helper phage production. The known helper phages in these systems are temperate phages. Interestingly, the interference of the pirate phage to the helper phage occurs in a different manner between the SaPI-helper system and the P4-P2 system. SaPIs cannot lyse a helper lysogen upon infection, while when a helper phage lyse a SaPI lysogen, most of the phage particles produced are the SaPI particles. On the contrary, in the P4-P2 system, a pirate phage P4 can lyse a helper P2 lysogen to produce mostly the P4 particles, while when P2 phage lyses a P4 lysogen, most of the produced phages are the P2 particles. Here, the consequences of these different strategies in the pirate and helper phage spreading among uninfected host is analyzed by using mathematical models. It is found that SaPI’s strategy interferes with the helper phage spreading significantly more than the P4’s strategy, because SaPI interferes with the helper phage’s main reproduction step, while P4 interferes only by forcing the helper lysogens to lyse. However, the interference is found to be weaker in the spatially structured environment than in the well-mixed environment. This is because, in the spatial setting, the system tends to self-organize so that the helper phages take over the front of propagation due to the need of helper phage for the pirate phage spreading.

Competing interests

The author declares no competing interest.
Pax9is required for cardiovascular development and interacts withTbx1in the pharyngeal endoderm to control 4thpharyngeal arch artery morphogenesis
Authors: Phillips Helen M. , Stothard Catherine A. , Shaikh Qureshi Wasay Mohiuddin , Kousa Anastasia I. , Alberto Briones-Leon J. , Khasawneh Ramada R. , Sanders Rachel , Mazzotta Silvia , Dodds Rebecca , Seidel Kerstin , Bates Timothy , Nakatomi Mitsushiro , Cockell Simon J. , Schneider Jürgen E. , Mohun Timothy J. , Maehr René , Kist Ralf , Peters Heiko , Bamforth Simon D.
Published: March 2019

Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity ofTBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects.Pax9is expressed in the pharyngeal endoderm and is downregulated inTbx1mutant mice. We show here thatPax9deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rdand 4thpharyngeal arch arteries to form correctly. Transcriptome analysis indicated thatPax9andTbx1may function together, and mice double heterozygous forTbx1/Pax9presented with a significantly increased incidence of interrupted aortic arch when compared toTbx1heterozygous mice. Using a novelPax9Creallele we demonstrated that the site of thisTbx1-Pax9genetic interaction is in the pharyngeal endoderm, therefore revealing that aTbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

Summary statement

Pax9is required for outflow tract and aortic arch development, and functions together withTbx1in the pharyngeal endoderm for 4tharch artery formation.
Dynamic changes in innate immune and T cell function and composition at the nasal mucosa across the human lifespan
Authors: Reiné Jesús , Carniel Beatriz F. , Solórzano Carla , Mitsi Elena , Pojar Sherin , Nikolaou Elissavet , German Esther L. , Hyder-Wright Angela D. , Hill Helen , Hales Caz , Brown Lynsey , Horsley Victoria , Hughes Lisa , Zaidi Seher , Connor Victoria , Morton Ben , Collins Andrea M. , Rylance Jamie , Adler Hugh , McNamara Paul S. , Ferreira Daniela M. , Jochems Simon P.
Published: March 2019

The very young and very old are at increased risk of serious infections, including pneumonia. This may relate to changes in the immune system as young children have limited immunological memory, while immunosenescence, inflammaging and a decreased pool of naïve immune cells are described with advanced age. How the immune system changes with age at mucosal surfaces, from where infections frequently develop, is not very clear as access to human tissue samples is limited. Therefore, we aimed to assess the composition and activation state of the immune system at the human mucosa. Here, we profiled nasal immune cells from 207 individuals between 1 to 80 years old using flow cytometry. Neutrophil and monocyte functionality were measured using whole blood assays. Levels of thirty nasal cytokines were measured from nasal lining fluid. Nasopharyngeal colonization by Streptococcus pneumoniae was assessed using classical microbiology and associated with immune responses. We found that young children have a striking paucity of granulocytes at the nasal mucosa compared to adults. In addition, T cell numbers at the nasal mucosa decreased progressively with age and were almost absent in older adults. While nasopharyngeal colonization by Streptococcus pneumoniae was associated with elevated levels of inflammation it had a limited effect on nasal immune composition, including levels of monocytes and neutrophils. These results show that the immune system at the nasal mucosal surface changes drastically with age and provides explanations for the increased susceptibility to infections in young and old age.

Significance statement

How the immune system changes with age is an intensive area of research, but has been primarily studied in blood. However, blood poorly reflects the immune system at the mucosa, from where infections develop. This manuscript provides a first characterization of how the composition and function of the immune system in the upper respiratory tract changes with age, providing explanations for increased susceptibility to infection in the very young and old. Furthermore, by linking mucosal and systemic measurements with pneumococcal colonization, we observed that reduced monocyte and neutrophil responses associate with the increased burden of pneumococcal colonization in children. This study highlights the need to study the immune system also at other mucosal sites in the context of aging.
Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?
Authors: Vasileiou Georgia , Hoyer Juliane , Thiel Christian T. , Schaefer Jan , Zapke Maren , Krumbiegel Mandy , Kraus Cornelia , Zweier Markus , Uebe Steffen , Ekici Arif B. , Schneider Michael , Wiesener Michael , Rauch Anita , Faschingbauer Florian , Reis André , Zweier Christiane , Popp Bernt
Published: March 2019

Objective

Large deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre- and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies.

Methods

Prenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants.

Results

In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum.

Conclusions

We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre- and postnatal clinical features, improving genetic counseling and prenatal decision-making.
Midgut barriers prevent the replication and dissemination of the yellow fever vaccine inAedes aegypti
Authors: Danet Lucie , Beauclair Guillaume , Berthet Michèle , Moratorio Gonzalo , Gracias Ségolène , Tangy Frédéric , Choumet Valérie , Jouvenet Nolwenn
Published: March 2019

Background

To be transmitted to vertebrate hostsviathe saliva of their vectors, arthropod-borne viruses have to cross several barriers in the mosquito body, including the midgut infection and escape barriers. Yellow fever virus (YFV) belongs to the genusFlavivirus, which includes human viruses transmitted byAedesmosquitoes, such as Dengue and Zika viruses. The live-attenuated YFV-17D vaccine has been used safely and efficiently on a large scale since the end of World War II. Early studies have shown, using viral titration from salivary glands of infected mosquitoes, that YFV-17D can infectAedes aegyptimidgut, but does not disseminate to other tissues.

Methodology/Principal Findings

Here, we re-visited this issue using a panel of techniques, such as RT-qPCR, Western blot, immunofluorescence and titration assays. We showed that YFV-17D replication was not efficient inAedes aegyptimidgut, as compared to the clinical isolate YFV-Dakar. Viruses that replicated in the midgut failed to disseminate to secondary organs. When injected into the thorax of mosquitoes, viruses succeeded in replicating into midgut-associated tissues, suggesting that, during natural infection, the block for YFV-17D replication occurs at the basal membrane of the midgut. Our NGS analysis revealed that YFV-Dakar genome exhibited a greater diversity than the vaccine strain; a trait that may contribute to its ability to infect and disseminate efficiently inAe. aegypti.

Conclusions/Significance

The two barriers associated withAe. aegyptimidgut prevent YFV-17D replication. Our study contributes to our basic understanding of vector–pathogen interactions and may also aid in the development of non-transmissible live virus vaccines.

Author summary

Most flaviviruses, including yellow fever virus (YFV), are transmitted between hosts by mosquito bites. The yellow fever vaccine (YFV-17D) is one of the safest and most effective live virus vaccine ever developed. It is also used as a platform for engineering vaccines against other health-threatening flaviviruses, such as Japanese encephalitis, West Nile, Dengue and Zika viruses. We studied here the replication and dissemination of YFV-17D in mosquitoes. Our data showed that YFV-17D replicates poorly in mosquito midgut and is unable to disseminate to secondary organs, as compare to a YFV clinical isolate. Our study contributes to our basic understanding of the interactions between viruses and their vectors, which is key for conceiving new approaches in inhibiting virus transmission and designing non-transmissible live virus vaccines.
Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium
Authors: Babler Anne , Schmitz Carlo , Büscher Andrea , Herrmann Marietta , Gremse Felix , Gorgels Theo , Floege Jürgen , Jahnen-Dechent Willi
Published: March 2019

Objective

Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.

Approach and Results

We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of theAbcc6gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.

Conclusions

We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.

Subject Codes

Animal Models of Human Disease, Fibrosis, Inflammation, Proteomics, Peripheral Vascular Disease
Cell-length heterogeneity: a population-level solution to growth/virulence trade-offs in the plant pathogen Dickeya dadantii
Authors: Cui Zhouqi , Yang Ching-Hong , Kharadi Roshni R. , Yuan Xiaochen , Sundin George W. , Triplett Lindsay R. , Wang Jie , Zeng Quan
Published: March 2019

Necrotrophic plant pathogens acquire nutrients from dead plant cells, which requires the disintegration of the plant cell wall and tissue structures by the pathogen. Infected plants lose tissue integrity and functional immunity as a result, exposing the nutrient rich, decayed tissues to the environment. One challenge for the necrotrophs to successfully cause secondary infection (infection spread from an initially infected plant to the nearby uninfected plants) is to effectively utilize nutrients released from hosts towards building up a large population before other saprophytes come. In this study, we observed that the necrotrophic pathogen Dickeya dadantii exhibited heterogeneity in bacterial cell length in an isogenic population during infection of potato tuber. While some cells were regular rod-shape (<10μm), the rest elongated into filamentous cells (>10μm). Short cells tended to occur at the interface of healthy and diseased tissues, during the early stage of infection when active attacking and killing is occurring, while filamentous cells tended to form when large amount of nutrients were released at a later stage of infection. Short cells expressed all necessary virulence factors and motility, whereas filamentous cells did not engage in virulence, were non-mobile and more sensitive to environmental stress. However, compared to the short cells, the filamentous cells displayed elevated metabolism and faster growth, which may benefit the pathogens to build up a large population necessary for the secondary infection. The segregation of the two subpopulations was dependent on differential expression of the alarmone guanosine tetraphosphate (ppGpp). When exposed to fresh tuber tissues or freestanding water, filamentous cells quickly transformed to short virulent cells. The pathogen adaptation of cell length heterogeneity identified in this study presents a model for how some necrotrophs balance virulence and vegetative growth to maximize fitness during infection.
pHluo_M153R-CD63, a bright, versatile live cell reporter of exosome secretion and uptake, reveals pathfinding behavior of migrating cells
Authors: Sung Bong Hwan , von Lersner Ariana , Guerrero Jorge , Inman David , Pelletier Roxanne , Zijlstra Andries , Ponik Suzanne M. , Weaver Alissa M.
Published: March 2019

Small extracellular vesicles called exosomes affect a variety of autocrine and paracrine cellular phenotypes, including cellular migration, immune activation, and neuronal function. Understanding the function of exosomes requires a variety of tools, including live cell imaging. We previously constructed a live-cell reporter, pHluorin-CD63, that allows dynamic subcellular monitoring of exosome secretion in migrating and spreading cells. However, there were some caveats to its use, including dim fluorescence and the inability to make cell lines that stably express the protein. By incorporating a stabilizing mutation in the pHluorin moiety, M153R, pHluorin-CD63 now exhibits higher and stable expression in cells and superior monitoring of exosome secretion. Using this improved construct, we demonstrate visualization of secreted exosomes in 3D culture andin vivoand identify a role for exosomes in promoting leader-follower behavior in 2D and 3D migration. By incorporating a further non-pH-sensitive red fluorescent tag, this reporter allows visualization of the exosome lifecycle, including multivesicular body (MVB) trafficking, MVB fusion, exosome uptake and endosome acidification. This new reporter will be a useful tool for understanding both autocrine and paracrine roles of exosomes.
Quantifying and understanding well-to-well contamination in microbiome research
Authors: Minich Jeremiah J , Sanders Jon G , Amir Amnon , Humphrey Greg , Gilbert Jack , Knight Rob
Published: March 2019

Microbial sequences inferred as belonging to one sample may not have originated from that sample. Such contamination may arise from laboratory or reagent sources or from physical exchange between samples. This study seeks to rigorously assess the behavior of this often-neglected between-sample contamination. Using unique bacteria each assigned a particular well in a plate, we assess the frequency at which sequences from each source appears in other wells. We evaluate the effects of different DNA extraction methods performed in two labs using a consistent plate layout including blanks, low biomass, and high biomass samples. Well-to-well contamination occurred primarily during DNA extraction, and to a lesser extent in library preparation, while barcode leakage was negligible. Labs differed in the levels of contamination. DNA extraction methods differed in their occurrences and levels of well-to-well contamination, with robotic methods having more well-to-well contamination while manual methods having higher background contaminants. Well-to-well contamination was observed to occur primarily in neighboring samples, with rare events up to 10 wells apart. The effect of well-to-well was greatest in samples with lower biomass, and negatively impacted metrics of alpha and beta diversity. Our work emphasizes that sample contamination is a combination of crosstalk from nearby wells and background contaminants. To reduce well-to-well effects, samples should be randomized across plates, and samples of similar biomass processed together. Researchers should evaluate well-to-well contamination in study design and avoid removal of taxa or OTUs appearing in negative controls, as many will be microbes from other samples rather than reagent contaminants.

Importance

Microbiome research has uncovered magnificent biological and chemical stories across nearly all areas of life science, at times creating controversy when findings reveal fantastic descriptions of microbes living and even thriving in once thought to be sterile environments. Scientists have refuted many of these claims because of contamination, which has led to robust requirements including use of controls for validating accurate portrayals of microbial communities. In this study, we describe a previously undocumented form of contamination, well-to-well contamination and show that contamination primarily occurs during DNA extraction rather than PCR, is highest in plate-based methods as compared to single tube extraction, and occurs in higher frequency in low biomass samples. This finding has profound importance on the field as many current techniques to ‘decontaminate’ a dataset simply relies on an assumption that microbial reads found in blanks are contaminants from ‘outside’ namely the reagents or consumables.
Ultra-widefield fluorescein angiography findings in patients with multiple retinal holes
Authors: Baek Jiwon , Jung Byungju , Kwon Hyunggu , Jeon Sohee
Published: March 2019

Purpose

To evaluate the ultra-widefield fluorescein angiography (UWFA) findings in patients with multiple retinal holes.

Methods

Seventy-five eyes, each with more than two retinal holes, underwent a comprehensive ophthalmologic examination, including UWFA, along with 77 age-matched control eyes with no retinal holes. The UWFA was scored according to a system suggested by the Angiography Scoring for Uveitis Working Group (ASUWG). UWFA findings from the patients with retinal holes were compared with those of the control group without retinal holes. Factors associated with a high ASUWG score were also evaluated.

Results

Patients with multiple retinal holes showed a significantly higher prevalence of retinal vascular staining/leakage, capillary leakage at the posterior pole, and capillary leakage at the periphery when compared to the control group (p<0.001, for each of them). Univariate analysis revealed that logMAR BCVA (r=0.271, p=0.027), spherical equivalent (r= −0.275, p=0.021), and number of retinal holes (r=0.271, p=0.027) were associated with a higher ASUWG score. After adjustments for age, gender, and logMAR BCVA, multivariate regression analysis revealed that the spherical equivalent was independently associated with a higher ASUWG score (r2=0.161, p=0.001).

Conclusions

Patients with multiple retinal holes showed profound peripheral vascular leakages on UWFA findings, suggesting the presence of chronic retinal traction induced by equatorial scleral elongation.
Foreign investment in Australian residential properties
Authors: Gholipour Hassan F. , Lean Hooi Hooi , Tajaddini Reza , Pham Anh Khoi
Published: March 2019

Purpose

The purpose of this study is to examine the impact that foreign investment in existing houses and new housing development has on residential house prices and the growth of the housing construction sector.

Design/methodology/approach

The analysis is based on a panel cointegration method, estimated using annual data for all Australian states and territories spanning the period of 1990-2013.

Findings

The results indicate that increases in foreign investment in existing houses do not significantly lead to increases in house prices. On the other hand, a 10 per cent increase in foreign investment for housing development decreases house prices by 1.95 per cent. We also find that foreign real estate investments have a positive impact on housing construction activities in the long run.

Originality/value

Existing studies used aggregate foreign real estate investment in their analyses. As foreign investment in existing houses and foreign investment for housing development have different impacts on the demand and supply sides of housing market, it is crucial that the analysis of the effects of foreign investment in residential properties on real estate market is conducted for each type differently.
Integration duration of post-merger and leverage dynamics of mergers: theory and evidence
Authors: Cheng Yao
Published: March 2019

Purpose

The purpose of this paper is to examine the effects of the post-merger integration duration on acquiring firms’ leverage behavior before and after a merger, using a dynamic model in which full merger benefits cannot be consumed at the instant of a merger, but rather after a pre-specified post-merger integration period.

Design/methodology/approach

This paper presents a dynamic model and empirical tests that describe the impact of the post-merger integration period on the capital structure dynamics of the acquiring and target firms before a merger and during the post-merger integration period. By incorporating costs associated with the post-merger integration period, the model can provide new implications for the leverage behavior around the merger.

Findings

The model generates new implications related to acquiring firms’ leverage dynamics along with method of payment choice. Specifically, the model indicates that the post-merger integration duration is negatively associated with the market leverage of newly-merged firms at the time of merger completion and during the integration period. Further, acquirer managers are more likely to use equity to finance a merger when the integration duration is likely to be lengthy.

Originality/value

This is the first model in the literature that assumes that both the acquiring and the target firms can change their capital structure overtime, which allows us to analyze both the financing structure and the merger timing. Previous empirical studies also ignore the integration period in the analysis of the method of payment choice and leverage behavior around mergers. In the tests reported in this paper, the authors control for the factors mentioned above and demonstrate that the expected integration duration is not subsumed by those variables implying that it has its own power in explaining the choice of leverage and merger financing method.
The Interrelation between Audit Quality and Managerial Reporting Choices and Its Effects on Financial Reporting Quality
Authors: Patterson Evelyn R. , Smith J. Reed , Tiras Samuel L.
Published: March 2019

Two distinct lines of research have been dedicated to empirically testing how financial reporting quality (measured as the earnings response coefficient or ERC) is associated with management's choice of reporting bias and with audit quality. However, researchers have yet to consider how ERCs are affected by either the auditor's reaction to changes in the manager's reporting bias or the manager's reaction to changes in audit quality. Our study provides theoretical guidance on these interrelations and how changes in the manager's or the auditor's incentives affect both reporting bias and audit quality. Specifically, when the manager's cost (benefit) of reporting bias increases (decreases), we find that expected bias decreases, inducing the auditor to react by reducing audit quality. Because we also find that the association between expected audit quality and ERCs is always positive, changes in managerial incentives for biased reporting lead to a positive association between ERCs and expected reporting bias. When the cost of auditing decreases or the cost of auditor liability increases, we find that expected audit quality increases, inducing the manager to react by decreasing reporting bias. In this case, changes in the costs of audit quality lead to a negative association between ERCs and expected reporting bias. Finally, we demonstrate the impact of our theoretical findings by focusing on the empirical observations documented in the extant literature on managerial ownership and accounting expertise on the audit committee. In light of our framework, we provide new interpretations of these empirical observations and new predictions for future research.
Editorial: shining a light on cholangiocarcinoma—a new dawn for photodynamic therapy?
Authors: Srinivasa Sanket , Wigmore Stephen J.
Published: March 2019

Linked Content

This article is linked to Gonzalez‐Carmona et al papers. To view
these articles, visit https://doi.org/10.1111/apt.15050 and https://doi.org/10.1111/apt.15134.