bluuebunny/crossref_metadata_2025 huggingface dataset:
Microstructural evolution and precipitation behavior of the 0.1C-18Cr-1Al-1Si ferritic heat-resistant stainless steel during hot deformation
Authors: Zhang Yingbo , Zou Dening , Wei Tongyu , Li Jiao , Tong Libo , Zhang Wei
Published: March 2020

The 0.1C-18Cr-1Al-1Si ferritic heat-resistant stainless steel has attracted considerable attention to high-temperature applications due to its favorable combination of creep and oxidation resistance. In this paper, the microstructural evolution and precipitation behavior of the 0.1C-18Cr-1Al-1Si ferritic heat-resistant stainless steel is studied from the compression deformation data in the temperature range of 850 °C–1050 °C and the strain rate range of 0.01–1 s−1. Experimental results demonstrate that higher temperatures and lower strain rates enhance the dynamic recrystallization (DRX) process with remarkable effectiveness. The main precipitates are proved as the AlN phases and the (Cr,Fe)23C6 carbides during hot deformation. With an increase in the deformation temperature, the size of (Cr,Fe)23C6 and AlN gradually increases, and volume fraction gradually decreases. When the strain rate decreases, the average size and volume fraction of (Cr,Fe)23C6 and AlN gradually increase. At the lower temperatures, the occurrence of dynamic recrystallization (DRX) is strongly influenced by (Cr,Fe)23C6 formed on the grain boundaries, mainly because it causes a pinning effect, which hinders the movement of dislocations and delays the occurrence of the DRX.
SAXS-CT: a nanostructure resolving microscopy for macroscopic biologic specimens
Authors: Conceição A L C , Perlich J , Haas S , Funari S S
Published: March 2020

SAXS-CT is an emerging powerful imaging technique which bridges the gap between information retrieved from high-resolution local techniques and information from low-resolution, large field-of-view imaging, to determine the nanostructure characteristics of well-ordered tissues, e.g., mineralized collagen in bone. However, in the case of soft tissues, features such as poor nanostructural organization and high susceptibility to radiation-induced damage limit the use of SAXS-CT. Here, by combining the freeze-drying the specimen, preceded by formalin fixation, with the nanostructure survey we identified and monitored alterations on the hierarchical arrangement of triglycerides and collagen fibrils three-dimensionally in breast tumor specimens without requiring sample staining. A high density of aligned collagen was observed precisely on the invasion front of the breast carcinoma, showing the direction of cancer spread, whereas substantial content of triglycerides was identified, where the healthy tissue was located. Finally, the approach developed here provides a path to high-resolution nanostructural probing with a large field-of-view, which was demonstrated through the visualization of characteristic nanostructural arrangement and quantification of content and degree of organization of collagen fibrils in normal, benign and malignant human breast tissue.
Gendering Foreign Policy: A Comparative Framework for Analysis
Authors: Aggestam Karin , True Jacqui
Published: March 2020

This article seeks to explain the rise of pro-gender norms and feminist strategies in foreign policy, which are increasingly salient in global politics. How can this trend be theorized? In what ways is this development resisted and contested by other states and international actors? To what extent can we trace continuity and change in regard to gender and foreign policy? To address these major research questions and to spur cross-national comparative studies, this article advances a theoretical framework on gendering foreign policy. It draws on two strands of research, which rarely engage with one another: international feminist theory (IFT) and foreign policy analysis (FPA). We identify three ways in which comparative analysis of gender in foreign policy can be advanced: first, by highlighting the variations of pro-gender norms and enhancing the analytical assessment of cross-national trends; second, by generating a more robust explanation of the rise, embeddedness, and continuity of, as well as resistance to, pro-gender norms in foreign policy in similar and diverse contexts; and third, by examining both continuity and change in pro-gender norms in order to reveal the contestation around gender, which is at the heart of foreign policy.
Novel Use of Stimulating Fence-Post Technique for Functional Mapping of Subcortical White Matter During Tumor Resection: A Technical Case Series
Authors: Han Seunggu Jude , Teton Zoe , Gupta Kunal , Kawamoto Aaron , Raslan Ahmed M
Published: March 2020

Background

Maximal safe resection remains a key principle in infiltrating glioma management. Stimulation mapping is a key adjunct for minimizing functional morbidity while “fence-post” procedures use catheters or dye to mark the tumor border at the start of the procedure prior to brain shift.

Objective

To report a novel technique using stereotactically placed electrodes to guide tumor resection near critical descending subcortical fibers.

Methods

Navigated electrodes were placed prior to tumor resection along the deep margin bordering presumed eloquent tracts. Stimulation was administered through these depth electrodes for subcortical motor and language mapping.

Results

Twelve patients were included in this preliminary technical report. Seven patients (7/12, 58%) were in asleep cases, while the other 5 cases (5/12, 42%) were performed awake. Mapping of motor fibers was performed in 8 cases, and language mapping was done in 1 case. In 3 cases, both motor and language mapping were performed using the same depth electrode spanning corticospinal tract and the arcuate fasciculus.

Conclusion

Stereotactic depth electrode placement coupled with stimulation mapping of white matter tracts can be used concomitantly to demarcate the border between deep tumor margins and eloquent brain, thus helping to maximize extent of resection while minimizing functional morbidity.
Viking Metal
Authors: Trafford Simon
Published: March 2020

Hardly any traces survive of the music of the Vikings, but considerable effort has been expended in the modern period in attempting to construct music that can represent the Vikings and their age for audiences attracted by the stirring and romantic role delineated for them by popular culture. Since the 1990s, “Viking metal”, a sub-genre of heavy metal originating in Scandinavia, has achieved lasting popularity and spawned its own sub-culture and concert circuit. This chapter traces the development of Viking metal from its origins to the present, exploring how music, lyrics, language and the visual imagery of bands have been deployed to fabricate a music that can successfully evoke a desired “Viking” Other. Band and audience members typically contrast a Viking Age depicted as exotic, authentic and exciting with a modern world stigmatized as dull, compromised and constrained. Beyond straightforward escapism, however, Viking metal also serves as a site for the exploration of a variety of other ideas. It has, for instance, been a focus for religious instincts: many scene members avow adherence to revived Norse paganism. More troublingly, a number of bands have framed their enthusiasm for the Vikings in terms that are explicitly nationalist or racist, extolling the superiority of a supposedly ‘pure’ primordial Scandinavian culture. In this way, Viking metal represents a telling reflex of the ongoing politically-charged appropriation of the medieval past across popular culture as a whole.
Medievalism and Identity Construction in Pagan Folk Music
Authors: Troyer Scott R.
Published: March 2020

European interest in its pagan or pre-Christian past has grown and flourished over the past two centuries, from Jean-Jacques Rousseau’s theorization of an ancient, polytheistic nature-based folk religion in the eighteenth century to the iconic 1973 horror film The Wicker Man and its failed 2006 remake. As popular interest has grown around this topic, so too have various groups claiming the heritage of medieval pagan Europe. These modern Pagans face the challenge of constructing a distinct identity tied to a pre-Christian past in a world where medieval pagan culture was suppressed and assimilated, creating a significant temporal gap between ancient practitioners and their more recent successors. Pagans often face this challenge by constructing identities that run counter to the modern, Christian-influenced world, revere a natural world untouched by industrial or postindustrial civilizations, and celebrate the human body. Throughout the past half century, Pagan musicians like the German band Faun and UK-based Omnia have cultivated particular identities through varied references to an idealized pagan Middle Ages. In their outputs, medievalism functions to establish an Otherness to modern society and Christianity, support an ecocentric message, and imagine a liberation of the human body from Christian oppression.
Indigenous Christianities
Authors: Orta Andrew
Published: March 2020

From the earliest moments of the colonial encounter, indigenous Christianity has been an object of scrutiny. This chapter examines indigenous Christianity in its connection with a founding problem of Latin American studies: the asymmetrical encounter of indigenous communities with external powers and the resulting complex of social, political, and economic entanglements is the origin story of the project. The discussion is framed around two correlated arguments. First, like many other “Spanish” forms, Christianity was quickly insinuated as a self-evident and potent component of indigenous experience. This had cosmological as well as more prosaic implications. Within this context, indigenous locality—the ground of indigenous Christianities—is best examined not as an insular embattled survival (the “closed corporate community” of classical social science), but as an ever-emergent project of cultural production undertaken always with respect to a more inclusive sacred and social universe. The second argument concerns the ways this founding entanglement has become constitutive of indigenous locality, and advocates approaching Christianity less as an index of degrees of assimilation or change, and more as a dynamic cultural resource and frame of continuing encounter that remains a generative component of an emerging indigenous modernity.
Bilateral Fascia Lata Flap: An Alternative for Massive Abdominal Wall Defect Repair
Authors: De Luna Gallardo Daniel , Cárdenas Salomon Carlos Michel , Barrera García Gabriel , Posada Torres José Antonio , Poucel Sánchez Medal Fernando
Published: March 2020

The abdominal wall represents a unique structure of dermo-myotendinous conformation that is considered a surgical challenge. The musculocutaneous pedicled flap, using tensor fasciae latae muscle (TFL), is a technique of abdominal wall repair, and it is becoming a more frequent reconstructive procedure. It is a well-suited procedure because it provides both a semirigid fascia layer and adequate skin coverage. We present a case of a 61-year-old man with the diagnosis of squamous cell carcinoma of the bladder, clinical stage IV (T4bN1M1), complicated with an ileo-recal-urethrocutaneous fistula. We reconstructed a massive defect of the abdominal wall by rotating bilateral pedicled TFL flaps. The therapeutic plan comprised 2 surgical procedures. The first surgical intervention was intended to obtain and temporarily fix the flap, and to allow the delay phenomenon to occur. Three weeks later, we performed the abdominal wall reconstruction by repositioning the bilateral TFL flaps and placing a dual prolene with regenerated oxidized cellulose mesh. We performed a successful palliative procedure in a terminal oncologic patient. Combined with a massive oncologic procedure (done by the oncologic surgeon), we were able to solve the cutaneous fistula and provided a significant improvement in the quality of life. The patient was discharged with no procedure-related complications. He has remained healthy 18 months after surgery, and there has been no evidence of ventral hernia. Bilateral TFL flaps represent a viable alternative for primary or secondary abdominal wall reconstruction in selected cases. This reconstructive strategy should be considered when plastic and reconstructive surgeon faces large and complex abdominal wall defects, associated with significant lack of skin cover.
Reconstruction of a Monodactylous Hand with Microsurgical Free Foot-to-Hand Transfer in Split-Hand/Split-Foot Malformation with Tibial Aplasia
Authors: Sabapathy S. Raja , Venkatramani Hari , Mohan Monusha , Zhang Dafang
Published: March 2020

Split-hand/split-foot malformation with long bone deficiency (SHLFD syndrome) is a rare congenital disorder, which may be sporadic or autosomal dominant with incomplete penetrance. When complete tibial aplasia is seen, the mainstay of treatment is amputation and lower limb prosthesis. This rare constellation of congenital differences presents an opportunity for microsurgical free tissue transfer using the principle of “spare parts” to improve the functionality of the hand. We present a rare case of split-hand/split-foot malformation with a monodactylous right hand and complete tibial aplasia, treated with microsurgical free foot-to-hand transfer at the time of lower limb amputation, reconstructing key pinch. At the latest 8 months follow-up, the patient had no pain, active key pinch, and ambulated independently with prostheses. He was able to use his right hand independently for a number of daily activities, such as stacking blocks, drinking from a cup, and playing with toys.
Multi-Level Predictors of Discharges Against Medical Advice: Identifying Contributors to Variation Using an All-Payer Database
Authors: Onukwugha Eberechukwu , Nagarajan Madhu , Offurum Ada , Gulati Mangla , Alfandre David
Published: March 2020

There is increasing evidence of the role of non–patient-level factors on discharge against medical advice (DAMA), but limited quantitative information regarding the extent of their impact. This study quantifies the contribution of discharge-level and hospital-level factors to the variation in DAMA. We grouped variables from the 2014 National Inpatient Sample data and ran incremental mixed-effects logit models with grouping at the level of the discharge, the hospital, and the census region. We obtained the intraclass correlation coefficients (ICCs), and evaluated the incremental change in ICC. The final sample included 2,687,430 discharges. 12.8% of the identified variation in the probability of DAMA was associated with the hospital, and 1.2% of the variation was associated with the census division in which the hospital was located. The final, fully-adjusted model had 7.3% of variation in DAMA associated with the hospital-level, with the greatest percentage reductions because of the addition of patient demographics. Even after adjusting for measured patient-level characteristics, there was a contribution of non–patient-level factors to DAMA outcomes. The findings identify a role for a multi-level approach to addressing DAMA.
Relationship Between Preoperative Time of Fasting and Postoperative Nausea and Vomiting
Authors: Şişman Hamide , Aslan Fatma Eti , Alptekin Dudu , Akpolat Refiye
Published: March 2020

The study, conducted in Turkey, explored preoperative fasting in children and post operative complications. The design was prospective, comparative and descriptive. Children (n=82) between 7 and 18 who underwent general anesthesia and who, along with their parents, consented/assented, were included. The researchers note that fasting after midnight, the common practice, often resulted in very long fasting periods in children operated upon as the surgical day progressed. The length of time the child fasted was correlated with presence or absence of post operative nausea and vomiting using the Baxter BARF Scale. The findings report that the longer a child fasted, the more likely he or she was to vomit post operatively. The authors recommend a reconsideration of the potential time each child will be required to fast.
United States liver allocation
Authors: Heimbach Julie K.
Published: March 2020

Purpose of review

The current review discusses the system of liver allocation in the United States, the adoption of the national liver review board (NLRB), and the pending major change to the system of distribution (acuity circle model).

Recent findings

The system of liver allocation in the United States is based on the model for end-stage liver disease (MELD) score, a formula which uses commonly available tests (international normalized ratio, bilirubin, creatinine, and recently, sodium) prioritizes candidates on the waitlist according to likelihood of death without access to transplant. This review provides an overview of modifications to MELD allocation and well as a summary of the benefits and weaknesses. The review also details the pending major revision to the distribution of liver allografts, which attempts to reduce the geographic disparity in access by sharing across a broader geographic area. Finally, the review describes the implementation of the NLRB, which replaced the previous system in May 2019.

The system of liver allocation and distribution in the United States has been subject to ongoing optimization, though the recent adoption of the NLRB, and pending change to distribution will significantly impact the system with the goal of reducing geographic disparity.
Reduction of Extramedullary Complications in Patients With Acute Myeloid Leukemia/Myelodysplastic Syndrome Treated With Azacitidine
Authors: Shabanova Iren , Cada Michaela , Johnston Donna L. , Abbott Lesleigh S. , Leung Elaine W. , Schechter Tal , Dror Yigal , Klaassen Robert J.
Published: March 2020

The distinction between myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) often relies on an arbitrary marrow blast cutoff of 30% in pediatrics and 20% in adults. There is little data about the treatment of children with extramedullary myeloid malignancy that has features of both, MDS and AML. Herein, we report for the first time 2 patients MDS/AML (1 with Shwachman-Diamond syndrome and 1 with idiopathic MDS and monosomy 7) who presented with extramedullary complications, received treatment with azacitidine, achieved complete remission and subsequently underwent hematopoietic stem cell transplantation.
Successful Umbilical Cord Blood Transplantation With Reduced-intensity Conditioning for Acute Myeloid Leukemia in a Child With Shwachman-Diamond Syndrome
Authors: Yoshimura Satoshi , Mizuno Takanori , Osumi Tomoo , Shioda Yoko , Kiyotani Chikako , Terashima Keita , Deguchi Takao , Nakadate Hisaya , Kato Motohiro , Matsumoto Kimikazu , Tomizawa Daisuke
Published: March 2020

Outcomes of patients with Shwachman-Diamond syndrome (SDS) who developed myeloid malignancies are poor because of refractory disease and high hematopoietic stem cell transplantation-related mortality. We herein report a case of a 7-year-old girl with SDS who developed acute myeloid leukemia with monosomy 7. She was successfully treated with chemotherapy followed by unrelated cord blood transplantation with reduced-intensity conditioning consisting of fludarabine, melphalan, and high-dose cytarabine without significant toxicity. Reduced-intensity conditioning presented in this report might be a preferable option for SDS patients with acute myeloid leukemia, although further evaluation in a larger number of similar cases is necessary.
Hard Science and “Soft” Skills
Authors: Davidson Sandra
Published: March 2020

Since the 1990s, complexity science has been utilized as a metaphor for understanding health care organizations and new ways of leading within them. In this article, 3 principles of complexity leadership put forth by Porter-O'Grady and Malloch in the text Quantum Leadership are explored: (1) wholes are not just the sum of their parts; (2) all health care is local; and (3) value is now the centerpiece of service delivery. Each of these principles is discussed from a 20th-century “organization as machine” perspective, a complexity science perspective, and a complex relational processes (CRP) view. The CRP lens provides a useful bridge from the hard science (nonhuman) systems metaphor to what we often think of as the soft skills of relationship building and communication. CRP does this by drawing on philosophy and the social sciences of sociology and psychology as a way to humanize the nonhuman metaphors of complexity science. This opens up new ways of understanding and talking about leadership in organizations. This shifts our traditional thinking of individuals as leaders to a more relational process of complex relational leading that occurs between people within organizations.
Organizational Trust, Psychological Empowerment, and Organizational Commitment Among Licensed Practical Nurses
Authors: Loes Chad N. , Tobin Mary B.
Published: March 2020

In this study, we examine the influence of organizational trust on organizational commitment among licensed practical nurses (LPNs). Guided by prior research and theory, we also consider whether psychological empowerment mediates the influence of organizational trust on organizational commitment. To accomplish these tasks, we examine data from our survey of all registered LPNs in a Midwestern US state on their levels of organizational trust, psychological empowerment, and organizational commitment. Using path decomposition procedures, we isolate the net effect of organizational trust on organizational commitment into total, direct, and indirect effects. Our findings suggest that organizational trust is positively associated with higher levels of organizational commitment. Furthermore, more than a fifth of this relationship is mediated through one's level of psychological empowerment. These findings provide some insight into antecedents of organizational commitment among LPNs. The results of this investigation are especially timely considering the extant issues associated with staffing levels in facilities employing LPNs in the United States.
Vitreimonas flagellata gen. nov., sp. nov., a novel member of the family Hyphomonadaceae isolated from an activated sludge sample
Authors: Asem Mipeshwaree Devi , Salam Nimaichand , Zheng Wei , Liao Li-Hua , Zhang Xiao-Tong , Han Ming-Xian , Jiao Jian-Yu , Guo Feng , Li Wen-Jun
Published: March 2020

A coccobacilli-shaped proteobacterium, designated strain SYSU XM001T, was isolated from an activated sludge sample collected from JiMei sewage treatment plant, Xiamen, PR China. Cells were Gram-stain-negative, catalase-positive and oxidase-negative. The 16S rRNA gene sequence of strain SYSU XM001T shared less than 92 % sequence identities with members of the class

Alphaproteobacteria

, with highest sequence similarity to

Aquidulcibacter paucihalophilus

TH1-2T (91.6 %; family

Hyphomonadaceae

, order

Rhodobacterales

). The strain exhibited growth at 25–37 °C, pH 7.0–9.0 and in the presence of up to 1 % (w/v) NaCl. Its chemotaxonomic features included ubiquinone-10 as the respiratory isoprenologue, iso-C16 : 0, 10-methyl C16 : 0 TSBA and anteiso-C17 : 0 as major cellular fatty acids and monoglycosyldiglyceride, glucuronopyranosyldiglyceride and two unidentified glycolipids as the main polar lipids. The DNA G+C content was determined to be 62.9 % (draft genome). Analyses of the phylogenetic data and differences in the chemotaxonomic and biochemical features from related genera in the family

Hyphomonadaceae

indicated that strain SYSU XM001T merits representation of a novel species of a novel genus, for which the name Vitreimonas flagellata gen. nov., sp. nov. is proposed. The type strain of Vitreimonas flagellata is SYSU XM001T (=CGMCC 1.16661T=KCTC 62915T).
Sulfurimonas xiamenensis sp. nov. and Sulfurimonas lithotrophica sp. nov., hydrogen- and sulfur-oxidizing chemolithoautotrophs within the Epsilonproteobacteria isolated from coastal sediments, and an emended description of the genus Sulfurimonas
Authors: Wang Shasha , Jiang Lijing , Liu Xuewen , Yang Suping , Shao Zongze
Published: March 2020

Strains 1-1NT and GYSZ_1T were isolated from marine sediments collected from the coast of Xiamen, PR China. Cells of the two strains were Gram-stain-negative, rod-shaped or slightly curved. Strain 1-1NT was non-motile, whereas strain GYSZ_1T was motile by means of one polar flagellum. The temperature, pH and salinity concentration ranges for growth of 1-1NT were 10–45 °C (optimum 30 °C), pH 5.5–8.0 (optimum 7.0) and 0–90 g l−1 NaCl (optimum 50 g l−1), while the growth of GYSZ_1T occurred at 4–45 °C (optimum 33 °C), pH 5.0–8.5 (optimum 6.5) and 5–90 g l−1 NaCl (optimum 20 g l−1). The two novel isolates were obligate chemolithoautotrophs capable of growth using hydrogen, thiosulfate, sulfide or elemental sulfur as the sole energy source, and nitrate, elemental sulfur or molecular oxygen as an electron acceptor. The major fatty acids of 1-1NT were C16 : 1ω7c, C16 : 0, C18 : 1ω7c and C18 : 0, while the predominant fatty acids of strain GYSZ_1T were C16 : 1ω7c, C16 : 0, C18 : 1ω7c and C14 : 0 3-OH. The DNA G+C contents of 1-1NT and GYSZ_1T were 34.5 mol% and 33.2 mol%, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that 1-1NT and GYSZ_1T represented members of the genus

Sulfurimonas

, with the highest sequence similarities to

Sulfurimonas crateris

SN118T (97.4 %) and

Sulfurimonas denitrificans

DSM 1251T (94.7 %), respectively. However, 1-1NT and GYSZ_1T shared 95.5 % similarity of 16S rRNA gene sequences, representing different species of the genus

Sulfurimonas

. On the basis of the physiological properties and the results of phylogenetic analyses, including average nucleotide identity and in silico DNA–DNA hybridization values, strains 1-1NT and GYSZ_1T represent two novel species within the genus

Sulfurimonas

, for which the names Sulfurimonas xiamenensis sp. nov. and Sulfurimonas lithotrophica sp. nov. are proposed, with the type strains 1-1NT (=MCCC 1A14514T=KCTC 15851T) and GYSZ_1T (=MCCC 1A14739T=KCTC 15853T), respectively. Our results also justify an emended description of the genus

Sulfurimonas

.
Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences
Authors: McNaughton Anna L. , Revill Peter A. , Littlejohn Margaret , Matthews Philippa C. , Ansari M. Azim
Published: March 2020

Hepatitis B virus (HBV) is a diverse, partially double-stranded DNA virus, with 9 genotypes (A–I), and a putative 10th genotype (J), characterized thus far. Given the broadening interest in HBV sequencing, there is an increasing requirement for a consistent, unified approach to HBV genotype and subgenotype classification. We set out to generate an updated resource of reference sequences using the diversity of all genomic-length HBV sequences available in public databases. We collated and aligned genomic-length HBV sequences from public databases and used maximum-likelihood phylogenetic analysis to identify genotype clusters. Within each genotype, we examined the phylogenetic support for currently defined subgenotypes, as well as identifying well-supported clades and deriving reference sequences for them. Based on the phylogenies generated, we present a comprehensive set of HBV reference sequences at the genotype and subgenotype level. All of the generated data, including the alignments, phylogenies and chosen reference sequences, are available online (https://doi.org/10.6084/m9.figshare.8851946) as a simple open-access resource.
Predicting Inpatient Glucose Levels and Insulin Dosing by Machine Learning on Electronic Health Records
Authors: Liu Xiran , Jankovic Ivana , Chen Jonathan H
Published: March 2020

Poorly controlled glucose levels are associated with serious morbidity and mortality in hospitalized patients. Hospital diabetes management aims to maintain the glucose level within a desired range, primarily via insulin administration. Current inpatient glucose control relies significantly on expert knowledge, but this results in large variability and often suboptimal blood sugars in practice. We applied supervised machine learning methods to electronic health record (EHR) data to build predictive models that can inform inpatient insulin management. We found that individual blood glucose levels and insulin dosing are highly erratic and cannot be predicted precisely (MAE 28mg/dL, R2 0.2). However, prescribing decisions can still be driven by the more reliable predictions of average daily glucose levels (MAE 21mg/dL, R2 0.4) and whether any patient’s glucose levels will be higher than the clinically desired range in the next day (sens 0.73, spec 0.79).
A unifying model to predict variable drug response for personalised medicine
Authors: van der Lee Maaike , Allard William G. , Vossen Rolf H.A.M , Baak-Pablo Renée F. , Menafra Roberta , Deiman Birgit A.L.M. , Deenen Maarten J. , Neven Patrick , Johansson Inger , Gastaldello Stefano , Ingelman-Sundberg Magnus , Guchelaar Henk-Jan , Swen Jesse J. , Anvar Seyed Yahya
Published: March 2020

Pharmacogenomics is a key component of personalized medicine. It promises a safer and more effective drug treatment by individualizing the choice of drug and dose based on an individual’s genetic profile1,2. The majority of commonly prescribed drugs are metabolized by a small set of Cytochrome P450 (CYP) enzymes3. In clinical practice, genetic biomarkers are being used to categorize patients into predefined *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. Yet, this approach has important limitations as it leaves a large part of variability in drug response unexplained4,5. Here, we present a novel approach and introduce a continuous scale (instead of categorical) assignments to predict metabolic enzyme activity. The proposed strategy uses full gene sequencing data, a neural network model and CYP2D6 mediated tamoxifen metabolism from a prospective study of 561 breast cancer patients. The model explains 79% of the interindividual variability in CYP2D6 activity compared to 54% with the conventional approach. It is capable of assigning accurate enzyme activity to alleles containing previously uncharacterized combinations of variants and were replicated in an independent cohort of tamoxifen treated patients, a cohort of Venlafaxine users as well as in vitro functional assays using HEK cells. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP450 enzyme activity and thereby enables more accurate prediction of individual drug response.
A modular chromosomally integrated toolkit for ectopic gene expression inVibrio cholerae
Authors: Dalia Triana N. , Chlebek Jennifer L. , Dalia Ankur B.
Published: March 2020

The ability to express genes ectopically in bacteria is essential for diverse academic and industrial applications. Two major considerations when utilizing regulated promoter systems for ectopic gene expression are (1) the ability to titrate gene expression by addition of an exogenous inducer and (2) the leakiness of the promoter element in the absence of the inducer. Here, we describe a modular chromosomally integrated platform for ectopic gene expression inVibrio cholerae. We compare the broadly used promoter elements Ptacand PBADto versions that have an additional theophylline-responsive riboswitch (Ptac-riboswitch and PBAD-riboswitch). These constructs all exhibited unimodal titratable induction of gene expression, however, max induction varied with Ptac> PBAD> PBAD-riboswitch > Ptac-riboswitch. We also developed a sensitive reporter system to quantify promoter leakiness and show that leakiness for Ptac> Ptac-riboswitch > PBAD; while the newly developed PBAD-riboswitch exhibited no detectable leakiness. We demonstrate the utility of the tightly inducible PBAD-riboswitch construct using the dynamic activity of type IV competence pili inV. choleraeas a model system. The modular chromosomally integrated toolkit for ectopic gene expression described here should be valuable for the genetic study ofVibrio choleraeand could be adapted for use in other species.
Prophages are associated with extensive CRISPR-Cas auto-immunity
Authors: Nobrega Franklin L. , Walinga Hielke , Dutilh Bas E. , Brouns Stan J.J.
Published: March 2020

CRISPR-Cas systems require discriminating self from non-self DNA during adaptation and interference. Yet, multiple cases have been reported of bacteria containing self-targeting spacers (STS), i.e. CRISPR spacers targeting protospacers on the same genome. STS has been suggested to reflect potential auto-immunity as an unwanted side effect of CRISPR-Cas defense, or a regulatory mechanism for gene expression. Here we investigated the incidence, distribution, and evasion of STS in over 100,000 bacterial genomes. We found STS in all CRISPR-Cas types and in one fifth of all CRISPR-carrying bacteria. Notably, up to 40% of I-B and I-F CRISPR-Cas systems contained STS. We observed that STS-containing genomes almost always carry a prophage and that STS map to prophage regions in more than half of the cases. Despite carrying STS, genetic deterioration of CRISPR-Cas systems appears to be rare, suggesting a level of escape from the potentially deleterious effects of STS by other mechanisms such as anti-CRISPR proteins and CRISPR target mutations. We propose a scenario where it is common to acquire an STS against a prophage, and this may trigger more extensive STS buildup by primed spacer acquisition in type I systems, without detrimental autoimmunity effects. The mechanisms of auto-immunity evasion create tolerance to STS-targeted prophages, and contribute both to viral dissemination and bacterial diversification.
Role of the C-terminal tail in regulating Proteinase Activated Receptor 2 (PAR2) signalling
Authors: Thibeault Pierre E. , Ramachandran Rithwik
Published: March 2020

The C-terminal tail of G-protein-coupled receptors contain important regulatory sites that enable interaction with intracellular signalling effectors. Here we examine the relative contribution of the C-tail serine/threonine phosphorylation sites (Ser383-385, Ser387-Thr392) and the helix-8 palmitoylation site (Cys361) in signalling regulation downstream of the proteolytically-activated GPCR, PAR2. We examined Gαq/11-coupled calcium signalling, β-arrestin-1/-2 recruitment, and MAPK activation (p44/42 phosphorylation) by wild-type and mutant receptors expressed in a CRISPR/Cas9 PAR2-knockout HEK-293 cell background. We find that alanine substitution of the membrane proximal serine residues (Ser383-385Ala) had no effect on SLIGRL-NH2- or trypsin-stimulated β-arrestin recruitment. Alanine substitutions in the Ser387-Thr392cluster resulted in a large (∼50%) decrease in β-arrestin-1/2 recruitment triggered by the activating peptide, SLIGRL-NH2,but was without effect on trypsin-activated β-arrestin-1/-2 recruitment. Additionally, we find that alanine substitution of the helix-8 cysteine residue (Cys361Ala) led to a (∼50%) decrease in β-arrestin-1/-2 recruitment in response to both trypsin and SLIGRL-NH2. We further show that Gαq/11inhibition with YM254890, inhibited ERK phosphorylation by PAR2 agonists, while genetic deletion of β-arrestin-1/-2 by CRISPR/Cas9 enhanced MAPK activation. Knockout of β-arrestins also enhanced Gαq/11-mediated calcium signalling. In line with these findings, C-tail serine/threonine and cysteine residue mutants that have decreased β-arrestin recruitment also showed enhanced ERK activation. Thus, our studies point to multiple mechanisms that regulate β-arrestin interaction with PAR2 to regulate receptor-mediated signalling.
Saturation of influenza virus neutralization and antibody consumption can both lead to bistable growth kinetics
Authors: Xu Shilian , Yan Ada W. C. , Peck Heidi , Gillespie Leah , Barr Ian G. , Yang Xiaoyun , Turner Stephen J. , Donato Celeste M , Zhang Tonghua , Olshansky Moshe , Vijaykrishna Dhanasekaran
Published: March 2020

Influenza virus is a major human health threat. Neutralizing antibodies elicited through prior infection or vaccination play an irreplaceable role in protection from subsequent infection. The efficacy of antibody-dependent vaccines relies on both virus replication and neutralization, but their quantitative relationship was unknown. Here we use mathematical models to quantitatively investigate viral survivability determined by antibody concentration and inocula size. We performed focus reduction assays for 49 seasonal influenza A/H3N2 viruses circulating during 2017–2019 against influenza antisera raised in ferrets, and find that the antibody consumption rates of individual reactions were either small or large, and this was strongly positively correlated with virus saturation. Regardless of antibody consumption rate, virus-antibody interactions always lead to antibody-induced bistable viral kinetics. As a result, at a specific interval of antibody concentration, small viral inocula are eliminated but not large virus inocula, which is triggered by saturated virus neutralization or antibody consumption. Our finding highlights virus-antibody interaction with different antigenic properties, thereby explaining commonly observed influenza re-infection and enhancing vaccine efficiency.
Pollinator niche partitioning and asymmetric facilitation contribute to the maintenance of diversity
Authors: Wei Na , Kaczorowski Rainee L. , Arceo-Gómez Gerardo , O’Neill Elizabeth M. , Hayes Rebecca A. , Ashman Tia-Lynn
Published: March 2020

Mechanisms that favor rare species are key to the maintenance of diversity. One of the most critical tasks for biodiversity conservation is understanding how plant–pollinator mutualisms contribute to the persistence of rare species, yet this remains poorly understood. Using a process-based model that integrates plant–pollinator and interspecific pollen transfer networks with floral functional traits, we show that niche partitioning in pollinator use and asymmetric facilitation confer fitness advantage of rare species in a biodiversity hotspot. While co-flowering species filtered pollinators via floral traits, rare species showed greater pollinator specialization leading to higher pollination-mediated male and female fitness than abundant species. When plants shared pollinator resources, asymmetric facilitation via pollen transport dynamics benefited the rare species at the cost of the abundant ones, serving as an alternative diversity-promoting mechanism. Our results emphasize the importance of community-wide plant–pollinator interactions that affect reproduction for biodiversity maintenance.
Persistence of remnant boreal plants in the Chiricahua Mountains, southern Arizona
Authors: Fescenko Anda , Downer James A. , Fescenko Ilja
Published: March 2020

Boreal plants growing along southern edge of their range on isolated mountains in a hot desert matrix live near the extreme of their physiological tolerance. Such plants are considered to be sensitive to small changes in climate. We coupled field observations (1974, 1993, 2019) about the abundance and vigor of small populations of ten remnant boreal plant species persisting in uppermost elevation spruce-fir forests of the Chiricahua Mountains, together with a theoretical modeling of the species' tolerances to three climate change cues: warming, drought, and forest fire, in order to explore the persistence of frontier boreal plant species in the frame of climate changes. We hypothesized that populations of these cryophilic plants have declined or become locally extinct during an adverse warming period since 1993, enforced by two large forest fires (1994, 2011). We used plant functional traits and principal component analysis to model tolerances of the plants to combined actions of warming, drought, and forest fire. Our model predicted selective sensitivity to warming for two species: Vaccinium myrtillus and Rubus parviflorus, while possible decline of the other species could be explained by drought and/or fire. We surveyed the study area in 2019 and found eight of the ten species still occur in the area. Five species occurred in wet canyons at lower elevations, but three species persisted in low vigor at the uppermost elevation highly affected by fires. Both warming-sensitive species did not show signs of decline: population of R. parviflorus increased in abundance and vigor, while V. myrtillus persists without significant changes since 1993. Despite the recorded increase in temperature in the study area over one degree Celsius between years 1975-1993 and 1994-2019, our study did not find evidence of the direct warming effect on the observed species. We conclude that severe wildfires and multi-decadal decrease in precipitation rather than warming are the main limiting factors of the remnant boreal species remarkable but limited persistence in the Chiricahua Mountains. Our study demonstrates how field observations can be combined with modeling to evaluate species selective responses to different environmental stresses for better environmental management decisions, particularly in light of climate change.
Sarcoptic mange; an emerging threat to Chilean wild mammals?
Authors: Montecino-Latorre Diego , Napolitano Constanza , Briceño Cristóbal , Uhart Marcela M.
Published: March 2020

Sarcoptic mange has been anecdotally reported in Chilean wildlife during the last decade. Although this disease can have devastating outcomes for biodiversity, there is no comprehensive assessment of this potential threat in Chile. Because the current capacity to monitor sarcoptic mange and other wildlife diseases is limited in this country, we used abnormal alopecia to search for suspect cases across several sources of information to identify, to the extent available data allow, the location and temporal trends of wild mammals with this characteristic across Chile. We surveyed park rangers, examined rehabilitation center databases, and collated citizen and media reports. The information gathered suggests that observations of alopecic wild mammals, mainly foxes (Lycalopexsp.), their presence in the country, and the number of species fulfilling our case definition have increased over the last 15 years. Moreover, abnormally alopecic mammals are currently located broadly in Chile. We also confirmed the utility of abnormal alopecia to define a suspect sarcoptic mange case in the most commonly affected group,Lycalopexfoxes. Our findings are highly concerning from a conservation perspective. We thus emphasize the need for an urgent surveillance and management plan for sarcoptic mange and other diseases that may be threatening Chilean biodiversity.
Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts
Authors: Bi Qifang , Wu Yongsheng , Mei Shujiang , Ye Chenfei , Zou Xuan , Zhang Zhen , Liu Xiaojian , Wei Lan , Truelove Shaun A. , Zhang Tong , Gao Wei , Cheng Cong , Tang Xiujuan , Wu Xiaoliang , Wu Yu , Sun Binbin , Huang Suli , Sun Yu , Zhang Juncen , Ma Ting , Lessler Justin , Feng Tiejian
Published: March 2020

Background

Rapid spread of SARS-CoV-2 in Wuhan prompted heightened surveillance in Shenzhen and elsewhere in China. The resulting data provide a rare opportunity to measure key metrics of disease course, transmission, and the impact of control.

Methods

The Shenzhen CDC identified 391 SARS-CoV-2 cases from January 14 to February 12, 2020 and 1286 close contacts. We compare cases identified through symptomatic surveillance and contact tracing, and estimate the time from symptom onset to confirmation, isolation, and hospitalization. We estimate metrics of disease transmission and analyze factors influencing transmission risk.

Findings

Cases were older than the general population (mean age 45) and balanced between males (187) and females (204). Ninety-one percent had mild or moderate clinical severity at initial assessment. Three have died, 225 have recovered (median time to recovery is 21 days). Cases were isolated on average 4.6 days after developing symptoms; contact tracing reduced this by 1.9 days. Household contacts and those travelling with a case where at higher risk of infection (ORs 6 and 7) than other close contacts. The household secondary attack rate was 15%, and children were as likely to be infected as adults. The observed reproductive number was 0.4, with a mean serial interval of 6.3 days.

Interpretation

Our data on cases as well as their infected and uninfected close contacts provide key insights into SARS-CoV-2 epidemiology. This work shows that heightened surveillance and isolation, particularly contact tracing, reduces the time cases are infectious in the community, thereby reducing R. Its overall impact, however, is uncertain and highly dependent on the number of asymptomatic cases. We further show that children are at similar risk of infection as the general population, though less likely to have severe symptoms; hence should be considered in analyses of transmission and control.
Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition
Authors: Stopfer Lauren E , Mesfin Joshua M , Joughin Brian A , Lauffenburger Douglas A , White Forest M
Published: March 2020

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire’s response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking robust normalization controls. We describe a novel approach that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma to profile the immunopeptidome response to CDK4/6 inhibition and interferon gamma, known modulators of antigen presentation, we uncovered treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.
Cell-type specific outcome representation in primary motor cortex
Authors: Lavzin Maria , Levy Shahar , Benisty Hadas , Dubin Uri , Brosh Zohar , Aeed Fadi , Mensh Brett D. , Schiller Yitzhak , Meir Ron , Barak Omri , Talmon Ronen , Hantman Adam W. , Schiller Jackie
Published: March 2020

Adaptive movements are critical to animal survival. To guide future actions, the brain monitors different outcomes, including achievement of movement and appetitive goals. The nature of outcome signals and their neuronal and network realization in motor cortex (M1), which commands the performance of skilled movements, is largely unknown. Using a dexterity task, calcium imaging, optogenetic perturbations, and behavioral manipulations, we studied outcome signals in murine M1. We find two populations of layer 2-3 neurons, “success”- and “failure” related neurons that develop with training and report end-result of trials. In these neurons, prolonged responses were recorded after success or failure trials, independent of reward and kinematics. In contrast, the initial state of layer-5 pyramidal tract neurons contains a memory trace of the previous trial’s outcome. Inter-trial cortical activity was needed to learn new task requirements. These M1 reflective layer-specific performance outcome signals, can support reinforcement motor learning of skilled behavior.