bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantum model for impulsive stimulated Raman scattering
Authors: Glerean Filippo , Marcantoni Stefano , Sparapassi Giorgia , Blason Andrea , Esposito Martina , Benatti Fabio , Fausti Daniele
Published: March 2019

The interaction between ultrashort light pulses and non-absorbing materials is dominated by impulsive stimulated Raman scattering (ISRS). The description of ISRS in the context of pump&probe experiments is based on effective classical models describing the interaction between the phonon and pulsed electromagnetic fields. Here we report a theoretical description of ISRS where we do not make any semi-classical approximation and we treat both photonic and phononic degrees of freedom at the quantum level. The results of the quantum model are compared with semiclassical results and validated by means of spectrally resolved pump&probe measurements on α-quartz.
Of Hammers, Hurricanes, and History: Oscar Casares’s Brownsville, Postracial Affect, and the Latina/o Studies Field-Imaginary
Authors: Varon Alberto
Published: March 2019

This essay examines the material objects in Oscar Casares’s short story collection Brownsville (2003), focusing on the short story “RG.” The story’s objects encode racial difference in the contemporary US. as affect—a feeling one knows but cannot prove—prefiguring the supposed postracial moment of the early twenty-first century. The objects serve as textual and material strategies that attempt to suture historical antagonism and that offer a model for the “objects” of study in Latina/o studies. Building on and against work in affect theory and new materialism, the essay argues for an affective mode of latinidad that links history and the present, contemporary Latina/o Studies with the past.
The Aesthetic Oculoplastic Surgery Video Teleconference Consult
Authors: Hwang Christopher J , Eftekhari Kian , Schwarcz Robert M , Massry Guy G
Published: March 2019

Background

Skype video telemedicine consults are gaining popularity to evaluate patients from distant locations. No study has analyzed the utility of this means of patient evaluation in a cosmetic oculoplastic patient population.

Objectives

The authors sought to provide an evidence-based analysis of the utility of Skype video consults in a cosmetic oculoplastic surgery patient population with regards to patient demographics, reasons for consult, and procedural conversion rate.

Methods

A 1-year retrospective chart review (May 2016 to May 2017) of patients who underwent aesthetic oculoplastic Skype consults from 2 authors’ practices was performed. The authors analyzed patient demographics, referral source, chief complaint, location of residence, length of consult, and conversion to face-to-face consultation and intervention.

Results

Seventy-nine patients (60 women and 19 men) underwent Skype evaluations. Mean age was 49 years. Sixty-four consults (81%) lasted 15 minutes or less. Referral sources included the internet (67%), another physician (19%), self-referral (7.5%), referred by former patients (4%), and social media sites (2.5%). Consultations were obtained for revision (49%), or first-time (30%) eyelid/eyebrow surgery, cosmetic ptosis surgery (6%), laser skin procedures (5%), cosmetic orbital decompression (5%), and lower eyelid fat prolapse (5%). Twenty patients (25%) followed-up with in-person consultation. Sixteen of these patients (80%) had surgical (56%) or nonsurgical (44%) interventions.

Conclusions

Skype consults are an efficient, in-office modality to increase patient flow through the office, expand patient base, and generate income. In this report, 25% of Skype contacts followed-up with formal in-person consultations, of which 80% had surgical or nonsurgical interventions.
Reputation Anxiety: Consumer Background Checks and the Cultivation of Risk
Authors: Draper Nora A
Published: March 2019

This article examines the role consumer background check companies play in the construction of reputation anxiety. Through an examination of corporate blogs and sponsored stories, this article argues these companies cultivate risk along two related axes: (a) fear of dangerous others; and (b) fear of the threat posed by personal information available to others. Through sponsored stories and promotional material, these companies encourage people to mitigate risk by using consumer background check services to seek out information about others and review available details about themselves. Consistent with other forms of risk anxiety in modern cultures, the advice offered by these companies encourages the acceptance of personal responsibility around the acquisition of and response to this information. This article concludes by arguing the cultivation of reputation anxiety around digital skeletons—belonging both to others and to oneself—is rooted in gendered notions of safety and personal responsibility.
Stenosis of the celiac trunk is associated with anastomotic leak after Ivor–Lewis esophagectomy
Authors: Brinkmann S , Chang D H , Kuhr K , Hoelscher A H , Spiro J , Bruns C J , Schroeder W
Published: March 2019

Transthoracic esophagectomy with gastric tube formation is the surgical treatment of choice for esophageal cancer. The surgical reconstruction induces changes of gastric microcirculation, which are recognized as potential risk factors of anastomotic leak. This prospective observational study investigates the association of celiac trunk (TC) stenosis with postoperative anastomotic leak.

One hundred fifty-four consecutive patients with esophageal cancer scheduled for Ivor–Lewis esophagectomy were included. Preoperative staging computed tomography (CT) was used to identify TC stenosis. Any narrowing of the lumen due to atherosclerotic changes was classified as stenosis. Percentage of stenotic changes was calculated using the North American Symptomatic Carotid Endarterectomy Trial formula. Multivariable analysis was used to identify possible risk factors for leak.

The overall incidence of TC stenosis was 40.9%. Anastomotic leak was identified in 15 patients (9.7%). Incidence of anastomotic leak in patients with stenosis was 19.4% compared to 2.3% in patients without stenosis. Incidence of stenosis in patients with leak was 86.7% (13 of 15 patients) and significantly higher than 38.8% (54 of 139 patients) in patients without leak (P < 0.001). There was a significant difference in median degree of TC stenosis (50.0% vs 39.4%; P = 0.032) in patients with and without leak. In the multivariable model, TC stenosis was an independent risk factor for anastomotic leak (odds ratio: 5.98, 95% CI: 1.58–22.61).

TC stenosis is associated with postoperative anastomotic leak after Ivor–Lewis esophagectomy. Routine assessment of TC for possible stenosis is recommended to identify patients at risk.
Risk factors for ‘microsize’ vs. usual myocardial infarctions in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study
Authors: Almarzooq Zaid I , Colantonio Lisandro D , Okin Peter M , Richman Joshua S , Brown Todd M , Levitan Emily B , Bryan Joanna , Safford Monika M
Published: March 2019

Aims

A recently described phenomenon is that of myocardial infarction (MI) events that meet criteria for MI, but that have very low peak troponin elevations, so-called ‘microsize MI’. These events are very common and associated with increased risk of all-cause mortality. Our aim is to compare risk factors for microsize MI vs. usual MI events.

Methods and results

Among 24 470 participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort free of coronary heart disease at baseline, heart-related hospitalizations were expert adjudicated for MI using published guidelines. Myocardial infarctions were classified as microsize MI (peak troponin <0.5 ng/mL) or usual MI (peak troponin ≥0.5 ng/mL). Competing risk analyses assessed associations between baseline risk factors and incident microsize vs. usual MI. Between 2003 and 2013 there were 891 MIs; 279 were microsize MI and 612 were usual MI. Risk factors for both usual MI and microsize MI include age, gender, diabetes, and urinary albumin to creatinine ratio. Risk factors for only usual MI include Residence in the Stroke Belt and Buckle regions and current smoking. Black race was associated with a uniquely lower risk of usual MI.

Conclusion

The similarities in risk profiles suggest a possible common aetiology and should encourage clinicians to both treat reversible risk factors for microsize MI and to initiate secondary prevention strategies following these events until this emerging clinical entity is better understood. Future studies should further assess the clinical outcomes of these two entities and their effect on future management.
Morphological modification of the aortic annulus in tricuspid and bicuspid valves after aortic valve reimplantation: an electrocardiography-gated computed tomography study†
Authors: Chirichilli Ilaria , Irace Francesco , Weltert Luca , Tsuda Kazumasa , Scaffa Raffaele , Salica Andrea , Galea Nicola , De Paulis Ruggero
Published: March 2019

OBJECTIVES:

Aortic valve-sparing operations have been shown to produce fewer valve-related complications than valve replacement. The aortic root is a morphological and functional unit in which the annulus plays an important role on dynamism, shape and geometry of the valve with different results in bicuspid aortic valves (BAVs) or tricuspid aortic valves (TAVs). The aim is to evaluate the differences in the size and shape of the aortic annulus between native BAVs and TAVs using ECG-gated computed tomography (CT) after a reimplantation procedure.

METHODS:

We selected 35 patients scheduled for aortic valve reimplantation who underwent good-quality preoperative and postoperative ECG-gated contrast-enhanced CT scan of the aortic root. Twenty-three patients had TAV, 8 patients type 1 BAV and 4 patients type 0 BAV. Major diameter and minor diameter, perimeter (P) and area (A) were measured. The shape of the aortic annulus was considered ‘circular’ or ‘elliptic’ according to the Ellipticity Index. We also selected a subgroup of 18 patients (9 TAVs and 9 BAVs) to evaluate annular shape and size variations through the cardiac cycle and to study the expansibility both in the preoperative and in the postoperative phases.

RESULTS:

Preoperative CT scans showed an elliptic shape of TAVs (Ellipticity Index 1.3 ± 0.1), a circular shape of type 0 BAVs (1.1 ± 0.1) and an intermediate behaviour of type 1 BAVs, suggesting a possible gradual spectrum of circularity from TAVs to type 1 BAVs to type 0 BAVs. Postoperative CT scans did not show any significant difference in annular shape among the 3 groups, which demonstated a similar roundness, obviating the preoperative differences. Analysing the expansibility of the aortic annulus during the cardiac cycle, we observed that it was completely absent in the preoperative phase in BAVs, while in the postoperative phase, both TAVs and BAVs showed a small but similar expansibility after the annular reduction.

CONCLUSIONS:

There is a possible gradual spectrum in terms of shape, from native TAVs, to type 1 BAVS to type 0 BAVs. These differences are eliminated in the postoperative phase, suggesting an active role of the annuloplasty on the geometry of the aortic annulus. The preoperative analysis showed a complete inelasticity of BAVs, which was partly restored in the postoperative phase.
Comparative effectiveness of allopurinol and febuxostat for the risk of atrial fibrillation in the elderly: a propensity-matched analysis of Medicare claims data
Authors: Singh Jasvinder A , Cleveland John D
Published: March 2019

Aims

Gout is associated with a higher risk of atrial fibrillation (AF). Comparative effectiveness of allopurinol or febuxostat for reducing the AF risk is unknown, which was our study’s main objective.

Methods and results

We used the 5% Medicare Beneficiary cohort (≥65 years) from 2006 to 2012 to identify people with a new filled prescription for allopurinol or febuxostat, with a baseline period of 365 days without respective medication and without AF. We used 5:1 propensity-matched Cox regression analyses to assess whether allopurinol use differed from febuxostat use regarding the hazard ratio (HR) of incident AF. We found 25 732 eligible episodes in 23 135 beneficiaries. Of these, 2311 incident allopurinol or febuxostat use episodes (9%) ended in incident AF with crude incidence rates of 8.0 and 10.5 per 100 person-years, respectively. In propensity-matched analyses, compared with allopurinol, febuxostat was associated with higher HR of AF, 1.25 [95% confidence interval (CI) 1.05–1.48]. Compared with allopurinol <200 mg/day, febuxostat 80 mg/day was associated with significantly higher HR of AF, 1.62 (95% CI 1.16–2.27), but not febuxostat 40 mg/day or higher allopurinol doses. Compared with 1–180 days of allopurinol use, febuxostat use for 1–180 days was associated with significantly higher HR of AF, 1.36 (95% CI 1.10–1.67), but longer durations were not.

Conclusion

Febuxostat was associated with a higher risk of AF compared with allopurinol in older adults. Increased AF risk was noted with febuxostat 80 mg/day dose and was most evident in the first 6 months of use. These findings need replication.
Are cannabis users less likely to gain weight? Results from a national 3-year prospective study
Authors: Alshaarawy Omayma , Anthony James C
Published: March 2019

Background

Pre-clinical studies indicate increased food intake and weight gain as cannabinoid effects. Cross-sectional epidemiological studies, however, indicate lower prevalence of obesity among cannabis users. Here, we aim to study the weight-gain research question in the prospectively conducted National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

Methods

NESARC was designed to produce nationally representative estimates for the US population. Participants (aged 18+) completed computer-assisted personal interviews on cannabis use, body weight and height at Waves 1 (W1, 2001–02) and 2 (W2, 2004–05). General linear modelling yields estimates for change in body mass index (BMI) regressed on cannabis-use status, with covariate adjustment based on a conceptual model for BMI determinants (n = 33 000).

Results

At W2, 77% of the participants never used cannabis, 18% had discontinued use (‘quit’), 3% were initiates and 2% were persistent users. Estimated W1-to-W2 BMI change shows an increase for all subgroups. Compared with never-users (reference), inverse slope estimates and attenuated change (%) in BMI between W1 and W2 are seen for cannabis-use subgroups: quitters [β = –0.81; 95% confidence interval (CI) = –1.01, –0.60], initiates (β = –0.97; 95% CI = –1.36, –0.57) and persistent users (β = –1.26; 95% CI = –1.81, –0.72).

Conclusion

This new prospective study builds from anecdotes, pre-clinical studies and cross-sectional evidence on inverse associations linking cannabis use and obesity and shows an inverse cannabis–BMI increase association. Confirmatory studies with rigorous cannabis and BMI assays will be needed.
Predicting extragalactic distance errors using Bayesian inference in multimeasurement catalogues
Authors: Chaparro-Molano Germán , Cuervo Juan Carlos , Restrepo Gaitán Oscar Alberto , Torres Arzayús Sergio
Published: March 2019

We propose the use of robust, Bayesian methods for estimating extragalactic distance errors in multimeasurement catalogues. We seek to improve upon the more commonly used frequentist propagation-of-error methods, as they fail to explain both the scatter between different measurements and the effects of skewness in the metric distance probability distribution. For individual galaxies, the most transparent way to assess the variance of redshift independent distances is to directly sample the posterior probability distribution obtained from the mixture of reported measurements. However, sampling the posterior can be cumbersome for catalogue-wide precision cosmology applications. We compare the performance of frequentist methods versus our proposed measures for estimating the true variance of the metric distance probability distribution. We provide pre-computed distance error data tables for galaxies in three catalogues: NED-D, HyperLEDA, and Cosmicflows-3. Additionally, we develop a Bayesian model that considers systematic and random effects in the estimation of errors for Tully–Fisher (TF) relation derived distances in NED-D. We validate this model with a Bayesian p-value computed using the Freeman–Tukey discrepancy measure as a posterior predictive check. We are then able to predict distance errors for 884 galaxies in the NED-D catalogue and 203 galaxies in the HyperLEDA catalogue that do not report TF distance modulus errors. Our goal is that our estimated and predicted errors are used in catalogue-wide applications that require acknowledging the true variance of extragalactic distance measurements.
Electromagnetic Radiation
Authors: Freeman Richard R. , King James A. , Lafyatis Gregory P.
Published: March 2019

Electromagnetic Radiation is a graduate level book on classical electrodynamics with a strong emphasis on radiation. This book is meant to quickly and efficiently introduce students to the electromagnetic radiation science essential to a practicing physicist. While a major focus is on light and its interactions, topics in radio frequency radiation, x-rays, and beyond are also treated. Special emphasis is placed on applications, with many exercises and homework problems. The format of the book is designed to convey the basic concepts of a topic in the main central text in the book in a mathematically rigorous manner, but with detailed derivations routinely relegated to the accompanying side notes or end of chapter “Discussions.” The book is composed of four parts: Part I is a review of basic E&M, and assumes the reader has a had a good upper division undergraduate course, and while it offers a concise review of topics covered in such a course, it does not treat any given topic in detail; specifically electro- and magnetostatics. Part II addresses the origins of radiation in terms of time variations of charge and current densities within the source, and presents Jefimenko’s field equations as derived from retarded potentials. Part III introduces special relativity and its deep connection to Maxwell’s equations, together with an introduction to relativistic field theory, as well as the relativistic treatment of radiation from an arbitrarily accelerating charge. A highlight of this part is a chapter on the still partially unresolved problem of radiation reaction on an accelerating charge. Part IV treats the practical problems of electromagnetic radiation interacting with matter, with chapters on energy transport, scattering, diffraction and finally an illuminating, application-oriented treatment of fields in confined environments.
Equity
Authors: Samet Irit
Published: March 2019

The Law of Equity is a unique junction where doctrinal private law, moral theory, and social perceptions of justice meet. This book explores the general principles that underlie Equity’s intervention in the Common Law, with Chapter 1 arguing that Equity should be preserved as a separate body of law which aims to align moral and legal duties in private law. Chapter 2 discusses the importance of proprietary estoppel and concludes with the argument that Equity, via the doctrine of proprietary estoppel, is redressing a significant failure in the Common Law to tackle behaviour that disregards both morality and efficiency. Chapter 3 deals with fiduciary law, highlighting the disadvantages of transforming the equitable duty of loyalty into an ordinary contractual obligation. Chapter 4 examines the clean hands doctrine, in which Equity employs the concept of integrity to construct a coherent system of reasoning about this highly-complex area. Finally, Chapter 5 discusses some findings from the analysis of fiduciary law, proprietary estoppel, and the clean hands doctrine. It highlights the family resemblance between the different doctrines we survey, and points out three areas where the distinctive nature of Equity serves the legal ideal of Accountability Correspondence, in a way that often increases the efficiency of the system.
Improving diagnosis and monitoring of treatment response in pulmonary tuberculosis using the molecular bacterial load assay (MBLA)
Authors: Sabiiti Wilber , Azam Khalide , Kuchaka Davis , Mtafya Bariki , Bowness Ruth , Oravcova Katarina , Farmer Eoghan C W , Honeyborne Isobella , Evangelopoulos Dimitrios , McHugh Timothy D , Xiao Han , Khosa Celso , Rachow Andrea , Heinrich Norbert , Kampira Elizabeth , Davies Gerry , Bhatt Nilesh , Ntinginya Nyanda Elias , Viegas Sofia , Jani Ilesh , Kamdolozi Mercy , Mdolo Aaron , Khonga Margaret , Boeree Martin J , Philips Patrick PJ , Sloan Derek J , Hoelscher Michael , Kibiki Gibson Sammy , Gillespie Stephen H
Published: March 2019

Objectives

Better outcomes in tuberculosis require new diagnostic and treatment monitoring tools. In this paper we evaluated the utility of a marker ofM. tuberculosisviable count, the Molecular Bacterial Load assay (MBLA) for diagnosis and treatment monitoring of tuberculosis in a high burden setting.

Methods

Patients with smear positive pulmonary tuberculosis from two sites in Tanzania and one each in Malawi and Mozambique. Sputum samples were taken weekly for the first 12 weeks of treatment and evaluated by MBLA and mycobacterial growth indicator tube method (MGIT).

Results

The results of high and low positive control samples confirmed inter site reproducibility. Over the 12 weeks of treatment there was a steady decline in the viable bacterial load as measured by the MBLA that corresponds to rise in time to a positive result (TTP) in the Mycobacterial Growth Indicator Tube. Both MBLA and MGIT provided similar time to test negativity. Importantly, as treatment progressed samples in MGIT were increasingly likely to be contaminated, which compromised the acquisition of results but did not affect MBLA samples.

Conclusions

MBLA produces a reproducible measure ofMtbviable count comparable to that of MGIT that is not compromised by contamination in a real-world setting. As a molecular test, the results can be available in as little as four hours and could allow health care professionals to identify rapidly patients who are failing therapy.
Distinct YFV lineages co-circulated in the Central-Western and Southeastern Brazilian regions from 2015 to 2018
Authors: Delatorre Edson , de Abreu Filipe Vieira Santos , Ribeiro Ieda Pereira , Gómez Mariela Martínez , dos Santos Alexandre Araújo Cunha , Ferreira-de-Brito Anielly , Santos Neves Maycon Sebastião Alberto , Bonelly Iule , de Miranda Rafaella Moraes , Furtado Nathália Dias , Souza Raphael Lidiane Menezes , de Fátima Fernandes da Silva Lucileis , de Castro Márcia Gonçalves , Ramos Daniel Gaskauskas , Martins Romano Alessandro Pecêgo , Kallás Esper Georges , Paulo Vicente Ana Carolina , Bello Gonzalo , Lourenço-de-Oliveira Ricardo , Bonaldo Myrna Cristina
Published: March 2019

The current outbreak of yellow fever virus (YFV) that is afflicting Brazil since the end of 2016 probably originated from a re-introduction of YFV from endemic areas into the non-endemic Southeastern Brazil. However, the lack of genomic sequences from endemic regions hinders the tracking of YFV’s dissemination routes. We assessed the origin and spread of the ongoing YFV Brazilian outbreak analyzing a new set of YFV strains infecting humans, non-human primates (NHP) and mosquitoes sampled across five Brazilian states from endemic and non-endemic regions between 2015 and 2018. We found two YFV sub-clade 1E lineages circulating in NHP from Goiás state (GO), resulting from independent viral introductions into the Araguaia tributary river basin: while the strain from 2017 clustered intermingled with Venezuelan YFV strains from 2000, the YFV strain sampled in 2015 clustered with sequences of the current YFV outbreak in the Brazilian Southeastern region (named YFV2015-2018 lineage), displaying the same molecular signature associated to the current YFV outbreak. After its introduction in GO at around mid-2014, the YFV2015-2018 lineage followed two paths of dissemination outside GO, originating two major YFV sub-lineages: 1) the YFVMG/ES/RJ sub-lineage spread sequentially from the eastern area of Minas Gerais state to Espírito Santo and then to Rio de Janeiro states, following the Southeast Atlantic basin; 2) the YFVMG/SP sub-lineage spread from the southwestern area of Minas Gerais to the metropolitan region of São Paulo state, following the Paraná basin. These results indicate the ongoing YFV outbreak in Southeastern Brazil originated from a dissemination event from GO almost two years before its recognition at the end of 2016. From GO this lineage was introduced in Minas Gerais state at least two times, originating two sub-lineages that followed different routes towards densely populated areas. The spread of YFV outside endemic regions for at least four years stresses the imperative importance of the continuous monitoring of YFV to aid decision-making for effective control policies aiming the increase of vaccination coverage to avoid the YFV transmission in densely populated urban centers.
Programmable bacteria induce durable tumor regression and systemic antitumor immunity
Authors: Chowdhury Sreyan , Hinchliffe Taylor E. , Castro Samuel , Coker Courtney , Arpaia Nicholas , Danino Tal
Published: March 2019

SUMMARY PARAGRAPH

Synthetic biology is driving a new era of medicine through the genetic programming of living cells1,2. This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics3–5. One particular focus area has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo6–8. Here, we engineered a non-pathogenic E. coli to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb)9, an anti-phagocytic receptor commonly overexpressed in several human cancers10,11. We show that intratumoral delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in a syngeneic tumor model. Moreover, we report that local injection of CD47nb bacteria stimulates systemic antitumor immune responses that reduce the growth of untreated tumors – providing, to the best of our knowledge, the first demonstration of an abscopal effect induced by a bacteria cancer therapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.
Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels
Authors: Wang Zhe , Chen Han , Bartz Traci M. , Bielak Lawrence F. , Chasman Daniel I. , Feitosa Mary F. , Franceschini Nora , Guo Xiuqing , Lim Elise , Noordam Raymond , Richard Melissa A. , Wang Heming , Cade Brian , Adrienne Cupples L. , de Vries Paul S. , Giulanini Franco , Lee Jiwon , Lemaitre Rozenn N. , Martin Lisa W. , Reiner Alex P. , Rich Stephen S. , Schreiner Pamela J. , Sidney Stephen , Sitlani Colleen M. , Smith Jennifer A. , van Dijk Ko Willems , Yao Jie , Zhao Wei , Fornage Myriam , Kardia Sharon L.R. , Kooperberg Charles , Liu Ching-Ti , Mook-Kanamori Dennis O , Province Michael A. , Psaty Bruce M. , Redline Susan , Ridker Paul M. , Rotter Jerome I. , Boerwinkle Eric , Morrison Alanna C.
Published: March 2019

Background

Alcohol intake influences plasma lipid levels and such effects may be modulated by genetic variants.

Objective

We aimed to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Design

In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 34,153 European Americans from five discovery studies and 32,275 individuals from six replication studies. Rare and low-frequency protein coding variants (minor allele frequency ≤ 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (GxE) test and a joint test of genetic main and GxE interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least two drinks per week, were considered.

Results

We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3 and CD300LG) remained significant after conditioning on the common index single nucleotide polymorphism (SNP) identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on TG was discovered at a Bonferroni corrected significance level (p-value <5×10−5) and replicated (p-value <0.013 for the interaction test) inSMC5.

Conclusions

In conclusion, this study applied new gene-based statistical approaches to uncover the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels.
A spatial cell culture model for predicting chemotherapy dosing strategies
Authors: Zhu Shu , Deb Dhruba , Danino Tal
Published: March 2019

Predicting patient responses to chemotherapy regimens is a major challenge in cancer treatment. To do this requires quantitative mathematical models to predict optimal dose and frequency for a particular drug, and experimental model systems such as three-dimensional organoids that accurately recapitulate the tumor microenvironment and heterogeneity. However, tracking the spatial dynamics of multiple cell types in three-dimensions can be a significant challenge in terms of time and throughput. Here we develop a two-dimensional system that allows for simple tracking of cell populations via fluorescence microscopy for modeling spatial dynamics in tumors. We first develop multiple 4T1 breast cancer cell lines resistant to varying concentrations of doxorubicin, and demonstrate how well mixed and spatially heterogeneous populations expand in a two-dimensional colony. We subject cell populations to varied dose and frequency of chemotherapy and measure colony growth radius and populations. We then build a mathematical model to describe the dynamics of both chemosensitive and chemoresistant populations, where we determine which number of doses can produce the smallest tumor size based on parameters in the system. In the future, this system can be adapted to quickly optimize dosing strategies in the setting of heterogeneous cell types or patient derived cells with varied chemoresistance.
Monarch butterfly declines reported in Boyle et al. (2019) are biased by unexamined changes in museum collections over time
Authors: Wepprich Tyson
Published: March 2019

Museum records provide an underutilized source of information for documenting long-term changes in phenology, species interactions, and trait evolution. However, non-systematic collection data must be treated carefully if they are to approximate abundance, as trends may be confounded with spatial or temporal changes in sampling effort. Boyle et al. (2019b) argue that the relative abundance of Eastern North American Monarch butterflies (Danaus plexippus) has been in a long-term decline since the mid-20th century, following a similar decline in milkweed (Asclepias spp.) herbarium records. I demonstrate that this reported abundance trend is biased by the choice to standardize Monarch records as a proportion of all Lepidoptera collected. The sampling of Lepidoptera has changed systematically over time to favor moths, causing the apparent trend in Monarch records. With the data standardized more appropriately, I show that the trend in Monarch records shows no mid-century decline and increases over recent decades. As the trend in Monarch museum specimens contradicts the recent trend in Monarch abundance documented from systematic population monitoring, I argue that these records are unreliable for abundance estimates. The conclusion in Boyle et al. (2019b) that Monarch declines started in the mid-20th century is unwarranted both because the trend is biased by sampling changes in museum records and because the trend in Monarch records, when corrected, does not correspond with real-world population abundance.
The laminar profile of sleep spindles in humans
Authors: Ujma Péter P. , Hajnal Boglárka , Bódizs Róbert , Gombos Ferenc , Erőss Loránd , Wittner Lucia , Halgren Eric , Cash Sydney , Ulbert István , Fabó Dániel
Published: March 2019

Sleep spindles are generated in thalamocortical, corticothalamic and possibly cortico-cortical circuits. Previous hypotheses suggested that slow and fast spindles or spindles with various spatial extent may be generated in different circuits with various cortical laminar innervation patterns. We used NREM sleep EEG data recorded from four human epileptic patients undergoing presurgical electrophysiological monitoring with subdural electrocorticographic grids (ECoG) and implanted laminar microelectrodes penetrating the cortex (IME). The position of IME electrodes within cortical layers was confirmed using postsurgical histological reconstructions. Many micro-domain spindles detected on the IME occurred only in one layer and were absent from the ECoG, but with increasing amplitude simultaneous detection in other layers and on the ECoG became more likely. Macro-domain spindles sufficiently large to be detected on the ECoG were in contrast usually accompanied by IME spindles. Neither micro-domain nor macro-domain spindle cortical profiles were strongly associated with sleep spindle frequency or globality. Multiple-unit and single-unit activity during spindles, however, was heterogeneous across spindle types, but also across layers and subjects. Our results indicate that extremely local spindles may occur in any cortical layer, but co-occurrence at other locations becomes likelier with increasing amplitude and the relatively large spindles detected on ECoG channels have a stereotypical laminar profile. We found no compelling evidence that different spindle types are associated with different laminar profiles, suggesting that they are generated in cortical and thalamic circuits with similar cortical innervation patterns. Local neuronal activity is a stronger candidate mechanism for driving functional differences between spindles subtypes.
Dietary restriction induces post-transcriptional regulation of longevity genes
Authors: Rollins Jarod A. , Snow Santina S. , Kapahi Pankaj , Rogers Aric N.
Published: March 2019

Dietary restriction increases lifespan through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome ofC. eleganssubjected to dietary restriction. Transcription of muscle regulatory and structural genes increased, while increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of post-transcriptional regulation identified putative roles for RNA binding proteins, RNA editing, microRNA, alternative splicing, and nonsense mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate lifespan. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally downregulated genes. Furthermore, 3’ UTR editing and intron retention increase under dietary restriction and correlate with diminished translation, while trans-spliced genes are refractory to reduced translation efficiency compared to messages with the native 5’ UTR. Finally, we find thatsmg-6andsmg-7, which are genes governing selection and turnover of nonsense mediated decay targets, are required for increased lifespan under dietary restriction.
Identification of RBPMS as a smooth muscle master splicing regulator via proximity of its gene with super-enhancers
Authors: Nakagaki-Silva Erick E. , Gooding Clare , Llorian Miriam , Jacob Aishwarya Griselda , Richards Frederick , Buckroyd Adrian , Sinha Sanjay , Smith Christopher W.J.
Published: March 2019

Alternative splicing (AS) programs are primarily controlled by regulatory RNA binding proteins (RBPs). It has been proposed that a small number of master splicing regulators might control cell-specific splicing networks and that these RBPs could be identified by proximity of their genes to transcriptional super-enhancers. Using this approach we identified RBPMS as a critical splicing regulator in differentiated vascular smooth muscle cells (SMCs). RBPMS is highly down-regulated during phenotypic switching of SMCs from a contractile to a motile and proliferative phenotype and is responsible for 20% of the AS changes during this transition. RBPMS directly regulates AS of numerous components of the actin cytoskeleton and focal adhesion machineries whose activity is critical for SMC function in both phenotypes. RBPMS also regulates splicing of other splicing, post-transcriptional and transcription regulators including the key SMC transcription factor Myocardin, thereby matching many of the criteria of a master regulator of AS in SMCs.
Noninvasive prenatal diagnosis for Hemophilia A by haplotype-based approach using cell-free fetal DNA in maternal plasma
Authors: He Zhihui , Chen Chao , Guo Fengyu , Jiang Lu , Zhu Yaping , Li Dan , Wu Renhua , Lu Rong , Zhao Mei , Chen Fang , Ni Peixiang , Sun Jun , Peng Zhiyu
Published: March 2019

Objectives

This study was used to demonstrate the feasibility of haplotype-based noninvasive prenatal diagnosis for Hemophilia A.

Methods

Two families affected by Hemophilia A participated in our study. Maternal haplotypes associated with pathogenic mutation was built using targeted region genotypes of mother and the proband. Combined with maternal pathogenic haplotype, a Hidden Markov Model was constructed to deduce fetal haplotype using high-coverage targeted sequencing of maternal plasma. The presence of pathogenic haplotype in male indicated affected fetus, in female indicated carrier. Prenatal diagnosis was confirmed with amniocentesis by long distance PCR.

Results

The haplotype-based noninvasive prenatal diagnosis was successfully performed in Hemophilia A. One fetus was identified to be normal, another fetus was identified as carrier, and the results were confirmed by amniocentesis .

Conclusion

Our research demonstrated the feasibility of noninvasive prenatal diagnosis for Hemophilia A by haplotype-based approach.
Efficient reaction deletion algorithms for redesign of constraint-based metabolic networks for metabolite production with weak coupling
Authors: Tamura Takeyuki
Published: March 2019

Background

Metabolic network analysis through flux balance is an established method for the computational redesign of production strains in metabolic engineering. The computational redesign is often based on reaction deletions from the original wild type networks. A key principle often used in this method is the production of target metabolites as by-products of cell growth. From a viewpoint of bioinformatics, it is very important to prepare a set of algorithms that can determine reaction deletions that achieve growth coupling whatever network topologies, target metabolites and parameter values will be considered in the future. Recently, the strong coupling-based method was used to demonstrate that the coupling of growth and production is possible for nearly all metabolites through reaction deletions in genome-scale metabolic models of Escherichia coli and Saccharomyces cerevisiae under aerobic conditions. However, when growing S. cerevisiae under anaerobic conditions, deletion strategies using the strong coupling-based method were possible for only 3.9% of all metabolites. Therefore, it is necessary to develop algorithms that can achieve growth coupling by reaction deletions for the conditions that the strong coupling-based method was not efficient.

Results

We developed an algorithm that could calculate the reaction deletions that achieve the coupling of growth and production for 91.3% metabolites in genome-scale models of S. cerevisiae under anaerobic conditions. This analysis was conducted for the worst-case-scenario using flux variability analysis. To demonstrate the feasibility of the coupling, we derived appropriate reaction deletions using the new algorithm for target production in which the search space was divided into small cubes (CubeProd).

Conclusions

We developed a novel algorithm, CubeProd, to demonstrate that growth coupling is possible for most metabolites in S.cerevisiae under anaerobic conditions. This may imply that growth coupling is possible by reaction deletions for most target metabolites in any genome-scale constraint-based metabolic networks. The developed software, CubeProd, implemented in MATLAB, and the obtained reaction deletion strategies are freely available.
Pharmacokinetics Modeling and Simulation of Voriconazole Dosing and Safety in Patients with Liver Cirrhosis
Authors: Wang Taotao , Yan Miao , Tang Dan , Dong Yuzhu , Zhu Li , Du Qian , Sun Dan , Xing Jianfeng , Dong Yalin
Published: March 2019

Voriconazole is used to treat invasive fungal disease and the optimal dose regimens are still unknown in cirrhotic Patients. The aim of this study was to determine the safety, to describe pharmacokinetics characteristics, and to optimize dosage regimens of voriconazole in cirrhotic patients. Data pertaining to voriconazole were collected retrospectively and analyzed using a population pharmacokinetics model. A total of 219 trough concentrations (Cmin) from 120 patients were analyzed. Voriconazole-related adverse events developed in 29 patients, with 69.0% of AEs developing within the first week after voriconazole treatment. The threshold Cmin for AEs was 5.12 mg/L. A one-compartment model with first-order absorption and elimination adequately described the data. The Child-Pugh class was the only covariate in final model. Voriconazole clearance in patients with Child-pugh A and B cirrhosis (CP-A/CP-B) and Child-pugh C cirrhosis (CP-C) were 1.79 L/h and 0.99 L/h, respectively, the volume of distribution was 159.6 L, and the oral bioavailability was 91.8%. The elimination half-life was significantly extended for up to 61.8 – 111.7 h in cirrhotic patients. Model-based simulations showed that the appropriate maintenance doses are 75 mg/12 h and 150 mg/24 h intravenously or orally for CP-A/CP-B patients, and 50 mg/12 h and 100 mg/24 h intravenously or orally for CP-C patients. The results support voriconazole maintenance doses in LC patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/CP-B patients compared to that for patients with normal liver function. Monitoring Cmin early could be a useful strategy to ensure the safety.
Ecological strategy and genetic load in the shepherd’s purse (Capsella bursa-pastoris) from the core and the limit of its natural range
Authors: Orsucci Marion , Milesi Pascal , Hansen Johanna , Girodolle Johanna , Glémin Sylvain , Lascoux Martin
Published: March 2019

Species range expansion is a complex process whose outcome depends on the interplay of demographic, environmental and genetic factors. In plants, self-fertilizing species that do not require a mate to reproduce usually show higher invasive ability. However, this comes at a cost as both selfing and bottlenecks occurring during colonization lead to an increase in deleterious mutations accumulation (genetic load). Although they are theoretically clearly spelled out, the relationships between genomic and phenotypic characteristics of expanding populations have hitherto rarely been characterized.

In the present study we analyzed how different accessions of the shepherd’s purse, C. bursa-pastoris, coming from the front of colonization or from the core of the natural range performed under increasing density of competitors. We first showed that, as expected, accessions from the front of colonization performed the worst for most life history traits compared with accessions from core populations. Second, competitor density had a negative impact on both vegetative growth and reproductive output in term of fruits production for all accessions. However, somewhat unexpectedly given their higher genetic load and their lower absolute performance, accessions from the front of colonization were less affected by competition than accessions from the core of the species range. This could be due to phenotypic tradeoffs and a shift in phenology that allow the accessions from the front of colonization to avoid competition. These results are discussed in terms of ecological strategies of expanding populations.
Islands in the desert: Environmental distribution modelling of endemic flora reveals the extent of Pleistocene tropical relict vegetation in southern Arabia
Authors: Borrell James S. , Issaey Ghudaina Al , Lupton Darach A. , Starnes Thomas , Hinai Abdulrahman Al , Hatmi Saif Al , Senior Rebecca A. , Wilkinson Tim , Milborrow Jo L.H. , Stokes-Rees Andrew , Patzelt Annette
Published: March 2019

Background and Aims

Southern Arabia is a global biodiversity hotspot with a high proportion of endemic desert-adapted plants. Here we examine evidence for a Pleistocene climate refugium in the southern Central Desert of Oman, and its role in driving biogeographical patterns of endemism.

Methods

Distribution data for seven narrow-range endemic plants were collected systematically across 195 quadrats, together with incidental and historic records. Important environmental variables relevant to arid coastal areas, including night time fog and cloud cover were developed for the study area. Environmental niche models were built and tuned for each species and spatial overlap examined.

Key Results

A region of the Jiddat Al Arkad reported independent high model suitability for all species. Examination of environmental data across southern Oman indicates that the Jiddat Al Arkad displays a regionally unique climate with higher intra-annual stability, due in part to the influence of the southern monsoon. Despite this, relative importance of environmental variables was highly differentiated among species, suggesting characteristic variables such as coastal fog are not major cross-species predictors at this scale.

Conclusions

The co-occurrence of a high number of endemic study species within a narrow monsoon-influenced region is indicative of a refugium with low climate change velocity. Combined with climate analysis, our findings provide strong evidence for a southern Arabian Pleistocene refugium in the Oman’s Central Desert. We suggest this refugium has acted as an isolated temperate and mesic island in the desert, resulting in the evolution of these narrow-range endemic flora. Based on the composition of species, this system may represent the northernmost remnant of a continuous belt of mesic vegetation formerly ranging from Africa to Asia, with close links to the flora of East Africa. This has significant implications for future conservation of endemic plants in an arid biodiversity hotspot.