bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicted dynamical couplings of protein residues characterize catalysis, transport and allostery
Authors: Alfayate Alvaro , Rodriguez Caceres Carlos , Gomes Dos Santos Helena , Bastolla Ugo
Published: April 2019

Motivation

Protein function is intrinsically linked to native dynamics, but the systematic characterization of functionally relevant dynamics remains elusive besides specific examples. Here we exhaustively characterize three types of dynamical couplings between protein residues: co-directionality (moving along collinear directions), coordination (small fluctuations of the interatomic distance) and deformation (the extent by which perturbations applied at one residue modify the local structure of the other one), which we analytically compute through the torsional network model.

Results

We find that ligand binding sites are characterized by large within-site coordination and co-directionality, much larger than expected for generic sets of residues with equivalent sequence distances. In addition, catalytic sites are characterized by high coordination couplings with other residues in the protein, supporting the view that the overall protein structure facilitates the catalytic dynamics. The binding sites of allosteric effectors are characterized by comparably smaller coordination and higher within-site deformation than other ligands, which supports their dynamic nature. Allosteric inhibitors are coupled to the active site more frequently through deformation than through coordination, while the contrary holds for activators. We characterize the dynamical couplings of the sodium-dependent Leucine transporter protein (LeuT). The couplings between and within sites progress consistently along the transport cycle, providing a mechanistic description of the coupling between the uptake and release of ions and substrate, and they highlight qualitative differences between the wild-type and a mutant for which chloride is necessary for transport.

Availability and implementation

The program tnm is freely available at https://github.com/ugobas/tnm

Supplementary information

Supplementary data are available at Bioinformatics online.
Bite performance surfaces of three ecologically divergent Iguanidae lizards: relationships with lower jaw bones
Authors: Simon Monique Nouailhetas , Brandt Renata , Kohlsdorf Tiana , Arnold Stevan J
Published: April 2019

Traits that interact to perform an ecologically relevant function are expected to be under multivariate non-linear selection. Using the lower jaw morphology as a biomechanical model, we test the hypothesis that lower jaw bones of lizards are subjected to stabilizing and correlational selection, associated with mechanical advantage and maximum bite force. We used three closely related tropidurine species that differ in size, head shape and microhabitat: Eurolophosaurus nanuzae, Tropidurus hispidus and Tropidurus semitaeniatus. We predicted a common pattern of correlational selection on bones that are part of in-levers or part of the out-lever of the lower jaw. The predicted pattern was found in E. nanuzae and T. hispidus, but this could not be shown to be statistically significant. For T. semitaeniatus, we found significant disruptive selection on a contrast involving the surangular, and also significant directional selection on linear combinations of traits in all species. The results indicate that the non-linear selection on lower jaw bones does not reflect an optimum to enhance mechanical advantage in all species. Divergent functional demands and specific ecological contexts of species seem relevant in shaping patterns of selection on morphology.
Growth differentiation factor 8 regulates SMAD2/3 signaling and improves oocyte quality during porcine oocyte maturation in vitro†
Authors: Yoon Junchul David , Hwang Seon-Ung , Kim Mirae , Jeon Yubyeol , Hyun Sang-Hwan
Published: April 2019

Growth differentiation factor 8 (GDF8), also known as myostatin, is a member of the transforming growth factor-β (TGF-β) family and has been identified as a strong physiological regulator of muscle differentiation. Recently, the functional role of GDF8 in reproductive organs has received increased interest following its detection in the human placenta and uterus. To investigate the effects of GDF8 during porcine oocyte in vitro maturation (IVM), we assessed the quality of matured oocytes. Furthermore, we investigated the specific gene transcription and protein activation levels in oocytes and cumulus cells after IVM and subsequent embryonic development after in vitro fertilization and parthenogenetic activation. Prior to these experiments, the concentration of GDF8 in porcine follicular fluid was determined. During the entire IVM period, 1.3 ng/mL GDF8 and its signaling inhibitor SB431542 (SB) at 5 μM were added as control, SB, SB + GDF8, and GDF8 groups, respectively. Our results demonstrate that supplementation with GDF8 during porcine oocyte IVM enhanced both meiotic and cytoplasmic maturation, with altered transcriptional patterns, via activation of Sma- and Mad-related protein 2/3 (SMAD2/3). Using the pharmacological inhibitor SB431542, we demonstrated that inhibition of GDF8-induced Smad2/3 signaling reduces matured oocyte quality. In conclusion, for the first time, we demonstrated paracrine factor GDF8 in porcine follicular fluid in vivo. Furthermore, we showed that GDF8 supplementation improved mature oocyte quality by regulating p38 mitogen-activated protein kinase phosphorylation and intracellular glutathione and reactive oxygen species levels during porcine IVM.
Intraflagellar transport protein 74 is essential for spermatogenesis and male fertility in mice†
Authors: Shi Lin , Zhou Ting , Huang Qian , Zhang Shiyang , Li Wei , Zhang Ling , Hess Rex A , Pazour Gregory J , Zhang Zhibing
Published: April 2019

Intraflagellar transport protein 74 (IFT74) is a component of the core intraflagellar transport complex, a bidirectional movement of large particles along the axoneme microtubules for cilia formation. In this study, we investigated its role in sperm flagella formation and discovered that mice deficiency in Ift74 gene in male germ cells were infertile with low sperm count and immotile sperm. The few developed spermatozoa displayed misshaped heads and short tails. Transmission electron microscopy revealed abnormal flagellar axonemes in the seminiferous tubules where sperm are made. Clusters of unassembled microtubules were present in the spermatids. Testicular expression levels of IFT27, IFT57, IFT81, IFT88, and IFT140 proteins were significantly reduced in the conditional Ift74 mutant mice, with the exception of IFT20 and IFT25. The levels of outer dense fiber 2 and sperm-associated antigen 16L proteins were also not changed. However, the processed A-Kinase anchor protein, a major component of the fibrous sheath, a unique structure of sperm tail, was significantly reduced. Our study demonstrates that IFT74 is essential for mouse sperm formation, probably through assembly of the core axoneme and fibrous sheath, and suggests that IFT74 may be a potential genetic factor affecting male reproduction in man.
CXCR4 signaling at the ovine fetal–maternal interface regulates vascularization, CD34+ cell presence, and autophagy in the endometrium†
Authors: Runyan Cheyenne L , McIntosh Stacia Z , Maestas Marlie M , Quinn Kelsey E , Boren Ben P , Ashley Ryan L
Published: April 2019

Placenta development is characterized by extensive angiogenesis and vascularization but if these processes are compromised placental dysfunction occurs, which is the underlying cause of pregnancy complications such as preeclampsia and intrauterine growth restriction. Dysregulation of placental angiogenesis has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. The signaling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulates angiogenesis in other tissues, and may be central to placental vascularization. We hypothesized that CXCL12-CXCR4 signaling governs the pro-angiogenic placental microenvironment by coordinating production of central angiogenic factors and receptors and regulates endometrial cell survival essential for placental function and subsequent fetal longevity. The CXCR4 antagonist, AMD3100, was used to elucidate the role of CXCL12-CXCR4 signaling regarding uteroplacental vascular remodeling at the fetal–maternal interface. On day 12 postbreeding, osmotic pumps were surgically installed and delivered either AMD3100 or PBS into the uterine lumen ipsilateral to the corpus luteum. On day 20, endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections preserved for immunofluorescent analysis. In endometrium from ewes receiving AMD3100 infusion, the abundance of select angiogenic factors was diminished, while presence of CD34+ cells increased compared to control ewes. Ewes receiving AMD3100 infusion also exhibited less activation of Akt/mTOR signaling, and elevated LC3B-II, a marker of cellular autophagy in endometrium. This study suggests that CXCL12-CXCR4 signaling governs placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.
Genome-wide copy number variation analysis identified ANO1 as a novel oncogene and prognostic biomarker in esophageal squamous cell cancer
Authors: Yu Yue , Cao Jing , Wu Weibing , Zhu Quan , Tang Yu , Zhu Chengxiang , Dai Juncheng , Li Zhihua , Wang Jun , Xue Lei , Zhen Fuxi , Liu Jinyuan , Huang Chenjun , Zhao Fei , Zhou Yue , Wen Wei , Pan Xianglong , Wei Haixing , Zhu Yining , He Yaozhou , Que Jun , Wang Wei , Luo Jinhua , Xu Jing , Chen Liang
Published: April 2019

Copy number variations (CNVs) represent one of the most common genomic alterations. This study aimed to evaluate the roles of genes within highly aberrant genome regions in the prognosis of esophageal squamous cell cancer (ESCC). Exome sequencing data from 81 paired ESCC tissues were used to screen aberrant genomic regions. The associations between CNVs and gene expression were evaluated using gene expression data from the same individuals. Then, an RNA expression array profile from 119 ESCC samples was adopted for differential gene expression and prognostic analyses. Two independent ESCC cohorts with 315 subjects were further recruited to validate the prognostic value using immunohistochemistry tests. Finally, we explored the potential mechanism of our identified novel oncogene in ESCC. In total, 2003 genes with CNVs were observed, of which 76 genes showed recurrent CNVs in more than three samples. Among them, 32 genes were aberrantly expressed in ESCC tumor tissues and statistically correlated with CNVs. Strikingly, 4 (CTTN, SHANK2, INPPL1 and ANO1) of the 32 genes were significantly associated with the prognosis of ESCC patients. Patients with a positive expression of ANO1 had a poorer prognosis than ANO1 negative patients (overall survival rate: 42.91% versus 26.22% for ANO1−/+ samples, P < 0.001). Functionally, ANO1 promoted ESCC cell proliferation, migration and invasion by activating transforming growth factor-β pathway. Knockdown of ANO1 significantly inhibited tumor progression in vitro and in vivo. In conclusion, ANO1 is a novel oncogene in ESCC and may serve as a prognostic biomarker for ESCC.
Bitter-Induced Salivary Proteins Increase Detection Threshold of Quinine, But Not Sucrose
Authors: Martin Laura E , Kay Kristen E , Torregrossa Ann-Marie
Published: April 2019

Exposures to dietary tannic acid (TA, 3%) and quinine (0.375%) upregulate partially overlapping sets of salivary proteins which are concurrent with changes in taste-driven behaviors, such as rate of feeding and brief access licking to quinine. In addition, the presence of salivary proteins reduces chorda tympani responding to quinine. Together these data suggest that salivary proteins play a role in bitter taste. We hypothesized that salivary proteins altered orosensory feedback to bitter by decreasing sensitivity to the stimulus. To that end, we used diet exposure to alter salivary proteins, then assessed an animal’s ability to detect quinine, using a 2-response operant task. Rats were asked to discriminate descending concentrations of quinine from water in a modified forced-choice paradigm, before and after exposure to diets that alter salivary protein expression in a similar way (0.375% quinine or 3% TA), or 1 of 2 control diets. Control animals received either a bitter diet that does not upregulate salivary proteins (4% sucrose octaacetate), or a nonbitter diet. The rats exposed to salivary protein-inducing diets significantly decreased their performance (had higher detection thresholds) after diet exposure, whereas rats in the control conditions did not alter performance after diet exposure. A fifth group of animals were trained to detect sucrose before and after they were maintained on the 3% TA diet. There was no significant difference in performance, suggesting that these shifts in threshold are stimulus specific rather than task specific. Taken together, these results suggest that salivary proteins reduce sensitivity to quinine.
Efficacy and Safety of Ascending Dosages of Moxidectin and Moxidectin-albendazole Against Trichuris trichiura in Adolescents: A Randomized Controlled Trial
Authors: Keller Ladina , Palmeirim Marta S , Ame Shaali M , Ali Said M , Puchkov Maxim , Huwyler Jörg , Hattendorf Jan , Keiser Jennifer
Published: April 2019

Background

Preventive chemotherapy is the main strategy to control soil-transmitted helminth (STH) infections. Albendazole and mebendazole are ubiquitously used, but they are not sufficiently effective against Trichuris trichiura. Moxidectin might be a useful addition to the small drug armamentarium. However, the optimal dosage of moxidectin alone and in combination with albendazole against T. trichiura and other STHs has not yet been determined.

Methods

A Phase II, randomized, placebo-controlled, dose-finding trial was conducted in 2 secondary schools on Pemba Island, Tanzania. Using a computer-generated list, T. trichiura–infected adolescents were randomly assigned to 7 treatment arms: 8, 16, or 24 mg of moxidectin monotherapy; 8, 16, or 24 mg of moxidectin plus 400 mg of albendazole combination therapy; or placebo. The primary outcome was cure rate (CR) against T. trichiura, analyzed 13 to 20 days after treatment by quadruple Kato-Katz thick smears.

Results

A total of 290 adolescents were enrolled (41 or 42 per arm). CRs against T. trichiura were 43, 46, and 44% for 8, 16, and 24 mg of moxidectin alone, respectively; 60, 62, and 66% for the same moxidectin dosages plus 400 mg of albendazole, respectively; and 12% for placebo. The moxidectin-albendazole arms also revealed higher CRs and egg reduction rates against hookworm than the monotherapy arms. Moxidectin and its combination with albendazole were well tolerated.

Conclusions

Moxidectin-albendazole is superior to moxidectin. There is no benefit of using doses above 8 mg, which is the recommended dose for onchocerciasis. The moxidectin-albendazole combination of 8 mg plus 400 mg should be investigated further to develop recommendations for appropriate control of STH infections.

Clinical Trials Registration

NCT03501251.
A Nationwide Spatiotemporal Analysis of Syphilis Over 21 Years and Implications for Prevention and Control in China
Authors: Tao Yusha , Chen Marcus Y , Tucker Joseph D , Ong Jason J , Tang Weiming , Wong Ngai Sze , Chu Minjie , Zhuang Xun , Fairley Christopher K , Zhang Lei
Published: April 2019

Syphilis control programs have been scaled up due to the substantial burden in China. We analyzed syphilis incidence according to demographic, spatiotemporal, and economic factors. The increasing latent syphilis diagnoses and declining congenital syphilis suggest the effectiveness of scale-up screening. However, primary and secondary cases persist, especially in inland provinces.
Prophylactic Versus Therapeutic Inoculation Treatments for Resistance to Influence
Authors: Compton Josh
Published: April 2019

One of the most significant departures from conventional inoculation theory is its intentional application for individuals already “infected”—that is, inoculation not as a preemptive strategy to protect existing positions from future challenges, but instead, inoculation as a means to change a position (e.g., from negative to positive) and to protect the changed position against future challenges. The issue is important for persuasion scholarship in general, as theoretical boundary conditions help at each stage of persuasion research development, serving as a guide for literature review, analysis, synthesis, research design, interpretation, theory building, and so on. It is an important issue for inoculation theory and resistance to influence research, specifically, for it gets at the very heart—and name and foundation—of inoculation theory. This article offers a theoretical analysis of inoculation theory used as both prophylactic and therapeutic interventions and concludes with a set of recommendations for inoculation theory scholarship moving forward.
Rhetorical Arbitrage: The Rhetoric of the Sharing Economy
Authors: Duerringer Christopher Michael
Published: April 2019

This article extends the growing conversation on the rhetoric of economics through a critical analysis of the rhetoric of the “sharing economy” firm Uber. After reconfiguring the economic concept of arbitrage from a rhetorical perspective, I demonstrate the means by which “ride sharing” services exploit their customers and workers. Ultimately, I contend that Uber’s rhetoric works by deploying the language of the private sphere in order that the company can operate like a taxi company even as it evades the obligations that ordinarily attach to providing taxi service to the public.
Work and Employment Characteristics of Deaf and Hard-of-Hearing Adults
Authors: Dammeyer Jesper , Crowe Kathryn , Marschark Marc , Rosica Mark
Published: April 2019

Studies have reported a higher level of unemployment among deaf and hard-of-hearing (DHH) adults compared to adults without hearing loss. However, little is known about factors explaining success in the labor market. This study presents the analysis of two data sets. The first was drawn from a survey of 804 DHH adults in Denmark. The second was a survey completed by 190 DHH adults with post-secondary qualification in the United States. In the Danish sample, among the spoken language users, higher ages, higher level of educational attainment, and no additional disabilities were associated with having a job. Among the sign language users, higher ages, higher level of educational attainment, earlier ages at hearing loss diagnosis, and not using cochlear implants were associated with having a job. In the US sample, male gender and better sign language skills were associated with having a job.
Transcatheter aortic valve implantation vs. surgical aortic valve replacement for treatment of symptomatic severe aortic stenosis: an updated meta-analysis
Authors: Siontis George C M , Overtchouk Pavel , Cahill Thomas J , Modine Thomas , Prendergast Bernard , Praz Fabien , Pilgrim Thomas , Petrinic Tatjana , Nikolakopoulou Adriani , Salanti Georgia , Søndergaard Lars , Verma Subodh , Jüni Peter , Windecker Stephan
Published: April 2019

Aims 

Owing to new evidence from randomized controlled trials (RCTs) in low-risk patients with severe aortic stenosis, we compared the collective safety and efficacy of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) across the entire spectrum of surgical risk patients.

Methods and results 

The meta-analysis is registered with PROSPERO (CRD42016037273). We identified RCTs comparing TAVI with SAVR in patients with severe aortic stenosis reporting at different follow-up periods. We extracted trial, patient, intervention, and outcome characteristics following predefined criteria. The primary outcome was all-cause mortality up to 2 years for the main analysis. Seven trials that randomly assigned 8020 participants to TAVI (4014 patients) and SAVR (4006 patients) were included. The combined mean STS score in the TAVI arm was 9.4%, 5.1%, and 2.0% for high-, intermediate-, and low surgical risk trials, respectively. Transcatheter aortic valve implantation was associated with a significant reduction of all-cause mortality compared to SAVR {hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.78–0.99], P = 0.030}; an effect that was consistent across the entire spectrum of surgical risk (P-for-interaction = 0.410) and irrespective of type of transcatheter heart valve (THV) system (P-for-interaction = 0.674). Transcatheter aortic valve implantation resulted in lower risk of strokes [HR 0.81 (95% CI 0.68–0.98), P = 0.028]. Surgical aortic valve replacement was associated with a lower risk of major vascular complications [HR 1.99 (95% CI 1.34–2.93), P = 0.001] and permanent pacemaker implantations [HR 2.27 (95% CI 1.47–3.64), P < 0.001] compared to TAVI.

Conclusion 

Compared with SAVR, TAVI is associated with reduction in all-cause mortality and stroke up to 2 years irrespective of baseline surgical risk and type of THV system.
Protein-based cardiogenic shock patient classifier
Authors: Rueda Ferran , Borràs Eva , García-García Cosme , Iborra-Egea Oriol , Revuelta-López Elena , Harjola Veli-Pekka , Cediel Germán , Lassus Johan , Tarvasmäki Tuukka , Mebazaa Alexandre , Sabidó Eduard , Bayés-Genís Antoni
Published: April 2019

Aims

Cardiogenic shock (CS) is associated with high short-term mortality and a precise CS risk stratification could guide interventions to improve patient outcome. Here, we developed a circulating protein-based score to predict short-term mortality risk among patients with CS.

Methods and results

Mass spectrometry analysis of 2654 proteins was used for screening in the Barcelona discovery cohort (n = 48). Targeted quantitative proteomics analyses (n = 51 proteins) were used in the independent CardShock cohort (n = 97) to derive and cross-validate the protein classifier. The combination of four circulating proteins (Cardiogenic Shock 4 proteins—CS4P), discriminated patients with low and high 90-day risk of mortality. CS4P comprises the abundances of liver-type fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1. Within the CardShock cohort used for internal validation, the C-statistic was 0.78 for the CardShock risk score, 0.83 for the CS4P model, and 0.84 (P = 0.033 vs. CardShock risk score) for the combination of CardShock risk score with the CS4P model. The CardShock risk score with the CS4P model showed a marked benefit in patient reclassification, with a net reclassification improvement (NRI) of 0.49 (P = 0.020) compared with CardShock risk score. Similar reclassification metrics were observed in the IABP-SHOCK II risk score combined with CS4P (NRI =0.57; P = 0.032). The CS4P patient classification power was confirmed by enzyme-linked immunosorbent assay (ELISA).

Conclusion

A new protein-based CS patient classifier, the CS4P, was developed for short-term mortality risk stratification. CS4P improved predictive metrics in combination with contemporary risk scores, which may guide clinicians in selecting patients for advanced therapies.
The Acidaminococcus sp. Cas12a nuclease recognizes GTTV and GCTV as non-canonical PAMs
Authors: Jacobsen Thomas , Liao Chunyu , Beisel Chase L
Published: April 2019

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) nuclease Acidaminococcus sp. Cas12a (AsCas12a, also known as AsCpf1) has become a popular alternative to Cas9 for genome editing and other applications. AsCas12a has been associated with a TTTV protospacer-adjacent motif (PAM) as part of target recognition. Using a cell-free transcription-translation (TXTL)-based PAM screen, we discovered that AsCas12a can also recognize GTTV and, to a lesser degree, GCTV motifs. Validation experiments involving DNA cleavage in TXTL, plasmid clearance in Escherichia coli, and indel formation in mammalian cells showed that AsCas12a was able to recognize these motifs, with the GTTV motif resulting in higher cleavage efficiency compared to the GCTV motif. We also observed that the -5 position influenced the activity of DNA cleavage in TXTL and in E. coli, with a C at this position resulting in the lowest activity. Together, these results show that wild-type AsCas12a can recognize non-canonical GTTV and GCTV motifs and exemplify why the range of PAMs recognized by Cas nucleases are poorly captured with a consensus sequence.
Potential for Sugar Maple to Provide High-Quality Sawlog Trees at the Northern Edge of Its Range
Authors: Guillemette François , Bédard Steve
Published: April 2019

The management of sugar maple (Acer saccharum) at the northern edge of its range is mainly oriented toward timber production, from trees of higher grades. However, both the quality of mature trees in natural stands and how the quality may vary depending on the silvicultural treatment are unknown, especially under northern conditions. The objective of this study was to describe the variation in stem quality of mature maple trees (diameter >33 cm) according to climatic, geographic or soil variables, and to evaluate the effects of a first selection cutting cycle on this quality. Annual temperature (1.7–4.1° C) was the most important variable explaining differences in the proportion of higher-grade trees, with a 16 percent gain associated with every additional increase in degrees Celsius. The practice of a first selection cutting was associated with an 11 percent gain in this proportion. Although the actual proportion of high-quality trees was below 35 percent on the coolest sites, a proper tree selection through silviculture could likely improve this proportion in future decades, whereas the potential effects of climate change are unclear.
Racial and Educational Disparities in Dementia and Dementia-Free Life Expectancy
Authors: Farina Mateo P , Hayward Mark D , Kim Jung Ki , Crimmins Eileen M
Published: April 2019

Objectives

We estimate life expectancy with and without dementia for Americans 65 years and older by education and race to examine how these stratification systems combine to shape disparities in later-life cognitive health.

Method

Based on the Health and Retirement Study (2000–2014), we use a multivariate, incidence-based life table approach to estimate life expectancy by cognitive health status for race–education groups. The models also simulate group differences in the prevalence of dementia implied by these rates.

Results

The life table results document notable race–education differences in dementia and dementia-free life expectancy, as well as stark differences in implied dementia prevalence. At each education level, blacks can expect to live more years with dementia and they have significantly higher rates of dementia prevalence. This distribution of disparities in the older population is anchored by 2 groups—blacks without a high school diploma and whites with some college or more.

Discussion

Dementia experience and dementia burden differ dramatically along race–education lines. Race and education combine to exaggerate disparities and they both have enduring effects. Future research should explicitly consider how race and education combine to influence dementia in the older American population.
DamMet: ancient methylome mapping accounting for errors, true variants, and post-mortem DNA damage
Authors: Hanghøj Kristian , Renaud Gabriel , Albrechtsen Anders , Orlando Ludovic
Published: April 2019

Background

Recent computational advances in ancient DNA research have opened access to the detection of ancient DNA methylation footprints at the genome-wide scale. The most commonly used approach infers the methylation state of a given genomic region on the basis of the amount of nucleotide mis-incorporations observed at CpG dinucleotide sites. However, this approach overlooks a number of confounding factors, including the presence of sequencing errors and true variants. The scale and distribution of the inferred methylation measurements are also variable across samples, precluding direct comparisons.

Findings

Here, we present DamMet, an open-source software program retrieving maximum likelihood estimates of regional CpG methylation levels from ancient DNA sequencing data. It builds on a novel statistical model of post-mortem DNA damage for dinucleotides, accounting for sequencing errors, genotypes, and differential post-mortem cytosine deamination rates at both methylated and unmethylated sites. To validate DamMet, we extended gargammel, a sequence simulator for ancient DNA data, by introducing methylation-dependent features of post-mortem DNA decay. This new simulator provides direct validation of DamMet predictions. Additionally, the methylation levels inferred by DamMet were found to be correlated to those inferred by epiPALEOMIX and both on par and directly comparable to those measured from whole-genome bisulphite sequencing experiments of fresh tissues.

Conclusions

DamMet provides genuine estimates for local DNA methylation levels in ancient individual genomes. The returned estimates are directly cross-sample comparable, and the software is available as an open-source C++ program hosted at https://gitlab.com/KHanghoj/DamMet along with a manual and tutorial.
Bony Patchwork: Mosaic Patterns of Evolution in the Skull of Electric Fishes (Apteronotidae: Gymnotiformes)
Authors: Evans Kory M , Vidal-García Marta , Tagliacollo Victor A , Taylor Samuel J , Fenolio Dante B
Published: April 2019

Mosaic evolution refers to the pattern whereby different organismal traits exhibit differential rates of evolution typically due to reduced levels of trait covariation through deep time (i.e., modularity). These differences in rates can be attributed to variation in responses to selective pressures between individual traits. Differential responses to selective pressures also have the potential to facilitate functional specialization, allowing certain traits to track environmental stimuli more closely than others. The teleost skull is a multifunctional structure comprising a complex network of bones and thus an excellent system for which to study mosaic evolution. Here we construct an ultrametric phylogeny for a clade of Neotropical electric fishes (Apteronotidae: Gymnotiformes) and use three-dimensional geometric morphometrics to investigate patterns of mosaic evolution in the skull and jaws. We find strong support for a developmental, three-module hypothesis that consists of the face, braincase, and mandible, and we find that the mandible has evolved four times faster than its neighboring modules. We hypothesize that the functional specialization of the mandible in this group of fishes has allowed it to outpace the face and braincase and evolve in a more decoupled manner. We also hypothesize that this pattern of mosaicism may be widespread across other clades of teleost fishes.
Spatial statism
Authors: Hirschl Ran , Shachar Ayelet
Published: April 2019

In this Foreword, we wish to insert a degree of innovation into debates about global law and the supposed demise of state-based public law. We do so by asking how considerations of space, place and density impact the conceptualization and utilization of state power in a world of growing complexity and interdependence. In an array of key policy areas, we examine in considerable detail how state-centered public law defines, and where required redefines, space and territory in order to tame potential threats—local or global, vertical and horizontal—to the state’s territorial sovereignty. Our exploration highlights the tremendous versatility and creativity of states in deploying and stretching, through the classic tools of public law, their spatial and juridical tentacles in a new and complex global environment. Taken in conjunction, these illustrations suggest that the disregard for and dismissal of the state as a potent actor in the public law arena is premature. State sovereignty may be metamorphosing, but it is evidently not vanishing.
On Zeroes of Random Polynomials and an Application to Unwinding
Authors: Steinerberger Stefan , Wu Hau-tieng
Published: April 2019

Let $\mu $ be a probability measure in $\mathbb{C}$ with a continuous and compactly supported density function, let $z_1, \dots , z_n$ be independent random variables, $z_i \sim \mu $, and consider the random polynomial $ p_n(z) = \prod _{k=1}^{n}{(z - z_k)}.$ We determine the asymptotic distribution of $\left \{z \in \mathbb{C}: p_n(z) = p_n(0)\right \}$. In particular, if $\mu $ is radial around the origin, then those solutions are also distributed according to $\mu $ as $n \rightarrow \infty $. Generally, the distribution of the solutions will reproduce parts of $\mu $ and condense another part on curves. We use these insights to study the behavior of the Blaschke unwinding series on random data.
In-hospital mortality among incident hemodialysis older patients in Peru
Authors: Herrera-Añazco Percy , Ortiz Pedro J , Peinado Jesus E , Tello Tania , Valero Fabiola , Hernandez Adrian V , Miranda J Jaime
Published: April 2019

Background

Understanding the pattern of mortality linked to end stage renal disease (ESRD) is important given the increasing ageing population in low- and middle-income countries.

Methods

We analyzed older patients with ESRD with incident hemodialysis, from January 2012 to August 2017 in one large general hospital in Peru. Individual and health system-related variables were analyzed using Generalized Linear Models (GLM) to estimate their association with in-hospital all-cause mortality. Relative risk (RR) with their 95% confidence intervals (95% CI) were calculated.

Results

We evaluated 312 patients; mean age 69 years, 93.6% started hemodialysis with a transient central venous catheter, 1.7% had previous hemodialysis indication and 24.7% died during hospital stay. The mean length of stay was 16.1 days (SD 13.5). In the adjusted multivariate models, we found higher in-hospital mortality among those with encephalopathy (aRR 1.85, 95% CI 1.21-2.82 vs. without encephalopathy) and a lower in-hospital mortality among those with eGFR ≤7 mL/min (aRR 0.45, 95% CI 0.31-0.67 vs. eGFR>7 mL/min).

Conclusions

There is a high in-hospital mortality among older hemodialysis patients in Peru. The presence of uremic encephalopathy was associated with higher mortality and a lower estimated glomerular filtration rate with lower mortality.
Examination of Homing Behaviors in Two Species of Crayfish Following Translational Displacements
Authors: Kamran Maryam , Moore Meghan E , Fisher Andrea M , Moore Paul A
Published: April 2019

Synopsis

Crayfish have been model systems for examining complex behaviors and the underlying neural mechanisms that guide these behaviors. While spatial learning has been examined in a subset of crayfish species, homing behaviors remained largely unexamined. Here we examined homing behavior following translational displacements in a primary burrowing (Creaserinus fodiens) and tertiary burrowing species (Faxonius rusticus). Individuals of both species were placed in an arena with artificial burrows embedded within the arena floor. The arena floor was fitted with a panel, which served as a treadmill belt to allow for translational displacement. Individuals were displaced after they had left the burrows. The movement pathways of displaced crayfish were compared with those in two control groups, one which underwent no displacement and the second in which the treadmill belt was displaced but returned to its original position almost immediately. Homing success for displaced individuals of both species was considerably reduced in comparison to the control groups. Moreover, displaced primary burrowers had significantly lower homing success in comparison to displaced tertiary burrowers. Primary burrowers exhibited greater homing error and significantly impaired homing behaviors compared with tertiary burrowers. Furthermore, heading angles in displaced groups (of both species) were significantly higher than the control group of both species. Species-specific differences in homing success and homing error indicate that primary burrowers were more negatively impacted by translational displacements. These homing differences indicate that these two species of crayfish have differing homing strategies.
Optimizing clinical trials recruitment via deep learning
Authors: Gligorijevic Jelena , Gligorijevic Djordje , Pavlovski Martin , Milkovits Elizabeth , Glass Lucas , Grier Kevin , Vankireddy Praveen , Obradovic Zoran
Published: April 2019

Objective

Clinical trials, prospective research studies on human participants carried out by a distributed team of clinical investigators, play a crucial role in the development of new treatments in health care. This is a complex and expensive process where investigators aim to enroll volunteers with predetermined characteristics, administer treatment(s), and collect safety and efficacy data. Therefore, choosing top-enrolling investigators is essential for efficient clinical trial execution and is 1 of the primary drivers of drug development cost.

Materials and Methods

To facilitate clinical trials optimization, we propose DeepMatch (DM), a novel approach that builds on top of advances in deep learning. DM is designed to learn from both investigator and trial-related heterogeneous data sources and rank investigators based on their expected enrollment performance on new clinical trials.

Results

Large-scale evaluation conducted on 2618 studies provides evidence that the proposed ranking-based framework improves the current state-of-the-art by up to 19% on ranking investigators and up to 10% on detecting top/bottom performers when recruiting investigators for new clinical trials.

Discussion

The extensive experimental section suggests that DM can provide substantial improvement over current industry standards in several regards: (1) the enrollment potential of the investigator list, (2) the time it takes to generate the list, and (3) data-informed decisions about new investigators.

Conclusion

Due to the great significance of the problem at hand, related research efforts are set to shift the paradigm of how investigators are chosen for clinical trials, thereby optimizing and automating them and reducing the cost of new therapies.
Barriers and facilitators to clinical information seeking: a systematic review
Authors: Aakre Christopher A , Maggio Lauren A , Fiol Guilherme Del , Cook David A
Published: April 2019

Objective

The study sought to identify barriers to and facilitators of point-of-care information seeking and use of knowledge resources.

Materials and Methods

We searched MEDLINE, Embase, PsycINFO, and Cochrane Library from 1991 to February 2017. We included qualitative studies in any language exploring barriers to and facilitators of point-of-care information seeking or use of electronic knowledge resources. Two authors independently extracted data on users, study design, and study quality. We inductively identified specific barriers or facilitators and from these synthesized a model of key determinants of information-seeking behaviors.

Results

Forty-five qualitative studies were included, reporting data derived from interviews (n = 26), focus groups (n = 21), ethnographies (n = 6), logs (n = 4), and usability studies (n = 2). Most studies were performed within the context of general medicine (n = 28) or medical specialties (n = 13). We inductively identified 58 specific barriers and facilitators and then created a model reflecting 5 key determinants of information-seeking behaviors: time includes subthemes of time availability, efficiency of information seeking, and urgency of information need; accessibility includes subthemes of hardware access, hardware speed, hardware portability, information restriction, and cost of resources; personal skills and attitudes includes subthemes of computer literacy, information-seeking skills, and contextual attitudes about information seeking; institutional attitudes, cultures, and policies includes subthemes describing external individual and institutional information-seeking influences; and knowledge resource features includes subthemes describing information-seeking efficiency, information content, information organization, resource familiarity, information credibility, information currency, workflow integration, compatibility of recommendations with local processes, and patient educational support.

Conclusions

Addressing these determinants of information-seeking behaviors may facilitate clinicians' question answering to improve patient care.
Charities Can Increase the Effectiveness of Donation Appeals by Using a Morally Congruent Positive Emotion
Authors: Goenka Shreyans , van Osselaer Stijn M J
Published: April 2019

Prosocial organizations have different moral objectives. Some seek to promote welfare (e.g., Red Cross), but others seek to promote justice and equality (e.g., ACLU). Additionally, these organizations can induce different positive emotions to motivate donations. If organizations are seeking to promote different moral objectives using positive emotions, which positive emotion will be the most effective for their respective campaigns? We demonstrate how the congruency between the moral domain of an emotion and the moral objective of an organization plays a role in influencing prosocial behaviors. Charities that seek to increase care in society (e.g., disaster-relief charities) should utilize compassion in their promotion campaigns, but charities that seek to promote fairness and equality in society (e.g., human rights charities) should utilize gratitude in their promotion campaigns. One field study (N = 2,112) and four experiments (N = 2,100) demonstrate that utilizing a positive emotion congruent with the charity’s moral objective increases monetary donations and preferences. The preferences are driven by the moral concerns made salient by the respective emotions. Further, the preferences attenuate when exchange norms are made salient. Altogether, these results underscore the importance of considering moral congruence in consumption contexts.
Association Between Ownership of Imaging Equipment and Appropriateness of Staging Positron-Emission Tomography in Non-Hodgkin Lymphoma
Authors: Huntington Scott F , Zhu Weiwei , Hoag Jessica R , Wang Rong , Zeidan Amer M , Giri Smith , Podoltsev Nikolai A , Gore Steven D , Ma Xiaomei , Gross Cary P , Davidoff Amy J
Published: April 2019

Physician ownership of imaging equipment has been shown to be associated with greater use of low-value imaging. However, it is unclear whether ownership also influences utilization of appropriate imaging. We conducted a cohort study of older adults diagnosed with three non-Hodgkin lymphomas with distinct guideline recommendations concerning the use of positron emission tomography (PET) during staging (recommended, not recommended, or equivocal). We found patients who were treated by oncologists with PET ownership were more likely to receive a staging PET regardless of lymphoma subtype. However, the difference in utilization by ownership status was smallest (6%, 95% confidence interval = 2% to 11%, P = .01) in the setting of diffuse large B cell lymphoma, where consensus guidelines recommend routine use of PET. Overall, removing financial incentives related to imaging self-referral may reduce utilization during cancer care, with the potential for greatest impact on imaging of equivocal or low clinical utility.
The Effects of Survey Enhancements on the Quality of Reporting in the Medical Expenditure Panel Survey, 2008–2015
Authors: Zuvekas Samuel H , Biener Adam I , Hicks Wendy D
Published: April 2019

It is well established that survey respondents imperfectly recall health care use in surveys. However, careful attention to both survey design and fielding procedures can enhance recall. We examine the effects of a comprehensive, multi-pronged approach to changing field procedures in the Medical Expenditure Panel Survey (MEPS) to improve quality of health care use reporting. Conducted annually since 1996, the MEPS is the leading large-scale nationally representative health survey with detailed individual and household information on health care use and expenditures. These survey enhancements were undertaken in 2013–2014 because of concerns over a drop in the quality of reporting in 2010 that persisted into 2011–2012. The approach combined focused retraining of field supervisors and interviewers, developing quality metrics and reports for ongoing monitoring of interviewers, and revising advanced letters and materials sent to respondents.

We seek to determine the extent to which changes in field procedures and trainings improved interviewer and respondent behaviors associated with better reporting, and more importantly, improved reporting accuracy. We use longitudinal MEPS data from 2008 through 2015, combining household reported use with sociodemographic and health status characteristics, and paradata on the characteristics of the interviews and interviewers. We exploit the longitudinal data and timings of major trainings and changes in field procedures in regression models, separating out the effects of the trainings and other fielding changes to the extent possible.

We find that the 2013–2014 data quality improvement activities substantially improved reporting quality. Positive interviewer behaviors increased substantially to above pre-2010 levels, and utilization reporting has recovered to above pre-2010 levels, returning MEPS to trend. Importantly, these substantial gains occurred in 2013, prior to extensive in-person training for most of the field force.

We examine the lessons learned from this data quality initiative both for the MEPS program and for other large household surveys.
Paradoxical Hypercholesterolemia in an Otherwise Healthy Adult Man
Authors: Mcpherson Peter A
Published: April 2019

Hypercholesterolemia is characterized by serum cholesterol levels greater than 5 mmol per L. However, the distribution of cholesterol among lipoprotein classes has a significant bearing on diagnosis: high–low-density lipoprotein (LDL) cholesterol suggests familial hypercholesterolemia, whereas high–high-density lipoprotein (HDL) cholesterol is associated with hyperalphalipoproteinemia. On routine screening, a 23-year-old man presented with a total cholesterol level of 7.6 mmol per L but was subsequently found to have an HDL cholesterol level of 5.6 mmol per L. The clinical picture was confounded by his use of red yeast rice extract, a popular health supplement with hypolipidemic effects. In this case individual, the use of red yeast rice extract caused a hyperlipidemic state, ostensibly through downregulation of cholesteryl ester transfer protein. This case emphasizes the extended role of laboratory medicine in complex cases of hyperlipidemia.