bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Conditioned Pain Modulation on the Nociceptive Flexion Reflex in Healthy People
Authors: Dhondt Evy , Van Oosterwijck Sophie , Coppieters Iris , Danneels Lieven , Van Oosterwijck Jessica
Published: July 2019

Objectives:

The nociceptive flexion reflex (NFR) is a spinal reflex induced by painful stimuli resulting in a withdrawal response. Research has shown that the NFR is inhibited through endogenous pain inhibitory mechanisms, which can be assessed by conditioned pain modulation (CPM) paradigms. Although accumulating research suggests that the NFR can be affected by CPM, no clear overview of the current evidence exists. Therefore, the present review aimed at providing such a synthesis of the literature. In addition, the influence of personal factors on the CPM of the NFR was investigated.

Materials and Methods:

A systematic review was performed and reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using predefined inclusion criteria. Risk of bias was investigated according to the modified Newcastle-Ottawa Scale. Levels of evidence and strength of conclusion were assigned following the guidelines of the Dutch Institute for Healthcare Improvement.

Results:

Forty articles were included. There is some evidence that CPM produced by thermal or mechanical stimuli induces inhibitory effects on the NFR. However, inconclusive evidence exists with regard to the effect of electrical conditioning stimuli. While several personal factors do not affect CPM of the NFR, increased cognitive interference is associated with reduced NFR inhibition.

Discussion:

The present review demonstrates that certain types of nociceptive conditioning stimuli have the potential to depress, at the spinal level, nociceptive stimuli elicited from distant body regions. Although CPM of the NFR seems to be robust to the influence of several personal factors, it can be affected by cognitive influences.
Outcomes of Neonates With Complex Medical Needs
Authors: Kieran Emily , Sara Rahnuma , Claydon Jennifer , Hait Valoria , de Salaberry Julie , Osiovich Horacio , Shivananda Sandesh
Published: July 2019

Background:

Children with complex medical needs (CMN) are high healthcare resource utilizers, have varying underlying diagnoses, and experience repeated hospitalizations. Outcomes on neonatal intensive care (NICU) patients with CMN are unknown.

Purpose:

The primary aim is to describe the clinical profile, resource use, prevalence, and both in-hospital and postdischarge outcomes of neonates with CMN. The secondary aim is to assess the feasibility of sustaining the use of the neonatal complex care team (NCCT).

Methods:

A retrospective cohort study was conducted after implementing a new model of care for neonates with CMN in the NICU. All neonates born between January 2013 and December 2016 and who met the criteria for CMN and were cared for by the NCCT were included.

Results:

One hundred forty-seven neonates with a mean (standard deviation) gestational age of 34 (5) weeks were included. The major underlying diagnoses were genetic/chromosomal abnormalities (48%), extreme prematurity (26%), neurological abnormality (12%), and congenital anomalies (11%). Interventions received included mechanical ventilation (69%), parenteral nutrition (68%), and technology dependency at discharge (91%). Mortality was 3% before discharge and 17% after discharge. Postdischarge hospital attendances included emergency department visits (44%) and inpatient admissions (58%), which involved pediatric intensive care unit admissions (26%).

Implications for Practice:

Neonates with CMN have multiple comorbidities, high resource needs, significant postdischarge mortality, and rehospitalization rates. These cohorts of NICU patients can be identified early during their NICU course and serve as targets for implementing innovative care models to meet their unique needs.

Implications for Research:

Future studies should explore the feasibility of implementing innovative care models and their potential impact on patient outcomes and cost-effectiveness.
Porphyromonas gingivalis and rheumatoid arthritis
Authors: Perricone Carlo , Ceccarelli Fulvia , Matteo Saccucci , Di Carlo Gabriele , Bogdanos Dimitrios P. , Lucchetti Ramona , Pilloni Andrea , Valesini Guido , Polimeni Antonella , Conti Fabrizio
Published: July 2019

Purpose of review

To explore the pathogenic association between periodontal disease and rheumatoid arthritis focusing on the role of Porphyromonas gingivalis.

Recent findings

In the last decades our knowledge about the pathogenesis of rheumatoid arthritis substantially changed. Several evidences demonstrated that the initial production of autoantibodies is not localized in the joint, rather in other immunological-active sites. A central role seems to be played by periodontal disease, in particular because of the ability of P. gingivalis to induce citrullination, the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker.

The pathogenic role of P. gingivalis has been demonstrated in mouse models in which arthritis was either triggered or worsened in infected animals. P. gingivalis showed its detrimental role not only by inducing citrullination but also by means of other key mechanisms including induction of NETosis, osteoclastogenesis, and Th17 proinflammatory response leading to bone damage and systemic inflammation.
A Case of Adjacent, Clonally Distinct Borderline Melanocytic Tumors on the Arm
Authors: Schuler Andrew , Smith Mallory , Zahn Joseph , Wang Min , Noh Iris , Chan May P. , Andea Aleodor A. , Harms Paul W.
Published: July 2019

Atypical Spitz tumor (AST) is a melanocytic proliferation that shares histopathologic features of Spitz nevus and spitzoid melanoma. Distinction of AST from spitzoid melanoma is critical because the majority of ASTs will follow an indolent course. Array-based comparative genomic hybridization (aCGH) has been suggested as a potential tool for evaluating malignant potential in spitzoid tumors. We present a case of a 52-year-old woman with an AST in which aCGH was crucial in guiding correct diagnosis and management. The patient first presented with a flesh-colored papule on her arm that was changing color. Biopsy revealed a dermal nevoid melanocytic tumor of indeterminate histopathology, favored to be a severely atypical nevus. The tumor was excised. One year later, another flesh-colored papule proximal to the excision site of the first tumor was biopsied and showed a predominantly dermal atypical spitzoid melanocytic proliferation with a differential diagnosis of AST versus spitzoid melanoma. Recurrent or metastatic melanoma was also a concern given proximity to the previous excision site. Molecular analysis of both lesions by aCGH revealed distinct molecular signatures, supporting the 2 tumors to be clonally unrelated. Furthermore, the new tumor displayed limited evidence of genomic instability, supporting classification as an AST with predicted indolent behavior. This case highlights the utility of aCGH in evaluating borderline melanocytic lesions, including assessment of malignant potential in ASTs, and clonality analysis to assist in exclusion of metastatic disease.
Intravascular Colonization of Kaposi Sarcoma: Expanding the Spectrum of Specific Infiltrates of B-Cell Chronic Lymphocytic Leukemia
Authors: Saggini Andrea , Del Poeta Giovanni , Santinelli Enrico , Bianchi Luca , Caposiena Caro Raffaele D. , Orlandi Augusto
Published: July 2019

B-cell chronic lymphocytic leukemia (CLL), a low-grade malignancy consisting of CD5(+), CD23(+), and CD43(+) small B lymphocytes, is the most frequent leukemia in the western world. Patients with CLL may exhibit skin changes characterized by histopathologic evidence of infiltration by atypical B lymphocytes, also known as “specific cutaneous infiltrates of CLL”; in addition, CLL is known to be associated with an increased risk of second cancers, including Kaposi sarcoma (KS). The combination of KS and CLL within the same cutaneous biopsy specimen has only rarely been described. We report a peculiar case of KS occurring in a patient with CLL, in which histopathological evaluation of KS lesions revealed prominent accumulation of CLL lymphocytes within neoplastic vascular spaces. We believe that our findings represent a novel example of intravascular colonization of vascular neoplasms by neoplastic lymphoid cells, further expanding the evergrowing spectrum of specific cutaneous infiltrates of CLL.
Official International Association for Therapeutic Drug Monitoring and Clinical Toxicology Guideline: Development and Validation of Dried Blood Spot–Based Methods for Therapeutic Drug Monitoring
Authors: Capiau Sara , Veenhof Herman , Koster Remco A. , Bergqvist Yngve , Boettcher Michael , Halmingh Otto , Keevil Brian G. , Koch Birgit C.P. , Linden Rafael , Pistos Constantinos , Stolk Leo M. , Touw Daan J. , Stove Christophe P. , Alffenaar Jan-Willem C.
Published: July 2019

Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM. Therefore, this guideline provides parameters required for the validation of quantitative determination of small molecule drugs in DBS using chromatographic methods, and to provide advice on how these can be assessed. In addition, guidance is given on the application of validated methods in a routine context. First, considerations for the method development stage are described covering sample collection procedure, type of filter paper and punch size, sample volume, drying and storage, internal standard incorporation, type of blood used, sample preparation and prevalidation. Second, common parameters regarding analytical validation are described in context of DBS analysis with the addition of DBS-specific parameters, such as volume-, volcano- and hematocrit effects. Third, clinical validation studies are described, including number of clinical samples and patients, comparison of DBS with venous blood, statistical methods and interpretation, spot quality, sampling procedure, duplicates, outliers, automated analysis methods and quality control programs. Lastly, cross-validation is discussed, covering changes made to existing sampling- and analysis methods. This guideline of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology on the development, validation and evaluation of DBS-based methods for the purpose of TDM aims to contribute to high-quality micro sampling methods used in clinical practice.
Tacrolimus Levels in the Prophylaxis of Acute Graft-Versus-Host Disease in the Chinese Early After Hematopoietic Stem Cell Transplantation
Authors: Tian Ji-Xin , Zhang Ping , Miao Wen-Juan , Wang Xiao-Dan , Liu Xue-Ou , Liao Ying-Xi , Li Shan , Yan Hai-Hong
Published: July 2019

Background:

Tacrolimus has been widely accepted as the backbone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (alloHSCT). The present work evaluated whether tacrolimus concentrations early after transplant correlate with the incidence of aGVHD in Chinese alloHSCT recipients.

Methods:

One hundred four Chinese alloHSCT recipients were included in this retrospective study. All patients received standard prophylaxis with tacrolimus and short-term methotrexate. Blood samples were taken at steady-state for those on i.v. tacrolimus (Cv) or predose (C0) and 2 hours after the last oral dose (C2).

Results:

In the first 8 weeks after alloHSCT, significant variability in Cv, C0, and C2 of Chinese patients was observed. It was found that higher tacrolimus C0 and C2 values tended to be associated with a reduced risk of aGVHD, although this was a nonsignificant trend due to the small sample size involved. Receiver operating characteristic curve analysis indicated that Cv levels of ≥16.52 ng/mL, C0 levels of ≥5.56 ng/mL, and C2 levels of ≥7.83 ng/mL minimized the incidence of treatment failure during weeks 3–4 with intravenous administration and weeks 5–6 with oral administration. There was no statistically significant association of the patient liver and kidney function with the blood concentration of tacrolimus in the desired range of 5–20 ng/mL.

Conclusions:

Tacrolimus therapeutic drug monitoring improved treatment outcomes of Chinese alloHSCT recipients. Cv measurements during weeks 3–4 and C0 or C2 measurements during weeks 5–6 better predicted aGVHD (I–IV) than the concentrations measured at other time points during the first 6 weeks after alloHSCT.
Association of the ESR1 polymorphism with menopause and MLXIPL genetic variant influence serum uric acid levels in Slovak midlife women
Authors: Vorobeľová Lenka , Danková Zuzana , Candráková-Čerňanová Veronika , Falbová Darina , Cvíčelová Marta , Beňuš Radoslav , Siváková Daniela
Published: July 2019

Objective:

This study examines associations between the ESR1 (XbaI, PvuII) and the MLXIPL (rs3812316) gene polymorphisms, and uric acid (UA) levels in Slovak midlife women, subdivided according to their menopause status.

Methods:

We assessed a total of 362 women from 38 to 65 years of age. Women were recruited from different localities in the western and middle parts of Slovakia. Participants were interviewed during their medical examination at local health centers. They were investigated with respect to a variety of aspects such as medical, anthropometrical, and lifestyle. Participants provided a blood sample for biochemical analyses and DNA genotyping. The MLXIPL gene (rs3812316 SNP variant) and ESR1 gene (PvuII and XbaI) genotypes were then detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using general linear models and multiple linear regression analyses to adjust for risk factors elevating the UA level such as fat mass (FM), triglycerides (TGs) and creatinine.

Results:

A positive association between MLXIPL and UA level was observed in the total sample of women after control for confounding covariates, including FM, TGs, and creatinine (P = 0.027). Women with the CC genotype had higher UA levels than the G-allele carriers (261.5 μmol/L ± 68.3 vs 241.1 μmol/L ± 55.1 P = 0.013). A statistically significant association was noticed between postmenopause status and the ESR1 XbaI genotype and their effect on UA (P = 0.028). The Bonferroni pairwise comparison determined that the G-allele carriers in the postmenopausal period had higher estimated UA marginal mean (269.7 μmol/L) than the AA-allele postmenopausal women (236.5 μmol/L) (P = 0.012). The estimated UA marginal mean showed a significant increasing trend according to the MS in G allele carriers (248.5 μmol/L in pre/peri-menopausal vs 269.7 μmol/L in postmenopausal, P = 0.009). In contrast, a decreasing trend was observed in AA carriers (250.6 μmol/L in pre/perimenopausal women vs 236.5 μmol/L in postmenopausal). However, this trend was not statistically significant (P = 0.288).

Conclusions:

This cross-sectional study suggests that MLXIPL (rs3812316) polymorphism is associated with higher serum UA levels and that the ESR1 (XbaI) polymorphism is associated with UA levels only in the postmenopausal cohort.
Disparities in Receipt of Bariatric Surgery in Canada
Authors: Zhang Joyce C. , Tomlinson George , Wnuk Susan , Sockalingam Sanjeev , Cram Peter
Published: July 2019

Background:

Patients with lower socioeconomic status (SES) in the United States have reduced access to many health services including bariatric surgery. It is unclear whether disparities in bariatric surgery exist in countries with government-sponsored universal health benefits. The authors used data from a large regional Canadian bariatric surgery referral center to examine the relationship between SES and receipt of bariatric surgery.

Methods:

The Toronto Western Hospital bariatric surgery registry was used to identify all adults referred for bariatric surgery assessment from 2010 to 2017. The authors compared demographics, SES measures, and clinical measures among patients who did not and did undergo bariatric surgery (Roux-en-Y or sleeve gastrectomy). Multiple logistic regression was used to examine differences in receipt of bariatric surgery according to patient demographic characteristics and SES factors.

Results:

Among 2417 patients included in the study, 646 (26.7%) did not receive surgery and 1771 patients (73.2%) did. Patients who did not undergo surgery were more likely to be male individual (29.1% vs. 19.3%; P<0.001), black (12.1% vs. 8.3%; P=0.005), South Asian/Middle Eastern (8.2% vs. 4.5%; P<0.001), and less likely to be white (68.9% vs. 76.7%; P<0.001). In multiple logistic regression, factors associated with not receiving surgery were male sex, Black and South Asian/Middle Eastern ethnicity, being single, lack of employment, and history of psychiatric illness.

Conclusions:

Among patients referred for bariatric surgery, those who were male individuals, nonwhite, single, and unemployed were less likely to undergo surgery. Our results suggest that even with equal insurance, there are disparities in receipt of bariatric surgery.
Uptake and Impact of Short Message Service Reminders via Sexually Transmitted Infection Partner Services on Human Immunodeficiency Virus/Sexually Transmitted Infection Testing Frequency Among Men Who Have Sex With Men
Authors: Ronen Keshet , Golden Matthew R. , Dombrowski Julia C. , Kerani Roxanne P. , Bell Teal R. , Katz David A.
Published: July 2019

Background

Sexually transmitted infection (STI) partner services (PS) allow provision of human immunodeficiency virus (HIV)/STI prevention interventions to high-risk individuals, including testing reminders via short message service (SMS).

Methods

In King County, Washington, PS attempt to reach all men who have sex with men (MSM) with early syphilis and those with gonorrhea or chlamydia as resources allow. Since 2013, PS offered quarterly SMS testing reminders. We evaluated correlates of reminder uptake and the association between reminder uptake and postinterview asymptomatic STI diagnosis using Poisson regression, and the association between preinterview SMS reminder use and intertest interval among HIV-negative MSM using median regression.

Results

During July 1, 2013 to January 17, 2018, 8236 MSM were reported with 1 or more STI diagnoses and 5237 received PS interviews. Of these, 4087 (78%) were offered SMS reminders; 545 (13%) accepted, 265 (7%) were already receiving SMS, 3277 (80%) refused. Of 2602 patients who refused and were asked about other reminders, 37% used none, 16% received reminders from medical providers, 20% tested at routine physicals, and 26% used other reminders. SMS reminder use before and after PS interview was associated with negative HIV status, younger age, and diagnosis with gonorrhea or chlamydia (vs. syphilis) (P < 0.05 for all). Preinterview intertest interval was longer among MSM testing at physicals (9.6 months) than those using no reminder (5.6), SMS reminders (4.7, P < 0.05 vs. physicals), and non-SMS reminders (3.6, P < 0.001 vs. SMS). Reminder uptake was not associated with postinterview STI diagnosis.

Conclusions

Offering SMS reminders through STI PS is feasible. Uptake was low, but higher among young MSM not on preexposure prophylaxis. The SMS reminders may increase testing frequency.
DIfferential Subsampling With Cartesian Ordering With Respiratory Triggering Versus Conventional Liver Acquisition With Volume Acquisition: A Multiple Reader Preference Study
Authors: Allen Brian C. , Ehieli Wendy L. , Wildman-Tobriner Benjamin , Chaudhry Mohammad , Bozdogan Erol , Janas Gemini , Ronald James , Bashir Mustafa R.
Published: July 2019

Objective

The aim of this study was to compare respiratory-triggered DIfferential Subsampling with Cartesian Ordering (rtDISCO) and breath-held Liver Acquisition with Volume Acquisition (LAVA) image quality.

Methods

In this institutional review board–approved, Health Insurance Portability and Accountability Act–compliant prospective study, 25 subjects underwent T1 imaging with rtDISCO and LAVA before and after intravenous contrast. Three readers scored individual series and side-by-side comparisons for motion and noise. Eight clinical tasks were qualitatively assessed.

Results

As individual series, readers rated rtDISCO images as more degraded by motion on both precontrast (mean rtDISCO score, 2.7; LAVA, 1.6; P < 0.001) and postcontrast images (rtDISCO, 2.4; LAVA, 1.8; P < 0.001). Readers preferred LAVA images based on motion on both precontrast (mean preference, −1.2; P < 0.001) and postcontrast images (mean preference, −0.7; P < 0.001) on side-by-side assessment. There was no preference between sequences for 6 of 8 clinical tasks on postcontrast images.

Conclusions

Readers preferred LAVA with respect to motion but not noise; there was no preference in most of the tested clinical tasks.
Synergistic removal of dust using the wet flue gas desulfurization systems
Authors: Wu Qirong , Gu Min , Du Yungui , Zeng Hanxiao
Published: July 2019

Coal is still a major energy source, mostly used in power plants. However, the coal combustion emits harmful SO
2
and fly ash. Wet flue gas desulfurization (WFGD) technology is extensively used to control SO
2
emissions in power plants. However, only limited studies have investigated the synergistic dust removal by the WFGD system. Spray scrubbers and sieve-tray spray scrubbers are often used in WFGD systems to improve the SO
2
removal efficiency. In this study, the synergistic dust removal of WFGD systems for a spray scrubber and a sieve-tray spray scrubber was investigated using the experimental and modelling approaches, respectively. For the spray scrubber, the influence of parameters, including dust particle diameters and inlet concentrations of dust particles, and the flow rates of flue gas and slurry of limestone/gypsum on the dust removal efficiency, was investigated. For the sieve-tray spray scrubber, the influence of parameters such as the pore diameter and porosity of sieve trays on the dust removal efficiency was examined. The study found that the dust removal efficiency in the sieve-tray spray scrubber was approximately 1.1–10.6% higher than that of the spray scrubber for the same experimental conditions. Based on the parameters investigated and geometric parameters of a scrubber, a novel droplets swarm model for dust removal efficiency was developed from the single droplet model. The enhanced dust removal efficiency of sieve tray was expressed by introducing a strength coefficient to an inertial collision model. The dust removal efficiency model for the sieve-tray spray scrubber was developed by combining the droplets swarm model for the spray scrubber with the modified inertial collision model for the sieve tray. The results simulated using both models are consistent with the experimental data obtained.
Agarwood wound locations provide insight into the association between fungal diversity and volatile compounds in
Aquilaria sinensis
Authors: Liu Juan , Zhang Xiang , Yang Jian , Zhou Junhui , Yuan Yuan , Jiang Chao , Chi Xiulian , Huang Luqi
Published: July 2019

The aim of the present study was to investigate the effect of wound location on the fungal communities and volatile distribution of agarwood in
Aquilaria sinensis
. Two-dimensional gas chromatography with high-resolution time-of-flight mass spectrometry revealed 60 compounds from the NIST library, including 25 sesquiterpenes, seven monoterpenes, two diterpenes, nine aromatics, nine alkanes and eight others. Of five agarwood types, Types IV and II contained the greatest number and concentration of sesquiterpenes, respectively. The fungal communities of the agarwood were dominated by the phylum Ascomycota and were significantly affected by the type of wound tissue. Community richness indices (observed species, Chao1, PD whole tree, ACE indices) indicated that Types I and IV harboured the most and least species-rich fungal communities, and the fungal communities of Types V, I, III and IV/II were dominated by
Lasiodiplodia
,
Hydnellum
,
Phaeoisaria
and
Ophiocordyceps
species, respectively. Correlations between fungal species and agarwood components revealed that the chemical properties of
A. sinensis
were associated with fungal diversity. More specifically, the dominant fungal genera of Types V, I and III (
Lasiodiplodia
,
Hydnellum
and
Phaeoisaria
, respectively) were strongly correlated with specific terpenoid compounds. The finding that wound location affects the fungal communities and volatile distribution of agarwood provides insight into the formation of distinct agarwood types.
The stress field near the tip of a plane stress crack in a gel consisting of chemical and physical cross-links
Authors: Guo Jingyi , Hui Chung-Yuen , Liu Mincong , Zehnder Alan T.
Published: July 2019

We study the time-dependent asymptotic stress fields near the tip of a mode I plane stress crack in a hydrogel. The analysis is based on a three-dimensional continuum model which describes the viscoelastic behaviour of a hydrogel gel with permanent and transient cross-links. The viscoelasticity results from the breaking and healing of the transient cross-links in the gel network. We show that the crack tip fields satisfy a local correspondence principle—that is, the spatial singularities of these fields are identical to a hyperelastic cracked body with the same but undamaged networks. Asymptotic results compare very well with finite-element simulations on a single-edge crack specimen loaded under constant stretch rate. We also compare the theoretical results (crack opening profile and crack tip strain field) with experiments and find excellent agreement.
Local interactions and their group-level consequences in flocking jackdaws
Authors: Ling Hangjian , Mclvor Guillam E. , van der Vaart Kasper , Vaughan Richard T. , Thornton Alex , Ouellette Nicholas T.
Published: July 2019

As one of nature's most striking examples of collective behaviour, bird flocks have attracted extensive research. However, we still lack an understanding of the attractive and repulsive forces that govern interactions between individuals within flocks and how these forces influence neighbours' relative positions and ultimately determine the shape of flocks. We address these issues by analysing the three-dimensional movements of wild jackdaws (
Corvus monedula
) in flocks containing 2–338 individuals. We quantify the social interaction forces in large, airborne flocks and find that these forces are highly anisotropic. The long-range attraction in the direction perpendicular to the movement direction is stronger than that along it, and the short-range repulsion is generated mainly by turning rather than changing speed. We explain this phenomenon by considering wingbeat frequency and the change in kinetic and gravitational potential energy during flight, and find that changing the direction of movement is less energetically costly than adjusting speed for birds. Furthermore, our data show that collision avoidance by turning can alter local neighbour distributions and ultimately change the group shape. Our results illustrate the macroscopic consequences of anisotropic interaction forces in bird flocks, and help to draw links between group structure, local interactions and the biophysics of animal locomotion.
Universal modesty in signal-burying games
Authors: Quillien Tadeg
Published: July 2019

Why would individuals hide positive information about themselves? Evolutionary game theorists have recently developed the signal-burying game as a simple model to shed light on this puzzle. They have shown that the game has an equilibrium where some agents are better off deliberately reducing the visibility of the signal by which they broadcast their positive traits. However, this equilibrium also features individuals who fully broadcast their positive traits. Here, we show that the signal-burying framework can also explain modesty norms that everyone adheres to: the game contains an equilibrium where all agents who send a signal voluntarily reduce its conspicuousness. Surprisingly, the stability of the two kinds of equilibria rely on very different principles. The equilibrium where some agents brag is stable because of costly signalling dynamics. By contrast, the universal modesty equilibrium exists because buried signals contain probabilistic information about a sender’s type, and receivers make optimal use of this information. In the latter equilibrium, burying a signal can be understood as a handicap which makes the signal more honest, but honesty is not achieved through standard costly signalling dynamics.
A horizontally acquired expansin gene increases virulence of the emerging plant pathogenErwinia tracheiphila
Authors: Rocha Jorge , Shapiro Lori R. , Kolter Roberto
Published: July 2019

All land plants depend on proteins called ‘expansins’ that non-enzymatically loosen structural cellulose, enabling cell wall extension during normal growth. Surprisingly, expansin genes are also present – but functionally uncharacterized – in taxonomically diverse bacteria and fungi that do not produce cellulosic cell walls. Here, we find thatErwinia tracheiphila(Enterobacteriaceae), the causative agent of bacterial wilt of cucurbits, has horizontally acquired an operon with a microbial expansin (exlx) gene and a glycoside hydrolase family 5 (gh5) gene.E. tracheiphilais an unusually virulent plant pathogen that induces systemic wilt symptoms followed by plant death, and has only recently emerged into cultivated cucurbit populations in temperate Eastern North America. Plant inoculation experiments with deletion mutants show that EXLX-GH5 is a secreted virulence factor that confers efficient xylem movement and colonization ability toE. tracheiphila. Bacterial colonization of xylem blocks sap flow, inducing wilt symptoms and causing plant death. Together, these results suggest that the horizontal acquisition of theexlx-gh5locus was likely a key step driving the recent emergence ofE. tracheiphila. The increase inE. tracheiphilavirulence conferred by microbial expansins, the presence of this gene in many other bacterial and fungal wilt-inducing plant pathogen species, and the amenability of microbial expansins to horizontal gene transfer suggest this gene may be an under-appreciated virulence factor in taxonomically diverse agricultural pathogens.

Importance

Erwinia tracheiphilais a bacterial plant pathogen that causes a fatal wilt infection in cucurbit crop plants. Here, we report thatE. tracheiphilahas horizontally acquired a microbial expansin gene (exlx) adjacent to a glycoside hydrolase family 5 (gh5) gene. Expansins are predominantly associated with plants due to their essential role in loosening structural cell wall cellulose during normal growth. We find that the EXLX and GH5 proteins inE. tracheiphilafunction as a single complex to facilitate xylem colonization, possibly by manipulating the size of xylem structures that normally exclude the passage of bacteria. This suggests that horizontal acquisition of theexlx-gh5locus was likely a key step in the recent emergence ofE. tracheiphilaas an unusually virulent plant pathogen. The presence of microbial expansin genes in diverse species of bacterial and fungal wilt-inducing pathogens suggests it may be an under-appreciated virulence factor for other microbes.
In silico karyotyping of chromosomally polymorphic malaria mosquitoes in theAnopheles gambiaecomplex
Authors: Love R. Rebecca , Redmond Seth N. , Pombi Marco , Caputo Beniamino , Petrarca Vincenzo , della Torre Alessandra ,   The Anopheles gambiae 1000 Genomes Consortium, Besansky Nora J.
Published: July 2019

Chromosomal inversion polymorphisms play an important role in adaptation to environmental heterogeneities. For mosquito species in theAnopheles gambiaecomplex that are significant vectors of human malaria, paracentric inversion polymorphisms are abundant and are associated with ecologically and epidemiologically important phenotypes. Improved understanding of these traits relies on determining mosquito karyotype, which currently depends upon laborious cytogenetic methods whose application is limited both by the requirement for specialized expertise and for properly preserved adult females at specific gonotrophic stages. To overcome this limitation, we developed sets of tag SNPs inside inversions whose biallelic genotype is strongly correlated with inversion genotype. We leveraged 1,347 fully sequencedAn. gambiaeandAnopheles coluzziigenomes in the Ag1000G database of natural variation. Beginning with principal components analysis (PCA) of population samples, applied to windows of the genome containing individual chromosomal rearrangements, we classified samples into three inversion genotypes, distinguishing homozygous inverted and homozygous uninverted groups by inclusion of the small subset of specimens in Ag1000G that are associated with cytogenetic metadata. We then assessed the correlation between candidate tag SNP genotypes and PCA-based inversion genotypes in our training sets, selecting those candidates with >80% agreement. Our initial tests both in held-back validation samples from Ag1000G and in data independent of Ag1000G suggest that when used forin silicoinversion genotyping of sequenced mosquitoes, these tags perform better than traditional cytogenetics, even for specimens where only a small subset of the tag SNPs can be successfully ascertained.
Presynaptic mitochondria volume and abundance increase during development of a high-fidelity synapse
Authors: Thomas Connon I. , Keine Christian , Okayama Satoko , Satterfield Rachel , Musgrove Morgan , Guerrero-Given Debbie , Kamasawa Naomi , Young Samuel M.
Published: July 2019

The calyx of Held, a large glutamatergic presynaptic terminal in the auditory brainstem undergoes developmental changes to support the high action-potential firing rates required for auditory information encoding. In addition, calyx terminals are morphologically diverse which impacts vesicle release properties and synaptic plasticity. Mitochondria influence synaptic plasticity through calcium buffering and are crucial for providing the energy required for synaptic transmission. Therefore, it has been postulated that mitochondrial levels increase during development and contribute to the morphological-functional diversity in the mature calyx. However, the developmental profile of mitochondrial volumes and subsynaptic distribution at the calyx of Held remains unclear. To provide insight on this, we developed a helper-dependent adenoviral vector (HdAd) that expresses the genetically encoded peroxidase marker for mitochondria, mito-APEX2, at the mouse calyx of Held. We developed protocols to detect labeled mitochondria for use with serial block face scanning electron microscopy to carry out semi-automated segmentation of mitochondria, high-throughput whole terminal reconstruction and presynaptic ultrastructure in mice of either sex. Subsequently, we measured mitochondrial volumes and subsynaptic distributions at the immature postnatal day 7 (P7) and the mature (P21) calyx. We found an increase of mitochondria volumes in terminals and axons from P7 to P21 but did not observe differences between stalk and swelling subcompartments in the mature calyx. Based on these findings, we propose that mitochondrial volumes and synaptic localization developmentally increase to support high firing rates required in the initial stages of auditory information processing.

Significance Statement

Elucidating the developmental processes of auditory brainstem presynaptic terminals is critical to understanding auditory information encoding. Additionally, morphological-functional diversity at these terminals is proposed to enhance coding capacity. Mitochondria provide energy for synaptic transmission and can buffer calcium, impacting synaptic plasticity; however, their developmental profile to ultimately support the energetic demands of synapses following the onset of hearing remains unknown. Therefore, we created a helper-dependent adenoviral vector with the mitochondria-targeting peroxidase mito-APEX2 and expressed it at the mouse calyx of Held. Volumetric reconstructions of serial block face electron microscopy data of immature and mature labeled calyces reveal that mitochondrial volumes are increased to support high firing rates upon maturity.
Automated methods enable direct computation on phenotypic descriptions for novel candidate gene prediction
Authors: Braun Ian R. , Lawrence-Dill Carolyn J.
Published: July 2019

1

Natural language descriptions of plant phenotypes are a rich source of information for genetics and genomics research. We computationally translated descriptions of plant phenotypes into structured representations that can be analyzed to identify biologically meaningful associations. These repre-sentations include the EQ (Entity-Quality) formalism, which uses terms from biological ontologies to represent phenotypes in a standardized, semantically-rich format, as well as numerical vector representations generated using Natural Language Processing (NLP) methods (such as the bag-of-words approach and document embedding). We compared resulting phenotype similarity measures to those derived from manually curated data to determine the performance of each method. Computationally derived EQ and vector representations were comparably successful in recapitulating biological truth to representations created through manual EQ statement curation. Moreover, NLP methods for generating vector representations of phenotypes are scalable to large quantities of text because they require no human input. These results indicate that it is now possible to computationally and automatically produce and populate large-scale information resources that enable researchers to query phenotypic descriptions directly.
Mutations beget more mutations – The baseline mutation rate and runaway accumulation
Authors: Ruan Yongsen , Chen Bingjie , Chen Qingjian , Wen Haijun , Wu Chung-I
Published: July 2019

There is a sizable literature on mutation rate evolution (Drake 1991; Makova and Li 2002; Lynch 2011; Scally and Durbin 2012; Sung, et al. 2012) but few studies incorporate the recent genomic data from somatic tissues that suggest the operation of mutators. These data show that the mutation burden among cancer samples may vary by several orders of magnitude (Kandoth, et al. 2013; Lawrence, et al. 2013). We now propose a runaway model, applicable to both the germline and the soma, whereby the accumulation of mutator mutations forms a positive-feedback loop. In this loop, any mutator mutation would increase the probability of acquiring the next mutator, thus triggering a runaway escalation in mutation rate. The process can be initiated more readily if there are many weak, rather than a few strong, mutators. Interestingly, even a small increase in the mutation rate at birth could trigger the runaway process, resulting in unfit progeny in slowly reproducing species. In such species, the need to minimize the risk of this uncontrolled accumulation would entail a mutation rate that may seem unnecessarily low. In comparison, species that starts and ends reproduction much sooner do not face the risk and may set the baseline mutation rate higher. The mutation rate would evolve as the generation time changes, therefore explaining many puzzling evolutionary phenomena (Elango, et al. 2006; Thomas, et al. 2010; Langergraber, et al. 2012; Thomas, et al. 2018; Besenbacher, et al. 2019).
Integrating NMR and Simulations Reveals Motions in the UUCG Tetraloop
Authors: Bottaro Sandro , Nichols Parker J. , Vögeli Beat , Parrinello Michele , Lindorff-Larsen Kresten
Published: July 2019

We provide an atomic-level description of the structure and dynamics of the UUCG RNA stem-loop by combining molecular dynamics simulations with experimental data. The integration of simulations with exact nuclear Overhauser enhancements data allowed us to characterize two distinct states of this molecule. The most stable conformation corresponds to the consensus three-dimensional structure. The second state is characterized by the absence of the peculiar non-Watson-Crick interactions in the loop region. By using machine learning techniques we identify a set of experimental measurements that are most sensitive to the presence of non-native states. We find that although our MD ensemble, as well as the consensus UUCG tetraloop structures, are in good agreement with experiments, there are remaining discrepancies. Together, our results show that i) the structural interpretation of experimental data for dynamic RNAs is highly complex, even for a simple model system such as the UUCG tetraloop ii) the MD simulation overstabilize a non-native loop conformation, and iii) eNOE data support its presence with a population of ≈10%.
HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer
Authors: Kalisz Mark , Bernardo Edgar , Beucher Anthony , Maestro Miguel Angel , del Pozo Natalia , Millán Irene , Haeberle Lena , Schlensog Martin , Safi Sami Alexander , Knoefel Wolfram Trudo , Grau Vanessa , de Vas Matías , Shpargel Karl B. , Vaquero Eva , Magnuson Terry , Ortega Sagrario , Esposito Irene , Real Francisco X. , Ferrer Jorge
Published: July 2019

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding the histone demethylase UTX, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutations phenocopy Utx deficient mutations, and both synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic and biochemical studies to show that HNF1A recruits UTX to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates a differentiation program, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Finally, we identify a subset of non-classical PDAC samples that exhibit the HNF1A/UTX-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A-deficiency promotes PDAC. They also connect the tumor suppressive role of UTX deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.
The Cu(II) reductase RclA protectsEscherichia coliagainst the combination of hypochlorous acid and intracellular copper
Authors: Derke Rhea M. , Barron Alexander J. , Billiot Caitlin E. , Chaple Ivis F. , Lapi Suzanne E. , Broderick Nichole A. , Gray Michael J.
Published: July 2019

Inflammatory bowel diseases (IBDs) are a growing health concern. Enterobacteria, includingEscherichia coli, bloom to high levels in the gut during inflammation and strongly contribute to the pathology of IBDs. To survive in the inflamed gut,E. colimust tolerate high levels of antimicrobial compounds produced by the immune system, including toxic metals like copper and reactive chlorine oxidants like hypochlorous acid (HOCl). In this work, we show that the widely-conserved bacterial HOCl resistance enzyme RclA catalyzes the reduction of copper (II) to copper (I), and specifically protectsE. coliagainst the combination of HOCl and intracellular copper, probably by preventing Cu(III) accumulation.E. colilacking RclA were highly sensitive to HOCl and were defective in colonizing an animal host. Our results indicate unexpected complexity in the interactions between antimicrobial toxins produced by innate immune cells and suggest an important and previously unsuspected role for copper redox reactions during inflammation.
Frequency but not phase specific modulation of binocular rivalry with transcranial alternating current stimulation
Authors: Delgado Jorge , Riesen Guillaume , Vildavski Vladimir Y. , Norcia Anthony M.
Published: July 2019

Recent transcranial alternating current stimulation (tACS) literature suggests that tACS effects can in principle be both frequency and phase specific. In a series of three experiments using 69 participants used binocular rivalry percepts as a read-out for the effects of phase-synchronized tACS stimulation. To test for phase specificity, with frequency the same in each eye, we visually stimulated each eye with 3Hz, with stimuli in each eye presented in temporal in antiphase. The frequency-specific paradigm visually stimulated the right eye with 3Hz, and the left eye with 5Hz. Each experiment was accompanied by 3Hz tACS, whose phase with respect to the visual stimulus was varied by 0°, 90°, 180°, or 270° in relation to the right eye’s stimulus. A baseline no-tACS block preceded the stimulation blocks and two more followed, immediately and ten minutes after. Individual blocks lasted 4 minutes. Additionally, a no-tACS control experiment identical to the 3 Hz anti-phase visual stimuli setup was conducted, keeping all parameters the same but eliminating tACS. During stimulation, the 3 Hz anti-phase visual stimuli setup slowed the rate of rivalry in both eyes. Conversely, the 3Hz-right, 5Hz-left setup slowed the right (targeted) eye significantly while leaving the left (unstimulated) eye unchanged. In both experiments, durations returned to baseline after 10 minutes. Our results are consistent with the frequency-specific model of tACS, and with the Leveltian hypothesis that stimulation weakens the stimulated eye, as the right eye got weaker when it was directly targeted, and both eyes got weaker when targeted in antiphase. tACS does not appear to preferentially modulating percept durations in one phase more than in another.