bluuebunny/crossref_metadata_2025 huggingface dataset:
Ageism and Health in Patients Undergoing Cosmetic Procedures
Authors: Pearl Rebecca L , Percec Ivona
Published: October 2018

Background

Ageism is a common form of prejudice that negatively affects the health of older adults. Anti-aging procedures are increasingly popular among patients seeking aesthetic surgery and minimally invasive treatments.

Objectives

This study aimed to identify the prevalence of age-based discrimination, and its relationship to health, among patients seeking cosmetic procedures.

Methods

Patients from a university-based, single-surgeon, aesthetic plastic surgery clinic completed the Everyday Discrimination Scale, which assesses the frequency with which individuals have experienced “microaggressions” and the main reason(s) for discrimination (including age). Participants also completed: measures of perceived age discrimination across interpersonal, romantic, work, and healthcare contexts and anticipation of age-based discrimination in the future; a single-item measure of self-rated health (rated 1-5); and the Rosenberg Self-Esteem Scale.

Results

Fifty patients consented to participate in the study (94% women, 78% white, mean age 49.4 ± 13.5 years). More than 30% of participants reported age as the main reason for everyday discrimination. Participants who reported experiencing age-based discrimination, compared with those who did not, had worse self-rated health, lower self-esteem, and greater anticipated age-based discrimination. Participants most frequently endorsed experiencing age-based discrimination in an interpersonal context (36.0%) followed by work settings (20.0%).

Conclusions

A significant portion of patients seeking cosmetic procedures may experience age-based discrimination, which could negatively affect their health and well-being. Patients might benefit from expectation management about how their procedure may or may not address their concerns about age-based discrimination. More research is needed to determine whether cosmetic procedures help to mitigate discrimination in aging patients.
Long-term context-dependent genetic adaptation of the viral genetic cloud
Authors: Braun Tzipi , Bordería Antonio V , Barbezange Cyril , Vignuzzi Marco , Louzoun Yoram
Published: October 2018

Motivation

RNA viruses generate a cloud of genetic variants within each host. This cloud contains high-frequency genotypes, and many rare variants. The dynamics of these variants is crucial to understand viral evolution and their effect on their host.

Results

We use an experimental evolution system to show that the genetic cloud surrounding the Coxsackie virus master sequence slowly, but steadily, evolves over hundreds of generations. This movement is determined by strong context-dependent mutations, where the frequency and type of mutations are affected by neighboring positions, even in silent mutations. This context-dependent mutation pattern serves as a spearhead for the viral population’s movement within the adaptive landscape and affects which new dominant variants will emerge. The non-local mutation patterns affect the mutated dinucleotide distribution, and eventually lead to a non-uniform dinucleotide distribution in the main viral sequence. We tested these results on other RNA viruses with similar conclusions.

Supplementary information

Supplementary data are available at Bioinformatics online.
Open Source Software Reliability Model with the Decreasing Trend of Fault Detection Rate
Authors: Wang Jinyong , Mi Xiaoping
Published: October 2018

Software reliability assessment methods have been changed from closed to open source software (OSS). Although numerous new approaches for improving OSS reliability are formulated, they are not used in practice due to their inaccuracy. A new proposed model considering the decreasing trend of fault detection rate is developed in this study to effectively improve OSS reliability. We analyse the changes of the instantaneous fault detection rate over time by using real-world software fault count data from two actual OSS projects, namely, Apache and GNOME, to validate the proposed model performance. Results show that the proposed model with the decreasing trend of fault detection rate has better fitting and predictive performance than the traditional closed source software and other OSS reliability models. The proposed model for OSS can further accurately fit and predict the failure process and thus can assist in improving the quality of OSS systems in real-world OSS projects.
Partial migration and early size of southern hake Merluccius australis: a journey between estuarine and oceanic habitats off Northwest Patagonia
Authors: Toledo Pamela , Darnaude Audrey M , Niklitschek Edwin J , Ojeda Vilma , Voué Raphaël , Leiva Félix P , Labonne Maylis , Canales-Aguirre Cristian B
Published: October 2018

Partial migration is a key adaptive strategy, increasingly observed across multiple taxa. To investigate partial migration and life-cycle diversity of Merluccius australis in northwestern Patagonia, we analysed isotopic (δ13C, δ18O) and elemental (11B, 23Na, 24 Mg, 55Mn, 86Sr, 138Ba) compositions of otoliths from juveniles, sub-adults, and adults to identify nursery origins, habitats used, and migratory behaviours of multiple cohorts (1990–2005). Influence of early size upon migration was assessed by comparing back-calculated sizes at demersal recruitment between resident and migratory adults. Although partial migration occurred at both estuarine and oceanic nursery habitats, migratory behaviour was more frequent in fish of estuarine origin (59%) than in fish of oceanic origin (17%). Adults of estuarine origin dominated both estuarine (92%) and oceanic (77%) sampling areas. Although we found no significant differences in size at demersal recruitment between oceanic-resident and oceanic-migratory fish, a strong relationship between size at demersal recruitment and migratory behaviour appeared in fish of estuarine origin, whose probability of migration increased from 5% to 95% as demersal recruitment size increased from 18.8 to 23.6 cm. Further research on M. australis life cycle is required to incorporate sub-population processes into the stock assessment and management models being used for this overexploited species.
Increased urinary miR-196a level predicts the progression of renal injury in patients with diabetic nephropathy
Authors: An Yu , Zhang Changming , Xu Feng , Li Wei , Zeng Caihong , Xie Lu , Liu Zhihong
Published: October 2018

Background

Recent data suggest that miR-196a is predominantly expressed in the kidney and plays an inhibitory role in the progress of renal interstitial fibrosis (IF). However, the predictive value of miR-196a in diabetic nephropathy (DN) remains unknown. We validated the role of urinary miR-196a in the progression of renal injury in a cohort of patients with type 2 diabetes mellitus.

Methods

Our study included 209 patients with biopsy-proven DN. The mean follow-up time was 54.03 ± 32.94 months. Histological lesions were assessed using the pathological classification established by the Renal Pathology Society. Percentages of IF and tubular atrophy were assessed using the Aperio ScanScope system. We measured the correlation of urinary miR-196a with clinical and pathological parameters using the Spearman’s correlation test. The influence of urinary miR-196a on renal outcomes was assessed using Cox regression analysis.

Results

Urinary miR-196a levels correlated positively with proteinuria (ρ = 0.385, P < 0.001), duration of diabetes mellitus (ρ = 0.255, P < 0.001) and systolic blood pressure (ρ = 0.267, P < 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (ρ = −0.247, P < 0.001 and ρ = −0.236, P = 0.001, respectively). Pathologically, urinary miR-196a levels correlated with glomerular sclerosis and IF in patients with DN. Urinary miR-196a was significantly associated with progression to end-stage renal disease [hazard ratio (HR) 2.03, P < 0.001] and a 40% reduction of baseline eGFR (HR 1.75, P = 0.001), independent of age, gender, body mass index, mean arterial pressure and hemoglobinA1c level. However, urinary miR-196a did not improve predictive power to proteinuria and eGFR in DN patients.

Conclusions

Increased urinary miR-196a was significantly associated with the progression of renal injury and might be a noninvasive prognostic marker of renal fibrosis in DN patients.
Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study
Authors: Madsen Christoffer V , Granqvist Henrik , Petersen Jørgen H , Rasmussen Åse K , Lund Allan M , Oturai Peter , Sørensen Søren S , Feldt-Rasmussen Ulla
Published: October 2018

Background

Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age.

Methods

This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included.

Results

In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1–13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of −0.8 ± 0.2 with an annual slope of −0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin–creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender.

Conclusions

ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.
Emergence of Cytomegalovirus Mononucleosis Syndrome Among Young Adults in Hong Kong Linked to Falling Seroprevalence: Results of a 14-Year Seroepidemiological Study
Authors: Sridhar Siddharth , Chung Tom W H , Chan Jasper F W , Cheng Vincent C C , Lau Susanna K P , Yuen Kwok-Yung , Woo Patrick C Y
Published: October 2018

Background

Cytomegalovirus (CMV) mononucleosis is a manifestation of primary CMV infection. This study aims to establish the link between long-term population CMV seroepidemiological trends and incidence of CMV mononucleosis requiring hospitalization. Furthermore, by analyzing serial laboratory data of patients hospitalized with CMV mononucleosis, we aim to provide insights into the natural history of this syndrome.

Methods

We conducted a 14-year observational study in a tertiary hospital in Hong Kong. Cytomegalovirus immunoglobulin G data of 2349 adults were analyzed for trends in CMV susceptibility during the study period. The clinical features, risk factors, antiviral treatment data, and laboratory findings of 25 adult patients presenting with CMV mononucleosis during this period were retrieved.

Results

Susceptibility to CMV infection among the adult population aged 18–45 in Hong Kong increased from 14.5% in 2004 to 32.2% in 2012–2017 (P < .001), and this led to doubling of observed CMV mononucleosis incidence among inpatients in our center during the study period. All patients with CMV mononucleosis were hospitalized for investigation of fever of unknown origin. Household contact with young children was the most common risk factor followed by recent overseas travel. Derangement of liver function tests was universally observed and was more severe than in previously published western CMV mononucleosis patient cohorts. Most patients showed clinical improvement within the third week of illness.

Conclusions

We conclude that increasing CMV susceptibility among young adults in Hong Kong has resulted in a rising observed incidence of CMV mononucleosis, which is typically a self-limited illness characterized by anicteric hepatitis.
Predictors of Surgical Intervention in Dialysis Patients With Infective Endocarditis
Authors: Woller III John A , Walsh Victoria L , Robichaux Chad , Thourani Vinod H , Jacob Jesse T
Published: October 2018

Background

The use of valve surgery for infective endocarditis (IE) in end-stage renal disease (ESRD) patients may be different than in the general population. We assessed predictors of early surgery in ESRD patients with IE.

Methods

We conducted a retrospective cohort study among dialysis patients with left-sided IE between 2005 and 2015. Indications for surgery were based on current endocarditis guidelines. Patients were categorized as early valve replacement surgery or delayed/no surgery. We used logistic regression to determine independent predictors of early surgery.

Results

Among 229 patients, 67 (29.3%) underwent early surgery. New congestive heart failure was the only high level of evidence indication independently associated with early surgery (odds ratio [OR], 12.1; 95% confidence interval [CI], 3.4–43.6). Transfer from outside hospital (OR, 5.4; 95% CI, 2.2–13.3), valve rupture (OR, 6.9; 95% CI, 2.6–17.9), coagulase-negative staphylococcus etiology (OR, 3.8; 95% CI, 1.4–10.6), and presence of any low level of evidence indication (OR, 5.9; 95% CI, 2.2–15.5) predicted early surgery. Preexisting valve disease (OR, 0.31; 95% CI, 0.12–0.82) and surgical contraindications (OR, 0.05; 95% CI, 0.005–0.4) predicted nonsurgical treatment.

Conclusions

Among ESRD patients with IE, most surgical indications are not predictive of early surgery.
T790M mutation in stage IV EGFR-mutated NSCLC patient with acquired resistance reverted to original 19Del mutation after administration of a series of precision treatments: a case report
Authors: Han Jialong , Wang Ya , Zhong Lili , Zhou Huijie , Yu Min , Li Yanying , Lu You , Wang Yan , Zhu Jiang
Published: October 2018

Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs. This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer (NSCLC) harboring an EGFR exon 19 deletion (19Del) mutation, who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI (gefitinib). The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI (osimertinib). This patient eventually achieved partial response (PR) with second generation TKI (afatinib) as a fourth-line treatment.
Evaluating the impact of an international short-term medical mission through diabetic glycemic control
Authors: Mach John C , Barone Hope , Boni Christopher , Jimenez Humberto , Tinglin Michael
Published: October 2018

Background

This prospective observational study evaluated the impact of a primary care-based, international, short-term medical mission’s (STMM) impact on diabetes disease burden as represented through reductions in hemoglobin A1C (HbA1c).

Methods

From November 2016 to May 2017, we tracked the HbA1c’s of diabetic individuals in Dajabon, Dominican Republic through care provided by Waves of Health (WOH). Participants were provided counseling, glucose monitoring equipment, a 6-month supply of anti-diabetic medications, and received a ‘check-in’ phone call at 3 months. HbA1c’s were re-measured at 6-month follow up. We hypothesized WOH diabetic care would have a modest impact of reducing mean HbA1c by 0.5%.

Results

In total, 75% (n = 76) of 101 participants presented for follow-up care. Mean and median HbA1c decreased from 8.71 (SD 2.0) and 8.5% to 8.36 (SD 2.1) and 7.7%, respectively (P = 0.07). The percentage of individuals with HbA1c ≤7.5 increased by 10.4% at follow-up. The mean HbA1c decrease was 1.1%.

Conclusions

Though limited by sample size, our results suggest that medical STMM’s may have a clinically meaningful impact in chronic disease management when utilizing a systematic combination of education, medical therapy, clearly documented medication instructions and regular trip intervals.
Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality
Authors: Richard Nicolas , Hudson Marie , Wang Mianbo , Gyger Geneviève , Proudman Susanna , Stevens Wendy , Nikpour Mandana ,   Canadian Scleroderma Research Group (CSRG), Baron M , Hudson M , Gyger G , Pope J , Larché M , Khalidi N , Masetto A , Sutton E , Robinson D , Rodriguez-Reyna T S , Smith D , Thorne C , Fortin P R , Fritzler M ,   Australian Scleroderma Interest Group (ASIG), Croyle L , de Jager J , Ferdowsi N , Hill C , Laurent R , Lester S , Major G , Morrisroe K , Nash P , Ngian G , Nikpour M , Proudman S , Rischmueller M , Roddy J , Sahhar J , Schrieber L , Stevens W , Strickland G , Sturgess A , Thakkar V , Tymms K , Walker J , Youseff P , Zochling J , Baron Murray
Published: October 2018

Objectives

To examine the incidence, predictors and outcomes associated with severe gastrointestinal (GI) disease in a large inception SSc cohort.

Methods

SSc subjects with <2 years of disease duration were identified from two multicentre cohorts. Severe GI disease was defined as: malabsorption, hyperalimentation, pseudo-obstruction and/or ⩾10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. Kaplan–Meier, multivariate logistic regression and Cox proportional hazard analyses were performed to determine the cumulative incidence rate, independent clinical correlates and mortality rate associated with severe GI disease. A longitudinal mixed model was used to assess the impact of severe GI disease on the Short Form Health Survey.

Results

In this inception SSc cohort, the probability of developing severe GI disease was estimated at 9.1% at 2 years and 16.0% at 4 years. In multivariate analysis, severe GI disease was associated with inflammatory myositis (odds ratio 4.68, 95% CI 1.65, 13.24), telangiectasias (odds ratio 2.45, 95% CI 1.19, 5.04) and modified Rodnan skin score (odds ratio 1.03, 95% CI 1.01, 1.07). Severe GI disease was associated with a >2-fold increase in the risk of death (hazard ratio 2.27, 95% CI 1.27, 4.09) and worse health-related quality of life [Short Form Health Survey physical (β = −2.37, P = 0.02) and mental (β = −2.86, P = 0.01) component summary scores].

Conclusion

Severe GI disease is common in early SSc and is associated with significant morbidity and increased mortality. More research is needed to understand, prevent and mitigate severe GI disease in SSc.
ASSESSMENT OF INDOOR GAMMA RADIATION AND DETERMINATION OF EXCESS LIFETIME CANCER RISK IN TEHRAN IN WINTER AND SPRING 2017
Authors: Hashemi Marjan , Akhoondi Leila , Saghi Mohammad Hossien , Eslami Akbar
Published: October 2018

Natural radiation is a feature of the environment in which we live. One of the contributions of human exposure to ionizing radiation due to natural sources arises from gamma radiation. Therefore, present study was aimed to evaluate and map indoor gamma dose rate in Tehran. The corresponding annual effective dose (AED) and excess lifetime cancer risk (ELCR) were also calculated. All measurements were performed by a Geiger Muller detector in 43 dwellings in Tehran. The average indoor gamma dose rate in Tehran was appointed as 343.2 nGy/h. AED and ELCR were calculated as 2.4 mSv and 10.3 × 10−3, respectively. The evaluated indoor gamma dose rate and calculated AEDs and lifetime cancer risk were found higher than the world average value.
Supra-molecular organization of the pyoverdine bio-synthetic pathway in Pseudomonas aeruginosa
Authors: Gasser Véronique , Malrieu Morgane , Forster Anne , Mély Yves , Schalk Isabelle J , Godet Julien
Published: October 2018

The bio-synthesis of the pyoverdine siderophore (PVD) in Pseudomonas aeruginosa involves multiple enzymatic steps including the action of Non-Ribosomal Peptide Synthetases (NRPS). One hallmark of NRPS is their ability to make usage of non-proteinogenic amino-acids synthesised by co-expressed accessory enzymes. It is generally accepted that different enzymes of a secondary metabolic pathway must organise into macro-molecular complexes. However, evidence for complexes like siderosomes in the cellular context are missing.

Here, we used in vitro single-molecule tracking and FRET–FLIM (Förster resonance energy transfer measured by fluorescence lifetime microscopy) to explore the spatial partitioning of the ornithine hydroxylase PvdA and its interactions with NRPS. We found PvdA was mostly diffusing bound to large complexes in the cytoplasm with a small exchangeable trapped fraction. FRET-FLIM clearly showed PvdA is physically interacting with PvdJ, PvdI, PvdL and PvdD, the four NRPS of the pyoverdine pathway. The binding modes of PvdA are strikingly different according to the NRPS it is interacting with suggesting that PvdA binding sites have co-evolved with the enzymatic active sites of NRPS.

Our data provide evidence for strongly organised multi-enzymatic complexes responsible for the bio-synthesis of PVD and suggest that finely controlled co-localisation of sequential enzymes seems to be required to promote metabolic efficiency.
DPPA2 and DPPA4 are necessary to establish a totipotent state in mouse embryonic stem cells
Authors: De Iaco Alberto , Coudray Alexandre , Duc Julien , Trono Didier
Published: October 2018

After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through so-called zygotic genome activation (ZGA), occurring in the mouse at the 2-cell stage. Amongst the first elements to be transcribed are the Dux gene, the product of which secondarily induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons, which regulate chromatin accessibility in the early embryo. The maternally-inherited factors that activate Dux and LINE-1 transcription have so far remained unknown. Here we identify the paralog proteins DPPA2 and DPPA4 as responsible for this process.
Proteomics reveals profound metabolic changes in the alcohol use disorder brain
Authors: Enculescu Charmaine , Kerr Edward D. , Benjamin Yeo K. Y. , Dodd Peter R. , Schenk Gerhard , Fortes Marina R. S. , Schulz Benjamin L.
Published: October 2018

Changes in brain metabolism are a hallmark of Alcohol Use Disorder (AUD). Determining how AUD changes the brain proteome is critical for understanding the effects of alcohol consumption on biochemical processes in the brain. We used data-independent acquisition mass spectrometry proteomics to study differences in the abundance of proteins associated with AUD in pre-frontal lobe and motor cortex from autopsy brain. AUD had a substantial effect on the overall brain proteome exceeding the inherent differences between brain regions. Proteins associated with glycolysis, trafficking, the cytoskeleton, and excitotoxicity were altered in abundance in AUD. We observed extensive changes in the abundance of key metabolic enzymes, consistent with a switch from glucose to acetate utilization in the AUD brain. We propose that metabolic adaptations allowing efficient acetate utilization contribute to ethanol dependence in AUD.
A Model for Time Interval Learning in The Purkinje Cell
Authors: Majoral Daniel , Zemmar Ajmal , Vicente Raul
Published: October 2018

Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. This finding adds to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we developed a biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We show that the model is able to learn along the 150-1000 ms interval range. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

Author Summary

The prevailing view in neurosciences considers synaptic weights between neurons the determinant factor for learning and processing information in the nervous system. Theoretical considerations [1, 2] and experiments [3, 4] examined some potential limitations of this classical paradigm, pointing out that adaptation and computation might also have to rely on other mechanisms besides the learning of synaptic weights. Recent experimental findings [5–7] indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. We propose here a biologically plausible model which complements the modification of synaptic weights for learning one time interval in one synapse of one Purkinje cell. In the model a calcium signal in a small domain keeps track of time. Several molecules read and modify this calcium signal to learn a time interval. We discuss how this model would allow the cerebellum to detect and generate specific patterns in space and time, a classical theory for cerebellar function proposed by Braitenberg [8, 9].
Brian2GeNN: a system for accelerating a large variety of spiking neural networks with graphics hardware
Authors: Stimberg Marcel , Goodman Dan F. M. , Nowotny Thomas
Published: October 2018

“Brian” is a popular Python-based simulator for spiking neural networks, commonly used in computational neuroscience. GeNN is a C++-based meta-compiler for accelerating spiking neural network simulations using consumer or high performance grade graphics processing units (GPUs). Here we introduce a new software package, Brian2GeNN, that connects the two systems so that users can make use of GeNN GPU acceleration when developing their models in Brian, without requiring any technical knowledge about GPUs, C++ or GeNN. The new Brian2GeNN software uses a pipeline of code generation to translate Brian scripts into C++ code that can be used as input to GeNN, and subsequently can be run on suitable NVIDIA GPU accelerators. From the user’s perspective, the entire pipeline is invoked by adding two simple lines to their Brian scripts. We have shown that using Brian2GeNN, typical models can run tens to hundreds of times faster than on CPU.
Coping with strangers: how familiarity and active interactions shape group coordination inCorydoras aeneus
Authors: Riley RJ , Gillie ER , Johnstone RA , Boogert NJ , Manica A
Published: October 2018

Social groups whose members have had sustained prior experience with each other frequently exhibit improved coordination and outperform groups whose members are unfamiliar with one another. The mechanisms by which familiarity assists coordination are not well known. Prior social experience may simply allow individuals to learn the behavioral tendencies of familiar group-mates and coordinate accordingly. In the absence of prior social experience, it would be adaptive for individuals to develop strategies for coping with unfamiliar others to minimize the disadvantage of unfamiliarity. To explore the dynamics of familiarity in shaping group behaviors, we used a highly social catfish,Corydoras aeneus, that utilizes a distinctive, observable tactile interactions. Here we describe this tactile interaction behavior, physical “nudges” that are deployed to initiate group movements and maintain contact with group-mates during group movements. We then report the results of two experiments exploring the relationship between nudges and coordination. First, within triplets of two familiar and one unfamiliar individual, we found no individual differences in nudging rate based on familiarity. Despite all individuals interacting at similar rates, however, unfamiliar individuals failed to coordinate as well as their familiar group-mates, and were more frequently absent from group movements. Second, comparing pairs of familiar with pairs of unfamiliar fish, there was no difference in the level of coordination between pairs. Instead, we found that unfamiliar pairs exhibited significantly higher nudging rates, suggesting that unfamiliar pairs could compensate for their unfamiliarity by nudging more frequently. In contrast, familiar individuals coordinated with comparatively little nudging, presumably because they were experienced with each other. Overall, these results suggest that nudges can be used to improve coordination of group activities, but that their usage is reduced in the case of familiar individuals, implying that these potential signals may be costly.
Receptor crosstalk improves concentration sensing of multiple ligands
Authors: Carballo-Pacheco Martín , Desponds Jonathan , Gavrilchenko Tatyana , Mayer Andreas , Prizak Roshan , Reddy Gautam , Nemenman Ilya , Mora Thierry
Published: October 2018

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptor’s cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.
Intracellular Burkholderia Symbionts Induce Extracellular Secondary Infections; Driving Diverse Host Outcomes that Vary by Genotype and Environment
Authors: Khojandi Niloufar , Haselkorn Tamara S. , Eschbach Madison N. , Naser Rana A. , DiSalvo Susanne
Published: October 2018

Symbiotic associations impact and are impacted by their surrounding ecosystem. The association between Burkholderia bacteria and the soil amoeba Dictyostelium discoideum is a tractable model to unravel the biology underlying symbiont-endowed phenotypes and their impacts. Several Burkholderia species stably associate with D. discoideum and typically reduce host fitness in food-rich environments while increasing fitness in food-scarce environments. Burkholderia symbionts are themselves inedible to their hosts but induce co-infections with secondary bacteria that can serve as a food source. Thus, Burkholderia hosts are “farmers” that carry food bacteria to new environments, providing a benefit when food is scarce. We examined the ability of specific Burkholderia genotypes to induce secondary co-infections and assessed host fitness under a range of co-infection conditions and environmental contexts. Although all Burkholderia symbionts intracellularly infected Dictyostelium, we found that co-infections are predominantly extracellular, suggesting that farming benefits are derived from extracellular infection of host structures. Furthermore, levels of secondary infection are linked to conditional host fitness; B. agricolaris infected hosts have the highest level of co-infection and have the highest fitness in food scarce environments. This study illuminates the phenomenon of co-infection induction across Dictyostelium associated Burkholderia species and exemplifies the contextual complexity of these associations.
Effect of fire and thinning on fine-scale genetic structure and gene flow in fire-suppressed populations of sugar pine (Pinus lambertianaDouglas)
Authors: Lind Brandon M. , North Malcolm P. , Maloney Patricia E. , Eckert Andrew J.
Published: October 2018

Historically, frequent, low-severity fires in dry western North American forests were a major driver of ecological patterns and processes, creating resilient ecosystems dominated by widely-spaced pine species. However, a century of fire-suppression has caused overcrowding, altering forest composition to shade-tolerant species, while increasing competition and leaving trees stressed and susceptible to pathogens, insects, and high-severity fire. Exacerbating the issue, fire incidence is expected to increase with changing climate, while fire season has been observed to begin earlier and last longer than historic trends. Forest thinning and prescribed fire have been identified as important management tools to mitigate these risks. Yet little is known of how thinning, fire, or their interaction affect contemporary evolutionary processes of constituent pine species that influence fitness and play an important role in the opportunity for selection and population persistence. We assessed the impact of widely used fuel reduction treatments and prescribed fire on fine-scale gene flow on an ecologically important and historically dominant shade-intolerant pine species of the Sierra Nevada,Pinus lambertianaDougl. Treatment prescription (no-thin-no-fire, thin-no-fire, and fire-and-thin) was found to differentially affect both fine-scale spatial and genetic structure as well as effective gene flow in this species. Specifically, the thin-no-fire prescription increases genetic structure (spatial autocorrelation of relatives) between adults and seedlings, while seed and pollen dispersal increase and decrease, respectively, as a function of increasing disturbance intensity. While these results may be specific to the stands at our study site, they indicate how assumptions relating to genetic effects based on spatial structure can be misleading. It is likely that these disequilibrated systems will continue to evolve on unknown evolutionary trajectories. The long-term impacts of management practices on reduced fitness from inbreeding depression should be continually monitored to ensure resilience to increasingly frequent and severe fire, drought, and pest stresses.
Loss of the Heparan Sulfate Proteoglycan Glypican5 facilitates long range Shh signaling
Authors: Guo Wei , Roelink Henk
Published: October 2018

As a morphogen, Sonic Hedgehog (Shh) mediates signaling at a distance from its sites of synthesis. After secretion, Shh must traverse a distance through the extracellular matrix (ECM) to reach the target cells and activate the Hh response. Extracellular matrix proteins, in particular the Heparan Sulfate Proteoglycans (HSPGs) of the Glypican family have both negative and positive effects on non-cell autonomous Shh signaling, all attributed to their ability to bind Shh. Using mouse embryonic stem cell-derived mosaic tissues with compartments that lack the glycosyltransferases Exostosin1 (Ext1) and Exostosin2 (Ext2), or the HSPG core proteinGlypican5we show that cells surrounded by a mutated extracellular matrix are highly proficient distributing Shh. In contrast, cells that lackExt1function poorly secrete Shh. Our results confirm earlier observations that HSPGs can have both positive (Shh export) and negative influences (Shh distribution), and are supporting a model in which Shh presented on the cell surface in the context of HSPGs preferentially distributes into ECM that lacks HSPGs, possibly due to the absence of Shh sequestering molecules.
CRISPR/Cas9 screens Reveal Dasatinib Targets of Inhibiting T cell Activation and Proliferation
Authors: Wang Mei , Chen Qilong , Liu Hailing , Chen Hao , Wang Binbin , Zhang Wubing , Mading Ailu , Li Wenjing , Li Shuangqi , Liu Hang , Gu ZhongKai , Liu Shuxian , Guo Rui , Li Wei , Xiao Tengfei , Wu Feizhen
Published: October 2018

Immune response by T cells is essential for a healthy body against cancer, infection, and pathophysiological alteration. The activation and expansion of T cells can be inhibited by dasatinib, a tyrosine inhibitor, thus improving the outcome of diseases, such as autoimmune disease, graft-versus-host disease, and transplant rejection. The underlying mechanism of inhibition by dasatinib is elusive. Here, we designed and synthesized a CRISPR/Cas9 screening library that includes 6,149 genes. Using the library, we performed dasatinib CRISPR/cas9 screening in Jurkat cell, a T lymphocyte cell. We firstly identified survival essential genes for Jurkat cells. Comparing with other CRISPR/Cas9 screenings, we obtained Jurkat cell specific essential genes. By comparing dasatinib treatment to control, we identified a set of dasatinib targets, which includes known targets: CSK, LCK, ZAP70, and previously unknown targets: ZFP36L2, LRPPRC, CFLAR, PD-1, CD45 et al. Visualizing these target genes on T cell receptor signaling pathway, we found several genes could be inhibited by dasatinib. Furthermore, we introduced a framework, 9-square, to classify genes and found a group of genes that are associated with dasatinib resistance, possibly linking the side effects of dasatinib. These data reveal a set of dasatinib targets and demonstrate the molecular potential functions of dasatinib. Identification of dasatinib targets will broaden our understanding to its molecular mechanism, and thus benefits to clinical outcome.
A piggyBac-based toolkit for inducible genome editing in mammalian cells
Authors: Schertzer Megan D. , Thulson Eliza , Braceros Keean C.A. , Lee David M. , Hinkle Emma R. , Murphy Ryan M. , Kim Susan O. , Vitucci Eva C.M. , Calabrese J. Mauro
Published: October 2018

We describe the development and application of a novel series of vectors that facilitate CRISPR-Cas9-mediated genome editing in mammalian cells, which we call CRISPR-Bac. CRISPR-Bac leverages the piggyBac transposon to randomly insert CRISPR-Cas9 components into mammalian genomes. In CRISPR-Bac, a single piggyBac cargo vector containing a doxycycline-inducible Cas9 or catalytically-dead Cas9 (dCas9) variant and a gene conferring resistance to Hygromycin B is co-transfected with a plasmid expressing the piggyBac transposase. A second cargo vector, expressing a single-guide RNA (sgRNA) of interest, the reverse-tetracycline TransActivator (rtTA), and a gene conferring resistance to G418, is also cotransfected. Subsequent selection on Hygromycin B and G418 generates polyclonal cell populations that stably express Cas9, rtTA, and the sgRNA(s) of interest. Using Mus musculus-derived embryonic and trophoblast stem cells, we show that CRISPR-Bac can be used to knockdown proteins of interest, to create targeted genetic deletions with high efficiency, and to activate or repress transcription of protein-coding genes and an imprinted long noncoding RNA. The ratio of sgRNA-to-Cas9-to-transposase can be adjusted in transfections to alter the average number of cargo insertions into the genome. sgRNAs targeting multiple genes can be inserted in a single transfection. CRISPR-Bac is a versatile platform for genome editing that simplifies the generation of mammalian cells that stably express the CRISPR-Cas9 machinery.
Cell type-specific role of lamin-B1 and its inflammation-driven reduction in organ building and aging
Authors: Yue Sibiao , Zheng Xiaobin , Zheng Yixian
Published: October 2018

Cellular architectural proteins often participate in organ development and maintenance. Although functional decay of some of these proteins during aging is known, the cell-type specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin-B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An upregulation of proinflammatory cytokines in the intra-thymic myeloid immune cells during aging accompanies a gradual reduction of adult TEC lamins-B1. These cytokines cause adult TEC senescence and lamin-B1 reduction. We identify 17 adult TEC subsets and show that TEC lamin-B1 maintains the composition of these TECs. Lamin-B1 supports the expression of TEC genes needed for maintaining adult thymic architecture and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation-driven decay which can in turn contribute to age-associated organ degeneration.
Risk of stillbirth in low‐risk singleton term pregnancies following fertility treatment: a national cohort study
Authors: Bay B , Boie S , Kesmodel US
Published: October 2018

Objective

To assess the risk of stillbirth in low‐risk in vitro fertilisation (IVF) pregnancies.

Design

Register‐based national cohort study.

Setting

Denmark 2003–2013.

Population

Cohort of 425 732 singleton pregnancies including 10 235 conceived following IVF/intracytoplasmic sperm injection (ICSI), 4521 conceived following intrauterine insemination (IUI), and 410 976 spontaneously conceived.

Methods

Information on pregnancy, obstetrical risk factors, stillbirth, and fertility treatment was obtained from the Danish national health registers for all pregnancies after gestational week 21+6. We estimated the overall and gestational age‐specific risk of stillbirth in low‐risk term pregnancies following IVF, ICSI, and IUI. Further, we estimated the association between stillbirth and IVF and ICSI respectively as well as fresh or frozen‐thawed embryo transfer.

Main outcome measures

Risk of stillbirth.

Results

The number of stillbirths in spontaneously conceived and IVF/ICSI low‐risk term pregnancies was 525 (0.1%) and 35 (0.3%), respectively. In multivariate analysis, the risk of stillbirth in pregnancies following IVF/ICSI was increased (odds ratio 2.1, 95% CI 1.4–3.1). The risk of stillbirth was correspondingly increased in time‐to‐event analyses taking risk time for each fetus into account from gestational week 37 and onwards (hazard ratio 2.4, 95% CI 1.6–3.6). In sub‐analyses, the risk of stillbirth was increased for pregnancies following ICSI (odds ratio 2.2, 95% CI 1.2–3.1), but not IVF (odds ratio 1.7, 95% CI 0.9–3.1).

Conclusion

We found a systematically increased risk of stillbirth in low‐risk term pregnancies following IVF/ICSI. Whether the risk was related to the treatment or to underlying subfertility is uncertain. The results may indicate a need for obstetrical surveillance for these pregnancies when reaching term.

Tweetable abstract

Increased risk of stillbirth in low‐risk term pregnancies following fresh cycle IVF/ICSI.
Heterologous coexpression of the benzoate‐para‐hydroxylase CYP53B1 with different cytochrome P450 reductases in various yeasts
Authors: Theron Chrispian W. , Labuschagné Michel , Albertyn Jacobus , Smit Martha S.
Published: October 2018

Cytochrome P450 monooxygenases (P450) are enzymes with high potential as biocatalysts for industrial applications. Their large‐scale applications are, however, limited by instability and requirement for coproteins and/or expensive cofactors. These problems are largely overcome when whole cells are used as biocatalysts. We previously screened various yeast species heterologously expressing self‐sufficient P450s for their potential as whole‐cell biocatalysts. Most P450s are, however, not self‐sufficient and consist of two or three protein component systems. Therefore, in the present study, we screened different yeast species for coexpression of P450 and P450‐reductase (CPR) partners, using CYP53B1 from Rhodotorula minuta as an exemplary P450. The abilities of three different coexpressed CPR partners to support P450 activity were investigated, two from basidiomycetous origin and one from an ascomycete. The various P450‐CPR combinations were cloned into strains of Saccharomyces cerevisiae, Kluyveromyces marxianus, Hansenula polymorpha, Yarrowia lipolytica and Arxula adeninivorans, using a broad‐range yeast expression vector. The results obtained supported the previous finding that recombinant A. adeninivorans strains perform excellently as whole‐cell biocatalysts. This study also demonstrated for the first time the P450 reductase activity of the CPRs from R. minuta and U. maydis. A very interesting observation was the variation in the supportive activity provided by the different reductase partners tested and demonstrated better P450 activity enhancement by a heterologous CPR compared to its natural partner CPR. This study highlights reductase selection as a critical variable for consideration in the pursuit of optimal P450‐based catalytic systems. The usefulness of A. adeninivorans as both a host for recombinant P450s and whole‐cell biocatalyst was emphasized, supporting earlier findings.
Radiological appearance of coal mine dust lung diseases in Australian workers
Authors: McBean Rhiannon , Newbigin Katrina , Dickinson Shannan , Edwards Robert
Published: October 2018

Coal Mine Dust Lung Disease (CMDLD) encompasses a spectrum of lung diseases caused by prolonged exposure to coal mine dust. This review presents high‐resolution computed tomography (HRCT) images from men diagnosed with a CMDLD since the resurgence of these diseases in Queensland in 2015.
Effects of serial phlebotomy on vascular endothelial function: Results of a prospective double‐blind randomized study
Authors: Jelani Qurat‐ul‐ain , Harchandani Bhisham , Cable Ritchard G. , Guo Yu , Zhong Hua , Hilbert Timothy , Newman Jonathan D. , Katz Stuart D.
Published: October 2018

Introduction

Blood donation has been proposed as a potential therapy to reduce risk of cardiovascular disease, but the effects of phlebotomy on vascular function in human subjects have not been well characterized.

Aims

We conducted a prospective randomized double‐blind study to determine the effects of serial phlebotomy on vascular endothelial function in the brachial artery. Eighty‐four iron‐replete, non‐anemic subjects were randomly assigned to one of three study treatment groups: (a) four serial phlebotomy procedures each followed by intravenous infusion of placebo normal saline; (b) four serial phlebotomy procedures each followed by intravenous infusion to replete lost iron; and (c) four serial sham phlebotomy procedures each followed by intravenous infusion of placebo normal saline. Assigned phlebotomy procedures were conducted at 56‐day intervals. We measured brachial artery reactivity (BAR, %) in response to transient oxidative stress induced by oral methionine with high‐resolution duplex ultrasound imaging before and one week after the fourth study phlebotomy.

Results

Before phlebotomy, oral methionine decreased BAR by −2.04% (95% CI −2.58%, −1.50%), P < 0.001) with no significant difference between groups (P = 0.42). After phlebotomy, the BAR response to oral methionine did not significantly change between groups (P = 0.53). Brachial artery nitroglycerin‐mediated dilation did not change in response to phlebotomy.

Conclusions

Four serial phlebotomy procedures over six months with or without intravenous iron supplementation did not alter vascular endothelial function in the brachial artery when compared with sham phlebotomy.